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Biomedical subjects

J Preston

Publications and source records attributed to J Preston.

At least 19 recordsLinked to original sources
PubMed1995

Kinetic characteristics of ZENECA ZD5522, a potent inhibitor of human and bovine lens aldose reductase.

Aldose reductase (aldehyde reductase 2) catalyses the conversion of glucose to sorbitol, and methylglyoxal to acetol. Treatment with aldose reductase inhibitors (ARIs) is a potential approach to decrease the development of diabetic complications. The sulphonylnitromethanes are a recently discovered class of aldose reductase inhibitors, first exemplified by ICI215918. We now describe enzyme kinetic characterization of a second sulphonylnitromethane, 3',5'-dimethyl-4'-nitromethylsulphonyl-2-(2-tolyl)acetanilide (ZD5522), which is at least 10-fold more potent against bovine lens aldose reductase in vitro and which also has a greater efficacy for reduction of rat nerve sorbitol levels in vivo (ED95 = 2.8 mg kg-1 for ZD5522 and 20 mg kg-1 for ICI 215918). ZD5522 follows pure noncompetitive kinetics against bovine lens aldose reductase when either glucose or methylglyoxal is varied (K(is) = K(ii) = 7.2 and 4.3 nM, respectively). This contrasts with ICI 215918 which is an uncompetitive inhibitor (K(ii) = 100 nM) of bovine lens aldose reductase when glucose is varied. Against human recombinant aldose reductase, ZD5522 displays mixed noncompetitive kinetics with respect to both substrates (K(is) = 41 nM, K(ii) = 8 nM with glucose and K(is) = 52 nM, K(ii) = 3.8 nM with methylglyoxal). This is the first report of the effects of a sulphonylnitromethane on either human aldose reductase or utilization of methylglyoxal. These results are discussed with reference to a Di Iso Ordered Bi Bi mechanism for aldose reductase, where the inhibitors compete with binding of both the aldehyde substrate and alcohol product. This model may explain why aldose reductase inhibitors follow noncompetitive or uncompetitive kinetics with respect to aldehyde substrates, and X-ray crystallography paradoxically locates an ARI within the substrate binding site. Aldehyde reductase (aldehyde reductase 1) is closely related to aldose reductase. Inhibition of bovine kidney aldehyde reductase by ZD5522 follows uncompetitive kinetics with respect to glucuronate (K(ii) = 39 nM), indicating a selectivity greater than 5-fold for bovine aldose reductase relative to aldehyde reductase.

Acetanilides↗
PubMed1992

Using telemedicine to improve health care in distant areas.

Many users consider telemedicine a partial solution to problems of delivering health care to remote areas or areas underserved by clinicians. Current telemedical technology benefits from recent developments such as the decreased cost and improved quality of the coder-decoder (codec) equipment used in interactive digital video systems and the expansion of fiber-optic cable networks. The authors outline some pioneering telemedicine programs of the 1960s and 1970s and describe two recently activated systems in Texas. One network, serving the western two-fifths of the state, links faculty members from four campuses of Texas Tech University Health Sciences Center with almost 40 rural communities. The other connects the state hospital and three other facilities in Austin with four health care sites in the town of Giddings, 65 miles away. Besides serving patients, the systems provide continuing medical education and support to reduce the isolation of rural health care professionals. Primary goals include evaluation and certification of telemedical training and analysis of the cost feasibility of telemedical services.

Delivery of Health Care↗
PubMed1991

(2,6-Dimethylphenylsulphonyl)nitromethane: a new structural type of aldose reductase inhibitor which follows biphasic kinetics and uses an allosteric binding site.

Many of the complications of diabetes seem to be due to aldose reductase (aldehyde reductase 2, ALR2) catalysing the increased conversion of glucose to sorbitol. Therapy with aldose reductase inhibitors (ARIs) could, therefore, decrease the development of diabetic complications. (2,6-Dimethylphenylsulphonyl)nitromethane (ICI 215918) is an example from a newly discovered class of ARIs, and we here describe its kinetic properties. Preparations of bovine lens ALR2 exhibit biphasic kinetics with respect to glucose and various inhibitors including ICI 215918. The inhibitor sensitive form (ALR2S) has a higher affinity for glucose than does the inhibitor insensitive form (ALR2I). Only ALR2S was characterized in detail because ALR2I activity is very low at physiological levels of glucose and is difficult to measure with accuracy. Aldehyde reductase (ALR1) is the most closely related enzyme to ALR2. Inhibition of ALR1 was, therefore, investigated in order to assess the specificity of ICI 215918. The values of Ki and Kies (dissociation constants for inhibitor from enzyme-inhibitor and enzyme-inhibitor-substrate complexes, respectively) for ICI 215918 with bovine kidney ALR1 and bovine lens ALR2S have been determined. When glucose is varied, the compound is an uncompetitive inhibitor of ALR2S (Kies = 0.10 microM and Ki is much greater than Kies), indicating that ICI 215918 associates with an allosteric site on the enzyme. These kinetic characteristics would cause a decrease in the concentration required to give 50% inhibition when glucose levels rise during hyperglycaemia. ICI 215918 is a mixed noncompetitive inhibitor of ALR1 (Ki = 10 microM and Kies = 1.8 microM) when glucuronate is varied. Thus, the compound has up to 100-fold specificity in favour of ALR2S relative to ALR1. Therapeutic interest has now centred upon at least three distinct structural types of ARIs: spirohydantoins, acetic acids and sulphonylnitromethanes. Using one representative of each type, we have demonstrated kinetic competition for inhibition of ALR2S. This observation strongly suggests that the different inhibitors use overlapping binding sites.

