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Biomedical subjects

D M Brown

Publications and source records attributed to D M Brown.

At least 217 records · Page 12Linked to original sources
PubMed1986

The effects of purine nucleoside analogs on the response of the RIF-1 tumor to melphalan in vivo.

The effect of several purine nucleoside analogs on the cytotoxicity of melphalan (L-PAM) in the RIF-1 tumor in vivo was investigated. All the analogs tested--3'-deoxyguanosine (3'-dG), 3'-deoxyadenosine (3'-dA), and N6-butyryl-3'-deoxyadenosine (N6-BC)--at a dose of 100 mg/kg, enhanced the tumor cell killing by L-PAM as measured by an in vivo/in vitro procedure. This enhancement was maximal when the drugs were given simultaneously. The mean enhancement ratios (ER's) determined from the L-PAM dose response curves were 1.4 for 3'-dG, 1.3 for 3'-dA, and 1.4 for N6-BC. A similar modification of the L-PAM-induced depression of white blood cell counts was not obtained. A large single dose of L-PAM (8 mg/kg) produced a transient drop in mouse body temperature. The analog 3'-dG (100 mg/kg) increased and prolonged this hypothermic effect. In addition 3'-dG also delayed the clearance of L-PAM from the plasma of C3H mice, such that the half-life of the chemotherapeutic agent was extended from 28 minutes to 35 minutes. The enhancement of the efficacy of L-PAM by these analogs probably results from this pharmacokinetic effect.

Animals↗
PubMed1986

Preferential tumor radiosensitization by analogs of nicotinamide and benzamide.

The effects of a range of different analogs of nicotinamide and benzamide on the X ray response of the EMT-6 tumor in vivo was investigated. Using an in vivo/in vitro survival assay, sensitization was seen at a dose of 2 mmole/kg for all but one of the analogs tested. The enhancement ratios (ER's) ranged from 1.0 to 1.5. Of particular interest were nicotinamide and SR-4350 which gave large ER's (1.5 and 1.4 respectively) at doses which were only about 12% of the LD50 values. In one normal tissue studied (skin reaction) a large single dose of nicotinamide (8 mmole/kg) only gave an ER of 1.1. These results will be discussed with reference to the mechanisms involved and the clinical implications.

Animals↗
PubMed1986

Changes in the response of the RIF-1 tumour to melphalan in vivo induced by inhibitors of nuclear ADP-ribosyl transferase.

The effect of inhibitors of nuclear ADP-ribosyl transferase (ADPRT) on the cytotoxicity of melphalan (L-PAM) in the RIF-1 tumour in vivo was investigated. A large single dose of nicotinamide (1000 mg kg-1) enhanced the tumour cell killing by L-PAM as measured by tumour cell survival. This enhancement was maximum when nicotinamide was administered within 1 h before injecting the L-PAM. When given at this time, the nicotinamide had a dose-modifying effect on all L-PAM doses tested, giving rise to a mean enhancement ratio (ER) of 2.2. Nicotinamide did not appear to inhibit the recovery from L-PAM induced potentially lethal damage. L-PAM (6 mg kg-1) produced a transient drop in mouse body temperature. This effect was both increased and prolonged by nicotinamide. In addition the inhibitor also delayed the clearance of L-PAM from the plasma of C3H mice, such that the half-life of the chemotherapeutic agent was extended from 41 min to 143 min. The effect of combining L-PAM with nicotinamide doses below 1000 mg kg-1 was also investigated. The results showed that as the nicotinamide dose was decreased, the enhancement of the effects on body temperature, pharmacokinetics and white blood cell counts were reduced. However, a concomitant loss in the enhancement of tumour cell killing was also observed. Similar results were obtained using 3-aminobenzamide, a more efficient inhibitor of ADPRT.

Animals↗
PubMed1986

Intensity changes of base and backbone Raman modes in the B to Z transition of poly(dG-dm5C).

Raman spectroscopy was employed to investigate the temperature-induced B to Z transition of poly(dG-dm5C). The transition midpoint was about 37 degrees C for a solvent containing 20 mM Mg2+. A 10-fold change in Mg2+ concentration altered the transition midpoint by at least 60 degrees C. Raman spectra of the B and Z forms of poly(dG-dm5C) exhibited characteristics similar to those observed with poly(dG-dC). The 682 cm-1 guanine mode and 835 cm-1 backbone mode were present in the B conformation. In the Z form the intensities of these two bands decrease substantially and new peaks were observed at 621 cm-1, 805 and 819 cm-1. Several bands unique to poly(dG-dm5C) were also observed. Transition profiles of band intensity vs. temperature were determined for fourteen Raman bands. The curves of all of the base vibrations and one backbone mode had the same slope and midpoint. This indicates that conformational changes in the guanine and methycytosine bases occur concurrently.

