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Biomedical subjects

G Harris

Publications and source records attributed to G Harris.

At least 19 recordsLinked to original sources
PubMed1992

Identification and selective inhibition of an isozyme of steroid 5 alpha-reductase in human scalp.

Steroid 5 alpha-reductase (EC 1.3.1.22) catalyzes the reduction of testosterone to dihydrotestosterone. The 5 alpha-reductase found in human scalp has been compared with the enzyme found in prostate. The scalp reductase has a broad pH optimum centered at pH 7.0. This is distinctly different from the pH optimum of 5.5 observed with the prostatic form of the enzyme. These enzymes also differ in the Km for testosterone, which is 25-fold higher for the scalp reductase. The most significant difference between the two enzymes is their affinity for inhibitors. Two 4-azasteroids and a 3-carboxyandrostadiene are potent inhibitors of the prostatic reductase but are weak inhibitors of the scalp reductase. In contrast, several N-4-methylazasteroids are good inhibitors of the scalp reductase. These findings support a proposal that different isozymes of 5 alpha-reductase may exist in scalp and prostate. The scalp reductase was also compared to 5 alpha-reductase 1, one of the two enzymes recently cloned from human prostate [Andersson, S. & Russell, D. W. (1990) Proc. Natl. Acad. Sci. USA 87, 3640-3644; and Andersson, S., Berman, D. M., Jenkins, E. P. & Russell, D. W. (1991) Nature (London) 354, 159-161]. The characteristics of the cloned reductase 1 are comparable to those of the scalp reductase.

Animals↗
PubMed1992

In vitro activity of meropenem and imipenem against mycobacteria: development of a daily antibiotic dosing schedule.

The activity of two carbapenem antibiotics, meropenem and imipenem, against Mycobacterium species was assessed by means of the Bactec 460 radiometric apparatus. This system allowed a result to be read in 4-10 days. The instability of imipenem, particularly, in the test system necessitated the development of a regimen of daily addition of antibiotic to permit a more accurate assessment of antibiotic activity to be made. When antibiotic-containing media are incubated for long periods, as is the case when determining antimycobacterial activity, the stability of test antibiotics is an important factor that must be considered.

Culture Media↗
PubMed1992

Single-dose and steady-state pharmacokinetics and pharmacodynamics of perindopril in hypertensive subjects.

In a double-blind, placebo-controlled, parallel group study, 24 essential hypertensive subjects were randomised to receive either placebo or 2, 4, or 8 mg perindopril. Perindopril, its deesterified metabolite, perindoprilat, and perindoprilat glucuronide were separated with an ion-exchange resin and determined by a radioimmunoassay (RIA). Pharmacokinetic and pharmacodynamic parameters were estimated for 96 h after the first dose and after 4-week once-daily treatment. Perindopril peak levels were achieved in less than or equal to 2 h after dosing with an elimination t1/2 of 1-2 h. Peak levels of perindoprilat were achieved more slowly, reaching a maximum level 5-8 h after dosing, and had an elimination t1/2 of 40 h. Levels of the perindopril glucuronide peaked approximately 0.5 h later than perindopril, with an elimination t1/2 of approximately 2 h. Perindopril, perindoprilat, and its glucuronide conjugate followed linear kinetics in the dose range of 2-8 mg, and there was no evidence of accumulation with chronic dosing. Perindopril 4 and 8 mg produced significant decreases in predose blood pressure (BP) with chronic dosing, with maximal decreases occurring 5-7 h after dosing. Perindopril also produced a prolonged dose-dependent inhibition of plasma angiotensin-converting enzyme (ACE) activity that was maximum after 4 h and had not fully recovered by 48 h after a single dose.

Aged↗
PubMed1992

Image processing for the study of brain structure and function: problems and programs.

