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Biomedical subjects

J Fox

Publications and source records attributed to J Fox.

At least 91 records · Page 5Linked to original sources
PubMed1998

Stimulation of calcitonin secretion by calcium receptor activators: evaluation using a new, highly sensitive, homologous immunoradiometric assay for rat calcitonin.

Current rat calcitonin immunoassays use human calcitonin antisera, and suffer from poor sensitivity, long incubation periods, nonspecific interferences, and unreliability. The homologous immunoradiometric assay (IRMA) for rat calcitonin described here overcomes these problems. Overnight incubation yields a detection limit of 0.4 pg/mL, a standard curve that is linear to >1800 pg/mL, and intra- and interassay coefficients of variation of <7%. Gel filtration chromatography of rat plasma and rat medullary thyroid carcinoma 44-2 cell media showed that the vast majority of immunoreactivity coeluted with calcitonin standard. In 44-2 cells, increasing extracellular Ca2+ concentration or incubation with the calcimimetic compound NPS R-467 markedly increased calcitonin secretion. Plasma calcitonin levels were elevated in rats anesthetized with ketamine/xylazine and in conscious rats with chronic renal insufficiency. Calcitonin levels decreased following EGTA-induced hypocalcemia and were undetectable after thyroparathyroidectomy. In normal conscious rats, plasma calcitonin levels averaged 3-5 pg/mL and increased up to 100-fold following calcium (Ca) infusion or NPS R-467 administration. The assay also quantified calcitonin in plasma of normal and Ca-injected mice. This assay has revealed that plasma calcitonin levels in normal rats are much lower than the detection limits of most existing assays, but can increase by 100-fold on activation of the C-cell Ca2+ receptor.

Anesthesia↗
PubMed1998

Enterohepatic Helicobacters: natural and experimental models.

The genus Helicobacter now includes at least 18 formally named species as well as several novel helicobacters that have not been formally named. Eleven Helicobacter spp. colonize the intestinal tract of mammals and birds. In addition, a number of the intestinal helicobacters can colonize the biliary tract and liver, induce hepatitis and one in particular, Helicobacter hepaticus, can cause liver cancer in susceptible strains of mice. Further studies are needed to ascertain whether these helicobacters are also responsible for enterohepatic diseases in humans.

Animals↗
PubMed1997

Evaluation of computer support for prescribing (CAPSULE) using simulated cases.

OBJECTIVE: To evaluate the potential effect of computer support on general practitioners' prescribing, and to compare the effectiveness of three different support levels. DESIGN: Crossover experiment with balanced block design. SUBJECTS: Random sample of 50 general practitioners (42 agreed to participate) from 165 in a geographically defined area of Oxfordshire. INTERVENTIONS: Doctors prescribed for 36 simulated cases constructed from real consultations. Levels of computer support were control (alphabetical list of drugs), limited support (list of preferred drugs), and full support (the same list with explanations available for suggestions). MAIN OUTCOME MEASURES: Percentage of cases where doctors ignored a cheaper, equally effective drug; prescribing score (a measure of how closely prescriptions matched expert recommendations); interview to elicit doctors' views of support system. RESULTS: Computer support significantly improved the quality of prescribing. Doctors ignored a cheaper, equally effective drug in a median 50% (range 25%-75%) of control cases, compared with 36% (8%-67%) with limited support and 35% (0-67%) with full support (P < 0.001). The median prescribing score rose from 6.0 units (4.2-7.0) with control support to 6.8 (5.8 to 7.7) and 6.7 (5.6 to 7.8) with limited and full support (P < 0.001). Of 41 doctors, 36 (88%) found the system easy to use and 24 (59%) said they would be likely to use it in practice. CONCLUSIONS: Computer support improved compliance with prescribing guidelines, reducing the occasions when doctors ignored a cheaper, equally effective drug. The system was easy to operate, and most participating doctors would be likely to use it in practice.

Decision Making, Computer-Assisted↗
PubMed1997

Base transitions dominate the mutational spectrum of a transgenic reporter gene in MSH2 deficient mice.