Magnesium↗
PubMed1986

Insulin and metabolic efficiency in rats. I. Effects of sucrose feeding and BAT axotomy.

The role of insulin and brown adipose tissue (BAT) thermogenesis in metabolic efficiency (ME, the efficiency of body wt gain) was examined in rats with varied basal insulin status. Long-lasting insulin was administered using a protocol that did not alter food intake, yet increased ME in both groups. Half the rats were fed sucrose to stimulate BAT growth and thermogenesis. Insulin overrode the exaggerated decrease in ME in sucrose-fed diabetics, with only partial attenuation in controls. Interscapular BAT (IBAT) lipoprotein lipase activity was decreased in diabetic rats, restored by insulin treatment, and not affected in controls. Sucrose-fed diabetics and controls had their IBAT sham or bilaterally surgically denervated. Insulin decreased the thermogenic potential of BAT [cytochrome oxidase activity (COA)] in intact controls and diabetics; in the latter, insulin restored COA independent of BAT innervation. We conclude that insulin can increase ME without an associated increase in energy intake, regardless of basal insulin status, both insulin deficiency and excess decrease BAT thermogenic potential (COA), and hyperinsulinemia-induced increases in ME may result from decreased BAT mitochondrial proliferation.

Adipose Tissue, Brown↗
PubMed1986

Insulin and metabolic efficiency in rats. II. Effects of NE and cold exposure.

The role of insulin in metabolic efficiency (ME, i.e., efficiency of body wt gain) was examined under conditions of maximal energy expenditure in control and diabetic rats. Long-lasting insulin was administered using a protocol that did not affect food intake and increased ME in both groups. Half the animals were injected chronically with norepinephrine (NE). NE alone in controls decreased body weight and ME and increased brown adipose tissue (BAT) growth, thermogenic potential [cytochrome c oxidase activity (COA)], and lipoprotein lipases (LPL) activity; however, in diabetics, body weight, ME, and food intake all decreased and only BAT LPL activity and DNA content increased. The combination of NE and insulin increased BAT protein and COA in diabetics; in controls, all BAT measures were further increased and ME was intermediate to that of either treatment alone. Cold exposure decreased body weight and ME, increased food intake and qualitatively produced similar increases in BAT growth, COA, and LPL activity in both controls and diabetics. In diabetics, combined cold exposure and insulin did not affect the increase in BAT growth or LPL activity resulting from either treatment alone, but in controls this combination decreased BAT growth and COA. It is concluded that, even under conditions of maximal energy expenditure, both extremes of basal insulin status result in decreased BAT growth and thermogenic potential, but have opposite effects on ME.

Acclimatization↗
PubMed1986

Protection by thyroxine in nephrotoxic acute renal failure.

Thyroxine (T4) protects against ischemic and nephrotoxic experimental acute renal failure (ARF). This study examined functional, biochemical, and morphological markers of uranyl nitrate (UN)-induced renal injury in the rat to determine the cellular site at which T4 exerts its protective effect. In experimental group UNT4, 1-thyroxine (10 micrograms/100 g body wt) was given for 10 days prior to and for 4 days following a single subcutaneous injection of UN (0.5 mg/kg body wt). Group UN received only UN, and group CT4 received only T4 for 14 days. Five days after UN administration, plasma creatinine rose from base line in group UNT4 (0.52 +/- 0.30 to 0.84 +/- 0.08 mg/dl, P less than 0.025) and group UN (0.52 +/- 0.03 to 1.64 +/- 0.13 mg/dl, P less than 0.001) but not in group CT4 (0.47 +/- 0.02 to 0.48 +/- 0.04 mg/dl, NS). However, plasma creatinine in group UNT4 was significantly lower than group UN (0.84 +/- 0.08 vs. 1.64 +/- 0.13 mg/dl, P less than 0.001). T4 administration stimulated the basolateral membrane-bound enzyme Na-K-ATPase in the renal cortex homogenate in group UNT4 (13.9 +/- 0.5 micron X mg protein-1 X h-1, P less than 0.005) and group CT4 (16.3 +/- 0.6 micron X mg protein-1 X h-1, P less than 0.001) when compared with controls (11.7 +/- 0.5 micron X mg protein-1 X h-1). Na-K-ATPase activity fell in group UN to 10.0 +/- 0.6 micron X mg protein-1 X h-1 (P less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1986

Glomerular proteoglycans in diabetes. Partial structural characterization and metabolism of de novo synthesized heparan-35SO4 and dermatan-35SO4 proteoglycans in streptozocin-induced diabetic rats.