Fundamental problems in the analysis of functional and structural imaging data include data transport, boundary identification (including manual tracing, edge detection, and tissue segmentation), volume estimation, three-dimensional reconstruction and display, surface and volume rendering, shape analysis, and image overlay. These problems require that research investigators have access to suitable methods of image analysis, implemented on a set of software programs, in order to conduct neuroimaging research. The authors describe a group of software programs designed to provide a comprehensive solution for these problems.

Brain↗
PubMed1991

Intermittent interferonemia and interferon responses in multiple sclerosis.

In view of the immunoregulatory and antiviral properties of the interferons (IFNs), the production of and response to these cytokines in vivo and in vitro were assessed in 42 patients with multiple sclerosis (MS), a disease with features of autoimmunity and a viral infection. Serum IFN, determined by bioassay of antiviral activity at 10 intervals over 18 months, was detectable at levels ranging from 16 to 250 IU/ml, at least once and up to five times in 37 of the 42 patients. Of 420 samples tested, 88 (21%) were positive. None of the 71 serum samples from 37 healthy subjects contained detectable IFN activity. Neutralization of antiviral activity by antibodies showed that the serum IFN type was IFN-alpha in 82 samples, IFN-gamma only in 2, and both IFN-alpha and IFN-gamma were present in 4. At the initial time point the activity of 2'-5' oligoadenylate synthetase (OAS), an IFN-induced enzyme, was elevated in peripheral blood leucocytes (PBL) from 13 patients, but not in 7 patients seropositive for IFN, indicating that in some patients there was a failure of PBL to respond to endogenous IFN. In most patients the capacity of PBL in vitro to produce IFNs-alpha/beta or -gamma after induction by virus or mitogens, respectively, was likewise reduced. These various abnormalities in IFN responses could not be correlated with clinical assessments of disease activity but may reflect subclinical attacks. The abnormalities described, in particular the intermittent interferonemia in MS, are more striking than in other diseases previously reported, indicating an unusual component to the stimulus for IFN production (viral or other) or the response to it. The effects of endogenous IFN production may have implications for the scheduling of therapy with IFN in MS.

2',5'-Oligoadenylate Synthetase↗
PubMed1991

Physostigmine in Alzheimer's disease: effects on cognitive functioning, cerebral glucose metabolism analyzed by positron emission tomography and cerebral blood flow analyzed by single photon emission tomography.

The effect of acute, intravenous administration of physostigmine on measures of brain activity and cognitive functioning were investigated in 14 patients with Alzheimer's disease. Regional cerebral glucose metabolism was assessed using (18F)-fluoro-2-deoxy-D-glucose and positron emission tomography, and cerebral blood flow was assessed using 123I-iodoamphetamine single photon emission tomography. Although physostigmine enhanced cerebral blood flow in most patients, only one patient showed significant clinical improvement. This patient, however, also showed a very pronounced improvement in cerebral glucose metabolism. It is concluded that these preliminary findings hold considerable promise for our appreciation of the pathophysiology of dementing illness as well as our understanding of centrally acting compounds of interest in Alzheimer's disease.

Aged↗
PubMed1990

Chemical induction of thymomas in AKR mice: interaction of chemical carcinogens and endogenous murine leukemia viruses. Comparison of N-methyl-N-nitrosourea and methyl methanesulphonate.

