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Biomedical subjects

C Kelly

Publications and source records attributed to C Kelly.

At least 235 records · Page 13Linked to original sources
PubMed1985

"Reverse" and "symmetrical" analogues of actinomycin D: metabolic activation and in vitro and in vivo tumor growth inhibitory activities.

Two new classes of actinomycin D analogues, tetracyclic "reverse" analogues and a tricyclic "symmetrical" analogue of actinomycin D, are reported. These analogues bind to DNA and the binding does not occur by an intercalation mechanism. The analogues inhibit the synthesis of DNA and RNA in P388 tumor cells and the growth of CCRF-CEM cells in vitro at nanomolar concentrations. The tetracyclic "reverse" analogues, which are structurally related to the previously reported actinomycin D oxazolyl analogues, are metabolized in the presence of rat hepatic microsomes and tumor cell homogenates. The metabolism takes place with the loss of the oxazole ring; thus the "reverse" analogues produce a major metabolite which is the "symmetrical" analogue; the actinomycin oxazolyl analogues generate 7-hydroxyactinomycin D. Further, the microsomes activate the analogues to free-radical states which catalyze the production of superoxide as shown by stimulation of epinephrine oxidation and also indicated by electron paramagnetic resonance studies. The "symmetrical" and "reverse" analogues also demonstrate very high activities in these systems. In in vivo studies using P388/S, P388/ADR leukemia, and B16 melanoma in mice, the analogues showed increased activity and superior therapeutic index values, in comparison to actinomycin D.

Animals↗
PubMed1985

Inhibitory role of dietary protein restriction on the development and expression of immune-mediated antitubular basement membrane-induced tubulointerstitial nephritis in rats.

The protective effect of dietary protein restriction on the development and expression of immune-mediated interstitial nephritis was evaluated in Brown Norway rats with anti-tubular basement membrane disease. In the first series of experiments, pair-fed rats received low protein (LP) (3% casein) or normal protein (NP) (27% casein), normocaloric diets. After 6 wk, each group was immunized with renal tubular antigen in adjuvant to produce anti-tubular basement membrane antibody (alpha TBM-Ab) and tubulointerstitial nephritis. The kidneys harvested from NP rats after four more weeks on the diet had histologically more severe interstitial disease than the LP rats (histologic severity; NP = 3.1 +/- 0.2 vs. LP = 1.1 +/- 0.3; P less than 0.001), and serum creatinine values were concordantly different (NP = 1.34 +/- 0.02 vs. LP = 0.82 +/- 0.03). Titers of alpha TBM-Ab were similar in both groups, while the T cell-mediated immune response, as measured by delayed-type hypersensitivity (DTH), was nonspecifically impaired in LP rats when compared with the NP group. Admixture cotransfers of LP plus NP cells failed to demonstrate active suppression as an explanation for the depressed DTH in LP rats. The therapeutic role of dietary protein restriction was also examined in rats with established alpha TBM disease. In these experiments, rats were first immunized and fed NP diets for 4 wk (histologic severity = 3.0 +/- 0.2; creatinine = 1.78 +/- 0.02), and then were divided into two groups and followed for six more weeks on either LP or NP diets. LP rats, under these conditions, developed less disease than those fed NP diet (histologic severity; NP = 3.2 +/- 0.3 vs. LP = 1.4 +/- 0.2; P less than 0.001), and serum creatinine values were concordantly different (NP = 1.92 +/- 0.05 vs. LP = 0.97 +/- 0.02). Again, the titers of alpha TBM-Ab in both LP and NP groups were similar. These data collectively suggest that LP diet has a protective effect both on the development and extent of tubulointerstitial nephritis that is perhaps, in part, related to the selective abrogation of effector T cell immunity.

Animals↗
PubMed1985

Studies of intestinal lymphoid tissue. IX. Dose-dependent, gluten-induced lymphoid infiltration of coeliac jejunal epithelium.

Jejunal biopsy specimens from coeliac patients who had received small, oral doses (100-1500 mg) of a peptic-tryptic gluten digest were analysed by morphometric methods. An increase in the total number of surface epithelial lymphocytes, maximal at 12 h after challenge, was dose-dependent, the mean percentage rise at this time being 53% (p less than 0.005), 44% (p = 0.01), and 25% (p greater than 0.05) with 1500, 1000, and 500 mg of gluten digest, respectively. This effect was not accompanied by any increased mitotic activity or blast transformation among the infiltrating lymphocytes, nor was there any demonstrable alteration in mucosal structure-that is, reduction in surface or increase in crypt epithelial volumes. The results of this controlled morphometric analysis indicate that oral gluten challenge causes an increase in the lymphocyte population of surface epithelium in coeliac disease but that this effect does not necessarily result in mucosal damage.