Aldehyde Reductase↗
PubMed1991

Manual resuscitators and spontaneous ventilation--an evaluation.

BACKGROUND AND METHODS: Although it is useful in certain clinical situations for manual resuscitator units to be used with spontaneously ventilating patients, there are few data regarding their performance in these settings. We measured the percent-delivered oxygen from 13 adult manual resuscitator units during simulated spontaneous ventilation in the range of respiratory frequency, tidal volume, and oxygen supply in which manual resuscitator units might be used with patients. We also measured the resistive pressure developed during simulated ventilation and at constant inspiratory flow of 50 L/min. RESULTS: Oxygen supply, tidal volume, minute ventilation, and reservoir volume all influenced percent-delivered oxygen, but the most important determinant of percent-delivered oxygen was valve design. Valves incorporating a "disc" element to prevent air entrainment from the expiratory port gave the most efficient oxygen delivery, while "duck-bill" valves did not reliably prevent air entrainment. Only two of the manual resuscitator units tested developed high resistive pressure. CONCLUSION: Reliable administration of high percent-delivered oxygen to spontaneously ventilating patients, while retaining the capability to manually ventilate them, is best achieved by a manual resuscitator unit with a valve of low resistance, incorporating a disc to prevent air entrainment. We recommend that manufacturers indicate on the product information sheet the degree (and confidence limits) to which their manual resuscitator unit presents resistance and delivers oxygen to a spontaneously ventilating subject.

Airway Resistance↗
PubMed1991

Effects of cost containment on the care of elderly diabetics.

OBJECTIVE: Because of rising costs in the Medicare program, the elderly have been encouraged to enroll in health maintenance organizations (HMOs). To evaluate the quality of care in these HMOs, detailed criteria on the treatment of elderly diabetics were established by an expert panel. DESIGN: Approximately 20 months of care for elderly diabetics was reviewed by medical record abstractions with a historical cohort design. SETTING: The care of elderly diabetics in eight HMOs was compared with the care received in fee-for-service (FFS) settings located in similar geographic areas. PATIENTS: Elderly diabetics enrolled in HMOs (n = 158) were compared with similar diabetics (n = 134) in FFS settings. RESULTS: Diabetic HMO enrollees were more likely to have funduscopic examinations (48% in HMOs vs 30% FFS) and urinalyses (89% in HMOs vs 74% FFS) performed. Enrollees with poor diabetic control were also more likely than FFS diabetics to be referred to an ophthalmologist (45% in HMOs vs 11% FFS). However, influenza vaccinations were administered to diabetics more often in FFS settings than to diabetic enrollees (19% in HMOs vs 62% FFS). One fifth of diabetics in both groups were treated with insulin and two thirds were treated with oral hypoglycemic agents, though HMO enrollees were more likely to have medication changes. CONCLUSION: We conclude that most aspects of the quality of diabetic care were similar in HMO and FFS settings and were unaffected by this effort at cost containment.

Aged↗
PubMed1988

Comparative separation of human plasma proteins on polysulphated chromatographic media.

Polysulphated chromatographic media, particularly Heparin Sepharose, are generally used to purify a variety of different plasma proteins. Heparin Sepharose, dextran sulphate Sepharose and sulphated dextran are compared with two recently available sulphated cellulose chromatographic media. The potential influence of structural features of different polysaccharides on the interaction with selected plasma proteins has been evaluated with the particular objective of developing an alternative medium for the preparation of specific therapeutic factor concentrates. The studies indicate that the degree of sulphation of the matrix is an important but not a critical determinant for resolution of factors IX and X. Despite large differences in the carbohydrate structure of the matrices, the new sulphated cellulose gel 5.2 had a total protein capacity and specific binding profile comparable to Heparin Sepharose. The sulphated cellulose which is competitively priced, and has excellent stability, is a potential alternative to Heparin Sepharose especially for larger scale industrial processing of factor IX concentrate.

Blood Proteins↗
PubMed1987

High extracellular Ca2+ and Mg2+ stimulate accumulation of inositol phosphates in bovine parathyroid cells.