The metabolism of glomerular proteoglycans was studied in an effort to understand the mechanisms leading to reduction of glomerular basement membrane (GBM) heparan sulfate (heparan-SO4) proteoglycan in diabetes. Glomeruli were isolated from control and streptozocin-induced diabetic rats after exposure to [35S]sulfate. A pool of rapidly metabolized 35S-glycosaminoglycans (GAG), predominantly heparan-35SO4, was present in GBMs from controls but not diabetics, whereas intact isolated glomeruli from the two groups contained similar quantities of 35S-macromolecules after 4 and 16 h in vitro. Glomeruli from diabetics contained less 35S-proteoglycan than controls after 16 h in vivo. A more rapid disappearance of [35S]sulfate from serum and an increased inorganic sulfate concentration in diabetes may account for this difference. Glomeruli from diabetics contained more heparan-35SO4 and less dermatan-35SO4 proteoglycan than control glomeruli in vitro. Diabetic glomerular heparan-35SO4 proteoglycan and its GAG chains had hydrodynamic sizes similar to controls (Mr, 13 and 1.25 X 10(4), respectively). A heparin-releasable heparan-35SO4 proteoglycan detected in isolated control glomeruli by gel electrophoresis was present in chase medium of glomeruli from diabetics in the absence of heparin. Two dermatan-35SO4 proteoglycans were synthesized in vitro. One had size and charge properties similar to glomerular heparan-35SO4 proteoglycan. A second, larger dermatan-35SO4 proteoglycan accumulated in tissue over 16 h. It was partially excluded from Sepharose CL-6B columns and eluted from Sepharose CL-4B columns at Kav = 0.32. The hydrodynamic sizes of both tissue forms of dermatan-35SO4 proteoglycans were similar in diabetics and controls. Differences in the biochemical characteristics of the major de novo synthesized glomerular proteoglycan pools could not be invoked to explain altered metabolism of GBM heparan sulfate in diabetic animals. These changes may result from diminished affinity of heparan sulfate proteoglycan for extracellular matrix or cell surfaces and may account for altered glomerular ultrafiltration properties in diabetes mellitus.

Animals↗
PubMed1985

Sequence analysis of mutations that affect the synthesis, assembly and enzymatic activity of the unc-54 myosin heavy chain of Caenorhabditis elegans.

We have sequenced 11 representative mutations of the unc-54 myosin heavy chain gene of Caenorhabditis elegans that affect the synthesis, assembly or enzymatic activity of the encoded myosin heavy chain. Six of the sequenced unc-54 mutations cause premature termination of protein synthesis. Four mutations (e1092, e1115, e1213, e1328) were ochre mutations, one mutation (e903) was a frameshift, which caused premature termination at a nearby UGA terminator, and one mutation (e190) was a deletion that altered the reading frame and caused termination at an ochre codon. Two mutations (e675 and s291) were inphase deletions, which resulted in a shortened myosin rod segment. These aberrant myosins fail to assemble into normal thick filaments. The sequence alterations of the missense mutations (e1152, s74, s95) indicated amino acid residues that are critical for myosin function. The mutation e1152 causes the production of a myosin heavy chain that fails to assemble into thick filaments. It had two adjacent amino acid substitutions at the extreme amino terminus of the rod, indicating a role for subfragment-2 in thick filament assembly. Mutants homozygous for s74 or s95 are very slow-moving, although they make myosin heavy chains that assemble normally. The encoded amino acid substitutions of s95 and s74 are in the 23 X 10(3) Mr and 50 X 10(3) Mr domains of the myosin head, flanking the ATP binding site. The sequenced mutations are distributed throughout the gene in the order predicted from genetic fine-structure mapping experiments. Seven of eight point mutations isolated following ethylmethane sulphonate mutagenesis were G X C to A X T transitions. A single X-ray-induced allele proved to be a deletion of two adjacent thymidine residues. The three deletion mutations were found in a region of the myosin rod with numerous direct and inverted nucleotide sequence repeats, but their origin cannot be accounted for by homologous recombination. Instead, a comparison of the deletion junctions suggests that the deletions arose by a site-specific mechanism.