Tumors derived from individuals with hereditary nonpolyposis colorectal cancer syndrome frequently demonstrate mutations in both alleles of hMSH2, a key gene in DNA mismatch repair (MMR). Sporadic tumors also frequently exhibit MMR deficiency. In keeping with the role of MMR in the maintenance of genome integrity, mice deficient in MSH2 via gene targeting demonstrate a high incidence of thymic lymphomas and small intestinal adenocarcinomas. To investigate the effects of MSH2 deficiency in normal tissues, mice containing a retrievable transgenic lacI reporter gene for mutation detection were crossed with MSH2-/- mice. Mice homozygous for MSH2 deficiency revealed 4.8, 11.0 and 15.2-fold elevations in spontaneous mutation frequency in DNA obtained from brain, small intestine, and thymus, respectively, as compared to heterozygous or wild-type mice. Mutations most frequently recovered from MSH2-/- mice were single base substitutions (77%), particularly base transitions (64%). Frameshifts occurred less frequently (19%) and fell within very short (3-5 bp) mononucleotide runs. Thus the number of key growth control genes potentially impacted by MMR deficiency extends beyond those containing repetitive sequences. These results highlight the capacity for MSH2 deficiency to serve as a potent driving force during the multi-step evolution of tumors.

Animals↗
PubMed1997

The effect of dietary enrichment with fish-oil on urinary excretion of N-acetyl-beta-D-glucosaminidase and renal function in proteinuric patients with primary glomerulopathies.

The rate of progression of renal disease depends on many factors including serum lipids and tubulo-interstitial injury. Aim of the study was to see whether fish-oil therapy may affect serum lipids and NAG excretion with urine (a marker of tubular cell damage) in humans with renal disease. The effects of dietary fish-oil fatty acids on the serum lipids, NAG urinary excretion and serum arachidonic acid concentration were examined in thirteen primary glomerulonephritic patients with proteinuria and normal renal function. The regular diet enriched with 1650 mg n-3 polyunsaturated fatty acids (18%: 20:5; n-3 EPA and 12%: 22:5; n-3 DHA) was ingested for three months. At the end of fish-oil enriched diet neither creatinine clearance nor urinary protein excretion changed significantly. But serum concentration of HDL and arachidonic acid increased (48.0 +/- 15 vs. 52.0 +/- 14; p < 0.05), (0.47 +/- 0.13 vs. 0.72 +/- 0.29; p < 0.01), respectively. Simultaneously urine NAG excretion and serum LDL decreased (11.2 +/- 7.1 vs. 10.3 +/- 7.3; p < 0.05), (163.0 +/- 57 vs. 149.0 +/- 51, p < 0.01), respectively. We presume that fish-oil supplementation may have a beneficial effect on renal tubular cells in humans and it could be linked with arachidonic acid metabolism.

Acetylglucosaminidase↗
PubMed1997

PROforma: a general technology for clinical decision support systems.

The need for flexible and well understood knowledge representations which are capable of capturing clinical guidelines and protocols for decision support systems is widely recognised. The PROforma method for specifying clinical guidelines and protocols comprises a graphical notation for their design, and a formal knowledge representation language to enable them to be executed by a computer to support the management of medical procedures and clinical decision making. PROforma technology consists of a graphical knowledge editor for the creation of guidelines, and an enactment engine for testing and executing them. This paper provides an overview of the motivation and structure of PROforma, and illustrates its use in the development of clinical applications.

Adult↗
PubMed1997

Stability of ranitidine and thiamine in parenteral nutrition solutions.

Our objectives were to ascertain the stability of thiamine HCl (3 mg/L) and ranitidine HCl (150 mg/L) at room and refrigeration temperatures in a central vein formula of parenteral nutrition (PN) solution (containing 6% amino acid, 25% carbohydrate, macro- and microminerals, and multivitamins) and to determine the effect of ranitidine on the stability of thiamine. Stability of thiamine and ranitidine in PN solutions was also compared with PN-salt solutions, which contained no amino acids or carbohydrates, to indirectly ascertain the impact of these macronutrients on the stability of these moieties. High-pressure liquid chromatography (HPLC) methods were developed to measure thiamine and ranitidine in the PN mixture. Stability studies were conducted in triplicate and each sample was assayed in duplicate using newly developed HPLC methods. Refrigeration provided stability for both ranitidine and thiamine for extended periods of time. At room temperature, ranitidine was also shown to be stable for about 188 h; there was, however, significant degradation of thiamine at 24 h with, and without, addition of ranitidine. The time required for 10% of thiamine to degrade was calculated to be 12.9 h for the PN mixture containing multivitamins and ranitidine; 11.1 h for the PN mixture containing multivitamins alone; and 33.4 h for the PN mixture containing only thiamine HCl. This work suggests that the concentration of thiamine in this central vein PN formula, with or without ranitidine, falls below the 90% acceptable stability within 24 h.

Chromatography, High Pressure Liquid↗
PubMed1997

A model for integrating image processing into decision aids for diagnostic radiology.