The time course of development of thymic lymphoma, which occurs spontaneously in mice of the AKR strain, is accelerated by the methylating agents N-methyl-N-nitrosourea (MNU) and methyl methanesulphonate (MMS). Since MNU is a potent mutagen inducing G----A transition mutations and MMS a relatively weak mutagen, it was of interest to examine the genetic alterations associated with each class of the chemically induced tumors and to compare these alterations with those found in the spontaneous tumors. The same spectrum of genetic alterations was found for MMS-induced and spontaneous thymomas. Both showed rearrangements of c-myc and Pim-1 genes that appeared to result from integration of recombinant mink cytopathic focus-forming (MCF) proviruses but failed to reveal evidence for activation of ras oncogenes, either by DNA transfection experiments or by hybridization of DNA to specific oligonucleotide probes. Some alteration in c-myc and Pim-1 genes were also found in MNU-induced tumors, but, mainly, these involved integration of ecotropic-like rather than recombinant MCF viruses. Furthermore, MNU-induced tumors frequently (in 24% of thymomas) contained G----A transition mutations, activating the Ki-ras oncogene at codon 12 position 2. Another feature that distinguishes the MNU-induced tumors from those occurring in untreated and MMS-treated mice was the consistently high level of c-myc mRNA that occurred in the absence of c-myc gene rearrangement. Taken together, the data indicate that the mechanisms of development of tumors following treatment with MNU and MMS are distinct, and that the effect of MMS is probably to speed up the process of viral leukemogenesis.

Animals↗
PubMed1990

Effects of chain-length and unsaturation on affinity and selectivity at muscarinic receptors.

1. Lengthening the chain in diphenylacetylcholine decreases affinity for muscarinic cholinoceptors in guinea-pig ileum. Diphenylacetoxypropyldimethylamine and its quaternary trimethylammonium salt are roughly equiactive: the dimethylamine and the piperidine have some selectivity for ileum compared with atria, but are not as active nor as selective as 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) methobromide (MeBr). With the weaker diphenylacetoxybutyl compounds the base is more active than the quaternary salt. 2. The diphenylacetoxybutyl-, cis-butenyl and trans-butenyl compounds have similar affinities. The quaternary salts are less active than the tertiary bases, but they are less selective than the butynyl analogues studied in earlier work. 3. 1,1-Diphenyl-1-hydroxy-2,4-hexadiynyl dimethylamine and its trimethylammonium salt are inactive in concentrations below 100 microM, as are the (+)-camphor-sulphonyl ester of 4-hydroxy-N-methyl piperidine and its methiodide. The (+/-)-phenylcyclopentylacetyl ester of 4-hydroxy-N-methylpiperidine methobromide is more active than its cyclohexyl analogue and than 4-DAMP MeBr but it is less selective than 4-DAMP MeBr. 4. The high selectivity of p-fluoro-hexahydrosila-diphenidol is confirmed but this compound has relatively low affinity (for ileum log K = 7.8). 5. The results indicate steric constraints to binding at muscarinic receptors which could be used to check molecular modelling of the receptor based on its known amino acid sequence. The group binding the charged nitrogen is probably at the mouth of a cavity which can accommodate two large rings (as in 4-DAMP MeBr) but with a depth less than about 7 A so that the rod-like hexadiynes cannot fit. Differences between types of receptor may only involve small changes in geometry secondary to differences in amino acids not directly involved in binding and the production of selectivity depends upon finding substituents which interfere with binding more at one type of receptor than at another.

Animals↗
PubMed1990

Use of a radiometric technique for rapid sensitivity testing of mycobacteria in Scotland: the first year's experience.

We report the first year's experience of the use of a radiometric technique for sensitivity testing of mycobacterial isolates in Scotland. The techniques (using the Bactec 460 instrument) was much quicker than conventional methods (for example the mean time to obtain results for 60 strains of M.tuberculosis was 14.4 days, compared with 44.9 days for conventional methods). There was good agreement between results obtained by the two methods. Preliminary results also indicated the value of the radiometric technique for rapid isolation of mycobacteria from clinical samples (mean of 10.6 days with the radiometric technique compared with 26.7 days using egg media) although for optimal recovery, both techniques should be used in parallel.

Carbon Radioisotopes↗
PubMed1989

Studies of insulin resistance in the streptozotocin diabetic and BB rat: activation of low Km cAMP phosphodiesterase by insulin.