Celiac Disease↗
PubMed1984

Physicochemical properties and N-terminal sequence of eel lectin.

Some physicochemical properties of the L-fucose-binding lectin from the serum of the European eel (Anguilla anguilla) were determined. The lectin is a dimer composed of identical subunits of Mr approx. 40000. In agreement with previous results [Horejsí & Kocourek (1978) Biochim. Biophys. Acta 538, 299-315], the subunit was shown to comprise two non-glycosylated polypeptides of Mr approx. 20000 and linked by disulphide bonds. N-Terminal sequence analysis, carboxypeptidase digestion and peptide mapping indicated identity of the polypeptides. There were two L-fucose-binding sites per subunit with KD 1.6 X 10(-3) M for the lectin-fucose complex, as determined by equilibrium dialysis.

Alkylation↗
PubMed1984

Morphometric analysis of small intestinal mucosa. II. Determination of lamina propria volumes; plasma cell and neutrophil populations within control and coeliac disease mucosae.

Morphometric techniques were employed to measure (i) lamina propria volumes and (ii) the absolute numbers of neutrophils and plasma cells, of A, M and G isotype, within the lamina propria of jejunal mucosa. Mucosal specimens were obtained with a Watson capsule (a) from 5 patients with untreated coeliac disease, and again at least 3 months after starting on a gluten-free diet, and (b) from 9 control individuals. Lamina propria volume of untreated coeliac mucosa (2.5 +/- 0.17 X 10(6) micron3 ) was increased 2.3-fold (p less than 0.01) above that of control mucosae (1.35 +/- 0.08 X 10(6) micron3 ). Compared with control mucosae, there was a 20-fold increase of neutrophils in untreated coeliac mucosae (p less than 0.005). The total complement of all plasma cells in untreated coeliac mucosae (309) was twice that (149) of control mucosae. The populations of each isotype were also significantly increased over controls by factors of 1.6 (IgA; p less than 0.05), 3.0 (IgM; p less than 0.01) and 3.5 (IgG; p less than 0.01). Their percentage distributions in untreated coeliac mucosae (A:M:G--52:43:5) differed from those in control mucosae (A:M:G--69:28:3) but were restored after treatment with a gluten-free diet. However, when each isotype was expressed per unit volume of lamina propria, there was an apparent fall (X 1.4) in IgA cells, while the increase in IgM and IgG cells was less marked i.e. X 1.4 and X 1.5 respectively. These precise measurements explain why many previous investigators found a paradoxical fall in IgA cells because the (increased) volume of distribution of these cells was not taken into account. The importance of morphometric techniques in achieving valid cell 'counts' within the intestinal mucosa is thus illustrated by this study.

Celiac Disease↗
PubMed1983

Tetracyclic chromophoric analogues of actinomycin D: synthesis, structure elucidation and interconvertibility from one form to another, antitumor activity, and structure-activity relationships.

Two different tetracyclic chromophoric analogues of actinomycin D have been synthesized by engaging two chromophoric DNA-binding functions in actinomycin D, i.e., 2-amino and 3-oxo, into either a 1,4-oxazin-2-one or an oxazole ring system. A third analogue has an extra quinone function at C-8 of the oxazole analogue. In all the analogues the chemical integrity of the peptide lactones of the parent antibiotic is kept intact, but their sterochemistry is altered. The analogues are designed as transport-modified prodrug forms of either the tricyclic active analogues of actinomycin D or actinomycin D itself. All analogues exhibit cytotoxicity that is several-fold less potent than AMD; they also have no binding affinity toward extracellular DNA. Nonetheless, the analogues of the first and the third series show improved antitumor activities (P388 leukemia, CDF1 mice). In fact, two of these analogues having a phenyl substituent at the C-3 site of the oxazinone ring or the C-2 position of the 8-oxo-8H-oxazole ring exhibit the highest antitumor effects. Most of the analogues are active over a broader dose range than actinomycin D and are 6- to 16-fold less cytotoxic to human lymphoblastic leukemia (CCFR-CEM) cells in vitro. The analogues with the most pronounced antitumor activity are those that retain most elements in the peptide stereochemistry of actinomycin D and have a quinone function or demonstrate susceptibility of their chromophores to biotransformation.

Animals↗
PubMed1983

The effects of sar1ala8-angiotensin II in vasopressin-treated dehydrated sheep.