Advances in imaging techniques have been mirrored by advances in the use of computers to extract and interpret image data. Helping clinicians to make effective use of this superabundance of information is a key aim of medical informatics research. One approach is to incorporate digital images and image processing within a knowledge-based decision aid for radiologists. This paper describes a generic design for such aids. The work is based on an abstract model of decision-making which is used to organize the presentation of information from a knowledge base. We describe a system in which the model of decision-making is augmented to describe processes underlying image interpretation. The augmented model, implemented as a logic program, is used to control the application of image processing operators to detect and describe radiological signs. Through the use of this model we are able to combine information from image processing with information from a symbolic knowledge base. The operation of the model is illustrated by considering three different applications in the domain of breast X-rays or mammograms.

Humans↗
PubMed1997

Plasma levels of parathyroid hormone that induce anabolic effects in bone of ovariectomized rats can be achieved by stimulation of endogenous hormone secretion.

Parathyroid hormone (PTH) administration increases bone mass in normal and osteopenic animals. However, this treatment currently requires the daily injection of large amounts of PTH, and the relationship of these doses to plasma levels of PTH that are achievable physiologically is unknown. We determined in ovariectomized (ovx) rats: 1) the plasma PTH levels that occur after the subcutaneous injection of graded doses of rat PTH, 2) whether similar PTH levels can be achieved by stimulation of endogenous PTH secretion, and 3) whether a plasma PTH profile that is achievable physiologically is anabolic on bone. Injection of 1, 5, or 25 micrograms/kg rat PTH-(1-34) increased plasma PTH by 46, 164, or 520 pg/mL, respectively, above basal levels within 60 min. Infusion of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid for 2 h reduced plasma Ca2+ by 0.36 mmol/L and produced a total plasma PTH response (area under the plasma PTH curve) similar to that with the 5 micrograms/kg rat PTH injection. Then, 1, 5, or 25 micrograms/kg doses of rat PTH-(1-34) were injected subcutaneously daily for 28 days in 19-week-old rats that were ovx 7 weeks earlier. The 5 and 25 micrograms/kg doses significantly increased bone mineral density in the distal femur and trabecular bone area and average trabecular thickness in the proximal tibia. All doses of PTH significantly increased indices of trabecular connectivity and cancellous bone formation, including double-labeled surface, mineralizing surface, and surface-referent bone formation rate. In conclusion, anabolic effects on bone can be achieved with a plasma PTH profile similar to that attained following stimulation of the parathyroid gland by induced hypocalcemia. These data suggest that agents that transiently increase endogenous PTH secretion may represent a novel means to promote anabolic effects in skeletal tissues.

Absorptiometry, Photon↗
PubMed1997

Clinical and human resource planning for the downsizing of psychiatric hospitals: the British Columbia experience.

Riverview Hospital, B.C.'s only and Canada's largest remaining provincial psychiatric hospital began a formal planned "downsizing" process in 1992. This initiative was an important element in the Province's strategic plan to shift to a more community-focused mental health system and to bring tertiary psychiatric services "closer to home" by redeveloping Riverview Hospital on three sites. The paper summarizes the literature pertaining to the "downsizing" of psychiatric hospital services in relation both to clinical and human resource planning. It describes the mental health system in B.C. and the service system context in which this exercise is occurring. It is based on the first three years of experience in identifying the major challenges and the strategies developed to meet these challenges. It draws some conclusions about the effectiveness of these strategies and it speculates about the likely future challenges as the "downsizing" process continues.

British Columbia↗
PubMed1997

In vivo regulation of chromogranin A messenger ribonucleic acid in the parathyroid by 1,25-dihydroxyvitamin D: studies in normal rats and in chronic renal insufficiency.

Chromogranin-A (CgA) and PTH are the two major secretory products of the parathyroid gland. In vitro, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] increases CgA, but decreases PTH messenger RNA (mRNA) levels. We investigated the physiological significance of the induced changes in CgA expression by examining the effects of 1,25-(OH)2D3 on parathyroid CgA mRNA levels in vivo. Normal rats were injected with 1,25-(OH)2D3 at 48 and 24 h before blood sampling and isolation of both parathyroid glands. Parathyroid total RNA was extracted and CgA and PTH mRNA quantified by Northern blot analysis. CgA mRNA levels increased 1.6-, 3.2- and 5.6-fold, whereas PTH mRNA levels decreased by 37, 63 and 97%, respectively, with 1,25-(OH)2D3 doses of 10, 50, and 250 pmol/100 g BW. Parathyroid gland CgA expression also was examined in rats with mild chronic renal insufficiency, induced by a 5/6 nephrectomy 5 weeks earlier. Chronic renal insufficiency rats, fed normal chow, had elevated serum urea, creatinine, and PTH levels and reduced 1,25-(OH)2D3 but normal serum levels of calcium and phosphate. PTH mRNA levels were elevated 4-fold and CgA mRNA levels were 50% lower in the uremic animals. This indicates that the regulation of CgA expression in normocalcemic rats occurs at physiological 1,25-(OH)2D3 concentrations. In summary, increases and decreases in serum 1,25-(OH)2D3 levels are associated with corresponding increases and decreases in CgA mRNA levels in the parathyroid glands of rats. Therefore, this study is the first to demonstrate the physiological relevance of the earlier in vitro observations.