The streptozotocin diabetic rat (STZ-DM) has been the best animal model for the study of insulin-deficient diabetes. A spontaneous diabetic BB Wistar Rat (SDR) has now been evaluated as a model for insulin-dependent diabetes that more closely reflects this disease in humans. The authors assessed the ability of insulin to stimulate the Vmax of a low Km cAMP phosphodiesterase (PDE) in adipose tissue of control, streptozotocin diabetic (STZ-DM) rats, and spontaneous diabetic BB rats (SDR). In addition, the authors examined the effect of streptozotocin on the nondiabetic littermates of the SDR animal, the NDR rat. Insulin stimulated Vmax of low Km cAMP PDE in control rat adipose tissue by 20% at 5 minutes. Insulin also stimulated Vmax of both SDR and NDR by 50% at 5 minutes. In contrast to control and both subgroups of the BB rat (SDR and NDR), insulin stimulated adipose tissue from STZ-DM less than 10% at 5 minutes. NDR animals rendered diabetic with streptozotocin were more responsive to insulin. The data demonstrate some similarities and differences between streptozotocin-induced diabetes and spontaneous diabetes in the BB rat. Reduced responsiveness to insulin appears to be more a part characteristic of streptozotocin diabetes than diabetes in the BB rat. The absence of significant insulin resistance in the spontaneous diabetic BB rat also is more consistent with the pathophysiological mechanisms usually seen both in other insulin-dependent diabetic rat models and insulin-dependent diabetes in man. However, both animal models of diabetes, ie, STZ-DM and BB, like man, respond to insulin therapy.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1979

Effect of T-lymphocytes on normal haemopoiesis: studies in congenitally athymic nude mice.

The germ-free nude mouse represents a most useful animal for investigating the effects of a congenital deficiency of T-lymphocytes on various physiological processes, including haemopoiesis. Nude mice (nu/nu) of the CBA strain, nonmutant inbred CBA mice, and inbred C3H mice were reared in germ-free isolators and used to compare (1) the haematological parameters of nu/nu mice and CBA mice at different ages and (2) the labelling pattern of circulating leucocytes at various times after a single intraperitoneal injection of 3H-thymidine into 3-month-old nu/nu and C3H mice. The data suggest that the deficiency of T-lymphocytes in nu/nu mice may lead to a disturbance of haemopoiesis in 2 to 6-month animals which is characterised by a mild macrocytosis and a very marked reduction in the proportion of labelled leucocytes which can be seen in the blood after an injection of 3H-thymidine. Despite these perturbations, unstressed nu/nu mice were able to maintain adequate numbers of blood cells (other than lymphocytes) in their circulation. Nine-month-old nu/nu mice did not show a macrocytosis and the disappearance of the marcrocytosis at this age was associated with an increase both in the blood lymphocyte count and in the mass of lymphoid tissue in the spleen and mesenteric lymph nodes.

Animals↗
PubMed1978

Transport of DNA from lymphocytes to fibroblasts in culture.

The exchange of radioactivity between lymphocytes, labelled with (3H) thymidine after stimulation with Concanavalin A, and recipient V79 fibroblasts in culture was studied. The radioactive material involved in this exchange was macromolecular deoxyribonucleic acid as well as its breakdown products. This deoxyribonucleic acid from lymphocytes localised in the nuclei of the host cells soon after contact between donor and recipients. This occurred even when the V79 fibroblasts were confluent at high cell density, and thus in a steady, non-growing state with respect to cell numbers. The fate of the radioactive donor lymphocyte deoxyribonucleic acid, substituted with bromodeoxyuridine, was followed in the recipient cells by analysing its buoyant density in caesium chloride gradients. This deoxyribonucleic acid was found to become associated with the nuclear deoxyribonucleic acid of the host cells, involving both retention of relatively intact donor deoxyribonucleic acid as well as its breakdown and re-utilisation for host cell deoxyribonucleic acid synthesis. Non-growing recipient cells were found to retain the donor deoxyribonucleic acid in relatively intact form for much longer periods than when the same cells were in logarithmic growth phase.

Cell Division↗