We examined the effects of the divalent cations Ca2+ and Mg2+ on inositol phosphate accumulation in bovine parathyroid cells prelabelled with [3H]inositol to determine whether the high extracellular Ca2+ and Mg2+-evoked transients in cytosolic Ca2+ in these cells might result from increases in cellular IP3 levels. In the presence of Li+, both Ca2+ and Mg2+ produced rapid, 2-6-fold increases in IP3 and IP2 and a linear increase in IP of 6-8-fold at 30 min. Smaller (1.5-2-fold) increases in IP2 and IP3 were evident within 7.5-15 s upon exposure to high (3 mM) Ca2+ in the absence of Li+. The relative potencies of Ca2+ and Mg2+ (Ca2+ 3-fold more potent than Mg2+) in elevating inositol phosphates were similar to those for their effects in inhibiting PTH release. Fluoride (5 and 10 mM) also produced similar increases in inositol phosphate accumulation, presumably through activation of phospholipase C by a guanine nucleotide (G) protein-dependent process. Thus, high extracellular Ca2+ and Mg2+-induced spikes in cytosolic Ca2+ in bovine parathyroid cells may be mediated by increases in IP3, perhaps through a receptor-mediated process linked to phospholipase C by a G-protein.

Animals↗
PubMed1987

Temporal characteristics of the speech of normal elderly adults.

A number of physical and psychological changes occur as a result of the normal aging process. These changes often result in an increase in the time subjects require to perform various motor (and sensory) tasks. Although the effects of aging upon a variety of behaviors have been quite well documented, considerably less information is available concerning how normal aging may affect speech production. The present study examined temporal characteristics of the speech of 10 normal, elderly adults and 10 young adults who produced a variety of words and sentences at both normal and fast speaking rates. Acoustic analyses indicated that the elderly adults' segment, syllable, and sentence durations were 20 to 25% longer than those of the young adults at both the normal and the fast rates of speech. In addition to comparisons that were made between these two groups of subjects, comparisons were also made with durations of the speech of young children studied in previous research. It was observed that the elderly subjects tended to produce durations comparable to those of 6- and 7-year-old children.

Adult↗
PubMed1987

Permeabilization reveals classical stimulus-secretion coupling in bovine parathyroid cells.

Unlike most secretory cells, high extracellular Ca2+ inhibits, rather than stimulates, PTH release from parathyroid cells. To gain more direct access to the potentially unique secretory apparatus of this cell type, we developed techniques for permeabilizing parathyroid cells using electroshock. Exposure of dispersed bovine parathyroid cells to five 2-kV discharges results in more than 90% uptake of trypan blue and rapid loss of intracellular 86Rb, documenting permeabilization of the plasma membrane. Unlike intact parathyroid cells, a high Ca2+ concentration increases PTH release 2.8-fold from permeabilized cells, with half-maximal and maximal stimulation at 10(-5) and 4 X 10(-4) M Ca2+, respectively, a pattern similar to classical stimulus-secretion coupling. Moreover, PTH release was low at Ca2+ concentrations equivalent to those in intact cells at low extracellular Ca2+ levels (approximately 2 X 10(-7) M). Cellular mechanisms other than changes in the cytosolic Ca2+ concentration per se, therefore, presumably mediate low Ca2+-stimulated PTH release in the intact cell. Diacylglycerol and protein kinase C may play a role in this process, since dioctanoylglycerol (10(-4) M) and 12-O-tetradecanoyl phorbol 13-acetate (10(-6) M) each enhance PTH release from permeabilized cells 2- to 4-fold at a Ca2+ concentration (approximately 2 X 10(-7) M) equivalent to that present in the intact cell at low extracellular Ca2+ concentrations.

Animals↗
PubMed1986

Guanine nucleotides are potent secretagogues in permeabilized parathyroid cells.

We studied the effects of GTP and its' analogues on PTH release in permeabilized parathyroid cells to assess their role in mediating the unusual inverse relationship between Ca2+ and PTH release in intact parathyroid cells. Both 10-5 M GppNHp and GTP gamma S, nonhydrolysable analogues of GTP, produce up to an 8-fold enhancement of PTH release, which is dose-dependent. This effect is specific for GTP analogues as we could not mimic it with other nucleotides. 10(-3) M GDP beta S, a nonhydrolysable GDP analogue, completely abolishes GppNHp-stimulated hormone release, providing further support for mediation of this effect by a guanine-nucleotide regulatory protein. In GppNHp-stimulated cells, PTH release is maximal at free [Ca2+] less than 200 nM and progressively decreases as the free [Ca2+] increases from 300 nM to 100 microM. These results suggest the presence of a guanine-nucleotide binding protein in the parathyroid cell that may play an important role in the regulation of PTH secretion by Ca2+ and perhaps other secretagogues.

Animals↗
PubMed1984

Marital therapy for the elderly.

Little attention has been paid to marital therapy for the elderly in spite of its relevance to morale and emotional problems. Physical illness is of particular significance in altering the dynamics of the marital relationship. Retirement and financial problems, as well as changes in sexual activity and gender roles, are also important. However, radical changes in patterns of behaviour cannot be expected. Therapeutic techniques must be altered for this age group, and the therapist must be active, giving and concretely helpful. As with therapy for younger couples, children may need to be involved in the therapy sessions. Family physicians should be a main source of help for marital problems among the elderly. However, because problems related to countertransference must be faced, working with the elderly will not be for everyone.

Aged↗