Animals↗
PubMed1985

A new linkage for solid phase synthesis of oligodeoxyribonucleotides.

An aryl diisocyanate has been used to attach an appropriately protected 2'-deoxyribonucleoside bearing a free 3'-hydroxyl group, to a long chain alkylamine controlled pore glass support via a urethane moiety, in a simple two step procedure. This obviates the need for the preparation and short column chromatographic purification of the 2'-deoxyribonucleoside-3'-O-succinates required for preparation of the widely used succinyl linked supports. The greater stability of the urethane bond compared to an ester bond led to substantially higher yields of oligodeoxyribonucleotides prepared by the solid phase phosphotriester method. More than twenty oligodeoxyribonucleotides have already been synthesized on the glass support bearing the new linkage.

Chromatography, High Pressure Liquid↗
PubMed1985

Primary structures of six antimicrobial peptides of rabbit peritoneal neutrophils.

Six microbicidal peptides, NP-1, NP-2, NP-3a, NP-3b, NP-4, and NP-5, from rabbit peritoneal neutrophils were characterized. As a family, the peptides were 32-34 residues in length, were cystine- and arginine-rich, and each contained three intramolecular disulfide bonds. Within their sequences, the six peptides shared 11-residue positions, which included the six half-cystines contained in each peptide. NP-1 and NP-2 differed by a single residue and were identical in their respective sequences to MCP-1 and MCP-2, the peptide analogs from rabbit alveolar macrophages. NP-4 and NP-5 were homologous in 27 of their residues, but NP-3a and NP-3b shared little more than the 11-residue backbone common to all members of this peptide family.

Amino Acids↗
PubMed1985

Photochemical demonstration of stacked C.C+ base pairs in a novel DNA secondary structure.

The secondary structure of the alternating polydeoxynucleotide sequence poly[d(C-T)] was studied as a function of pH by ultraviolet absorbance and circular dichroism spectroscopy and by the analysis of UV-induced photoproducts. As the pH was lowered, poly[d(C-T)] underwent a conformational transition that was characterized by changes in the long-wavelength region (280-320 nm) of the CD spectrum. These changes have previously been interpreted as evidence for the formation of a core of stacked, protonated C X C+ base pairs in a double-helical complex of poly[d(C-T)], with the thymidyl residues being looped out into the solvent [Gray, D. M., Vaughan, M., Ratliff, R. L., & Hayes, F. N. (1980) Nucleic Acids Res. 8, 3695-3707]. In the present work, poly[d(C-T)] was labeled with [U-14C]cytosine and [methyl-3H]thymine and irradiated at pH values both above and below the conformational transition point (monitored by CD spectroscopy). The distribution of radioactivity in uracil means value of uracil dimers, uracil means value of thymine dimers (the deamination products of cytosine means value of cytosine and cytosine means value of thymine dimers, respectively), and thymine-means value of thymine dimers was then determined. As the pH was decreased, we found an increase in the yield of uracil means value of uracil dimers and a decrease in the yield of uracil means value of thymine dimers, which occurred concomitantly with the change in the CD spectrum.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Composition↗
PubMed1985

Histamine H2 receptors on chondrocytes derived from human, canine and bovine articular cartilage.

Histamine (1-100 microM) induced a concentration-dependent increase in intracellular cyclic AMP in monolayer cultures of human, canine and foetal-bovine articular chondrocytes. The dose-response curve for histamine in each culture was progressively displaced to the right with increasing concentrations of cimetidine, an H2-receptor antagonist. The histamine-induced cyclic AMP elevation in human articular chondrocytes was also significantly decreased by ranitidine, another H2 antagonist, but not by the H1 antagonists mepyramine and chlorpheniramine. These findings indicate that histamine activates chondrocyte adenylate cyclase through an H2 receptor. The cyclic AMP response of human chondrocytes to histamine was many times greater than that measured for synovial fibroblasts under similar conditions. Such findings suggest that mast-cell-chondrocyte interactions in vivo may contribute to changed chondrocyte metabolism in joint disease.

Animals↗
PubMed1985

Environment modulates naloxone's suppressive effect on feeding in diabetic and non-diabetic rats.