Mildly dehydrated conscious Merino ewes were infused with vasopressin (AVP) at 5 mu x min-1 alone and simultaneously with the angiotensin II receptor blocker sar1ala8-angiotensin II (saralasin) at 15 micrograms x min-1. AVP was slightly pressor and produced an increase in the calculated total peripheral resistance, and an increase in glomerular filtration rate, urine flow and electrolyte excretion, without a change in total renal plasma flow. These results indicate renal efferent arteriolar vasoconstriction as well as other non-renal vasoconstriction. Saralasin infusion checked the rise in total peripheral resistance (which continued to increase after saralasin withdrawal), but caused a marked increase in renal vascular resistance resulting in a decrease in renal plasma flow and to a lesser extent in glomerular filtration rate. These results suggest that saralasin was acting as an angiotensin II agonist in the kidney, but as an antagonist elsewhere. Deductions from previous experiments in the literature of the renal function of angiotensin II, based on its supposed inhibition by saralasin, may not be justified.

Angiotensin II↗
PubMed1979

Diagnostic significance of selected serum enzymes in a rat heatstroke model.

A total of 171 untrained, unacclimatized, and unanesthetized rats were either exercised to exhaustion at one of four ambient temperatures (5, 20, 26, or 30 degrees C), or were restrained and heated at an ambient temperature of 41.5 degrees C until their core temperatures reached a preselected end point between 41.0 and 43.3 degrees C. The serum levels of creatine phosphokinase (CRK) and two transaminases (SGOT and SGPT) were determined at 30 min, 24, 48, 72, and 96 h posttreatment. Peak enzyme activity for CPK was noted primarily at the 30-min sampling period and at 24 h for the transaminases. The data indicated that under these conditions a) the transaminase SGOT was elevated in the serum as a consequence of the extent and duration of prior hyperthermia, b) the transaminase SGOT was released in moderate amounts after exhaustive exercise but reached its greatest activity levels following hyperthermia, and c) the activity of CPK was increased by the duration of exhaustive exercise and was less sensitive than either transaminase to prior hyperthermia. As a result, each of the three experimental conditions: a) exercise without hyperthermia, b) exercise with hyperthermia, and c) sedentary hyperthermia, produced a unique pattern of serum enzyme activity that would appear useful in diagnosing a variety of heat- and/or work-induced disorders.

Alanine Transaminase↗
PubMed1978

Day care complements hospitalization.

A program of day care for psychiatric patients can reduce costs and provide a more suitable environment for the treatment program. Such programs hold considerable promise for other types of programs in various types of hospitals.

Community Mental Health Services↗
PubMed1978

Role of physical effort in the etiology of rat heatstroke injury and mortality.

A total of 171 untrained, unacclimatized, and unanesthetized rats were used to evaluate the effects of sedentary and work-induced hyperthermia on the incidence of mortality and cellular injury, 24 h postexposure. Cellular injury was defined as serum transaminase activity (SGPT and SGOT) exceeding 1,000 IU/l (heatstroke levels). Both the percent mortality and the percentage of 24-h survivors with transaminase levels above 1,000 IU/l were plotted against maximum core temperatures. Exertion-induced hyperthermia produced a significantly higher incidence of cellular injury and heatstroke death at lower core temperatures than hyperthermia alone. With hyperthermia only, the SGPT and SGOT dose-response curves were identical. When work was combined with hyperthermia, there was a greater incidence of elevated SGOT at lower core temperatures. These curves bore a striking resemblance to curves reflecting heat- and/or work-induced mortality in humans. The results suggest a direct role of physical effort in causing heatstroke injury and mortality.

Alanine Transaminase↗
PubMed1975

The hydroxylation of tyrosine by an enzyme from third-instar larvae of the blowfly Calliphora erythrocephala.

1. Two pro-(phenol oxidase) were distinguished when the blood of late-third-instar larvae of Calliphora erythrocephala was electrophoresed in polyacrylamide gels with Tris-glycine buffer, pH 8.3. One pro-(phenol oxidase), after activation by an enzyme readily catalyses the oxidation of both L-tyrosine and L-3,4-dihydroxyphenylalanine (L-dopa). The second enzyme catalyses the oxidation of L-dopa but not of L-tyrosoine. 2. One of the pro-(phenol oxidases) was purified over 2000-fold from homogenates of whole larvae. This enzyme, after activation, catalyses the oxidation of both dopa and tyrosine. On electrophoresis in polyacrylamide gels with Tris-glycine buffer, pH 8.3, it has the same mobility as the enzyme in the blood which catalyses the oxidation of both tyrosine and dopa. 3. The pro-(phenol oxidase)-activating enzyme was purified over 100-fold from homogenates of whole larvae. 4. The oxidation of L-tyrosine, in the presence of the activated purified phenol oxidase, reached a steady maximum rate after a lag period that was directly related to tyrosine concentration and inversely related to enzyme concentration. 5. The effect of the addition of electron donors on the lag period was studied. Dopa, dopamine (3,4-dihydroxyphenethylamine) and 2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydropteridine are the most effective hydrogen donors. 3,4-Dihydroxybenzoic acid, the oxidation of which was not catalysed by the activated pro-(phenol oxidase), did not affect the lag period.

Animals↗