Animals↗
PubMed1996

A novel lacI transgenic mutation-detection system and its application to establish baseline mutation frequencies in the scid mouse.

To assess DNA mutations in vivo, we have established a new transgenic mouse line, BC-1, carrying a lacI target gene for mutation detection within a bacteriophage shuttle-vector. The lacI gene was positioned within sequences derived from a rearranged murine immunoglobulin gene locus, a feature that distinguishes the BC-1 transgene from other shuttle vector systems. As mutations in lacI transgenes likely reflect mutations occurring throughout the genome, these systems have been successfully used to investigate spontaneous and induced mutations in a variety of tissues. An important additional application of the transgenic systems is the characterization of lacI mutations occurring in murine strains having specific DNA repair defects. For this study, scid (severe combined immunodeficiency) mice were selected as animals with this mutation have a defect in double-strand DNA break repair. To determine what impact the scid mutation might have on spontaneous mutation frequencies within DNA recovered from various tissues, these mice were crossed with the BC-1 line. Interestingly, mutation frequencies within BC-1/scid mouse DNA were not significantly different from those of BC-1 control mice. Furthermore, spontaneous lacI mutations obtained from BC-1 and from BC-1/scid liver DNA were similar in spectrum. As spontaneous BC-1 liver mutations were similar to those reported previously for other lacI systems, such as the Big Blue transgenic line, this suggested that the nature of the DNA sequences flanking the reporter gene did not modify lacI mutation rate or character.

Animals↗
PubMed1996

The parathyroid calcium receptor: a novel therapeutic target for treating hyperparathyroidism.

Parathyroid cells, C-cells, and certain cells in the kidney express a cell surface calcium (Ca2+) receptor which enables these cells to detect and respond to changes in the concentration of extracellular Ca2+. This receptor protein is a member of the G protein-coupled receptor superfamily and shares limited sequence homology only with metabotropic glutamate receptors. The Ca2+ receptor is the primary physiological mechanism regulating the secretion of parathyroid hormone (PTH) and plays a pivotal role in maintaining systemic Ca2+ homeostasis. Compounds that act as Ca2+ receptor agonists are called calcimimetics because they mimic or potentiate the effects of extracellular Ca2+ on parathyroid cell function. NPS R-568 is a small organic calcimimetic compound that acts as a positive allosteric modulator to increase the sensitivity of the Ca2+ receptor to activation by extracellular Ca2+. In normal rats, orally administered NPS R-568 decreases plasma levels of PTH and Ca2+ and, at higher doses, increases plasma levels of calcitonin. The changes in the circulating levels of these two hormones explain the hypocalcemia caused by this compound. NPS R-568 also effectively lowers plasma PTH levels in normal humans and in rat models of secondary hyperparathyroidism. Calcimimetic compounds that target the Ca2+ receptor provide a novel therapeutic approach for treating primary and secondary hyperparathyroidism.

Animals↗
PubMed1996

Effects of continuous glucocorticoid infusion on bone metabolism in the rat.

The effects of continuous administration of supraphysiologic doses of dexamethasone (DEX) on bone metabolism were examined in rats. Adult, male, Sprague Dawley rats were infused with DEX at a constant rate of 16.25 microg/day for 19 days. Despite soft tissue catabolism, DEX treatment led to a significant increase in bone volume in all experiments. This was accompanied by a significant gain in femoral weight and calcium content. These findings were also observed in DEX-treated parathyroidectomized animals indicating that intact parathyroid function was not required for this effect. DEX treatment did not affect mean levels of serum calcium or phosphorus but led to significant declines in circulating levels of PTH and 1,25(OH)2D and in the urinary calcium/creatinine ratio. This latter finding was also observed in PTX animals in which 1,25(OH)2D levels did not change. Serum concentrations of osteocalcin and tartrate-resistant acid phosphatase both declined in a time-dependent manner with DEX treatment suggesting a slowing of bone turnover with the net effect favoring formation. However, histomorphometric findings were variable. Two of three experiments demonstrated a decrease in cellular parameters of formation and resorption and in one experiment, these indices increased. Mineralized surface increased with DEX treatment. We conclude that, in marked contrast to the findings in man and certain other species, DEX treatment increases bone mass in rats. This may in part relate to a relatively greater suppression of resorption vis à vis formation.

Animals↗