We evaluated the effect of environment on naloxone-induced suppression of feeding in streptozotocin rats and sham injected controls. Naloxone was administered to animals fasted for 24 hours and food intake was measured at 30, 60 and 120 minutes. Diabetic rats, in their home cages, were insensitive to naloxone's suppressive effect for the first 30 minutes and the 5 mg/kg dose suppressed feeding only at 120 minutes. In control rats, feeding was suppressed at 1 and 5 mg/kg naloxone during the first 30 minutes. In contrast, when animals were placed in novel plastic cages, control animals were insensitive to naloxone at all time points at doses as high as 5 mg/kg. In novel cages, diabetic rats responded to doses of 1 and 5 mg/kg during the first 30 minute period by lowering food intake. It should also be noted that basal food intake was suppressed (40-53%) when animals were placed in novel cages. These data suggest that stress of a novel environment alters the neuroregulatory system involved in inducing feeding. Lack of response of normal rats to naloxone's suppressive effect in a novel environment suggests that (1) a non-opioid feeding system operates under these conditions, or (2) opioid receptors are occupied as a result of the release of endogenous opioids due to stress. The opposite result observed in the diabetics indicates that glucose has a modulating effect on opioid effects.

Animals↗
PubMed1985

Surgical experience in descending thoracic aneurysmectomy with and without adjuncts to avoid ischemia.

Over the past twelve years, surgical treatment of descending thoracic aneurysms has been performed in 360 patients. Three different operative strategies were employed during resection to provide distal aortic perfusion by temporary bypass (Group 1, 75 patients) or shunt (Group 2, 22 patients) or to simplify the operative procedure with aortic cross-clamping alone (Group 3, 263 patients). The surgical results were determined primarily by patient-related and disease-related variables. Advanced age (older than 70 years), atherosclerotic cause, and emergency operation significantly increased the risks of early mortality and morbidity. The incidence of death (11.7%), paraplegia (6.5%), or renal failure (6%) was not reduced by the use of adjunctive perfusion, and bleeding complications increased significantly in Groups 1 and 2. Spinal cord injury was increased significantly by emergency operations, cross-clamp times exceeding 30 minutes, and extensive aneurysms (p less than 0.05). The risk of renal failure was increased by advanced age and atherosclerotic cause (p less than 0.05). With an experienced surgical team, the primary risks of descending thoracic aneurysmectomy are not influenced by the method of adjunctive perfusion, but are determined by patient factors such as the nature and extent of the aneurysm.

Adolescent↗
PubMed1985

Effects of mesangial localization of polyvinyl alcohols on glomerular basement membrane thickness.

We studied the effects of mesangial localization of polyvinyl alcohols (PVA) on glomerular basement membrane (GBM) thickness in inbred Lewis rats. To avoid possible influences of PVA redistribution after localization in liver, lung, and other organs, the kidneys of rats given PVA were transplanted into uninephrectomized normal rats. Normal kidneys transplanted into normal rats served as a control. GBM thickness at the time of transplantation was the same in PVA kidneys as in normal kidneys. However, by 18 weeks post-transplant GBM thickness was greater in PVA kidneys, and this increase was sustained at 30 weeks. Within the glomeruli of PVA kidneys, lobules with marked mesangial PVA accumulation had more marked GBM thickening than lobules with little or no PVA accumulation. It is concluded that changes within the mesangium can influence GBM thickness. Whether this represents a direct effect of mesangial architectural distortion, a consequence of local phlogistic activities such as the influx of macrophages into the mesangium of glomeruli with PVA localization, or the result of intraglomerular hemodynamic perturbations is unclear.

Animals↗
PubMed1985

Alterations in immunological reactivity in encephalomyocarditis virus-induced murine diabetes. I. Defective primary IgM plaque forming cell responses to sheep erythrocytes: correction by islet cell transplantation.

Increasing data suggest a possible viral aetiology of juvenile onset, insulin-dependent diabetes mellitus. The M variant of the encephalomyocarditis (EMC) virus infects murine pancreatic beta cells and causes a diabetes like syndrome in susceptible strains of mice. Abnormalities in immunological function have been documented in patients with diabetes mellitus and in spontaneous, streptozotocin-induced and alloxan-induced diabetes in animals. The present study documents a significant impairment of the ability of mice with EMC virus (M variant)-induced diabetes to generate a direct, IgM PFC response after in vivo immunization with sheep erythrocytes. This abnormality appears to be a direct consequence of the diabetic state and not EMC virus infection, per se, since mice infected with EMC virus that do not become diabetic have normal direct PFC responses and islet cell transplantation, which cures the diabetes, corrects the defect in PFC responsiveness.

Animals↗