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Biomedical subjects

B A Davis

Publications and source records attributed to B A Davis.

At least 19 recordsLinked to original sources
PubMed2005

Recent insights into interactions of deferoxamine with cellular and plasma iron pools: Implications for clinical use.

Despite the availability of deferoxamine (DFO) for more than three decades, its rates of interaction with cellular iron pools in different tissues, and the effects of its pharmacokinetics on the interaction with plasma iron pools, remain incompletely understood. The positive charge of DFO, together with the negative resting potential in vertebrate cells, favors cellular uptake, whereas the low lipophilicity and high molecular weight counter this effect. The findings presented suggest a facilitated uptake of DFO into hepatocytes, being several hundred-fold faster than into red cells. Antibodies that selectively recognize ferrioxamine (FO) show that initial hepatocellular iron chelation is cytosolic, but later transposes to lysosomal and ultimately canalicular compartments. Strong FO staining is visible in myocytes within 4-8 h after commencing a subcutaneous DFO infusion, indicating effective chelation of myocyte iron. A methodology was developed to study the interaction of DFO and its metabolites with plasma iron pools by stabilizing DFO with aluminum ions, thereby preventing iron shuttling from non-transferrin-bound iron (NTBI) onto DFO after plasma collection. DFO removes only about a third of NTBI rapidly, and NTBI is rarely cleared completely. Increasing DFO dosing does not increase NTBI removal, but instead leads to a greater rebound in NTBI on cessation of intravenous infusion. Thus, intermittent infusions of high-dose DFO are less desirable than continuous infusions at low doses, particularly in high-risk patients. Here the benefits of continuous DFO on heart function occur before changes in T2*-visible storage iron, consistent with early removal of a toxic labile iron pool within myocytes.

Animals↗
PubMed2002

The enigma of conditioned taste aversion learning: stimulus properties of 2-phenylethylamine derivatives.

The functional aversive stimulus properties of several IP doses of (+/-)-amphetamine (1.25-10 mg.kg-1), 2-phenylethylamine (PEA, 2.5-10 mg.kg-1, following inhibition of monoamine oxidase with pargyline 50 mg.kg-1) and phenylethanolamine (6.25-50 mg.kg-1) were measured with the conditioned taste aversion (CTA) paradigm. A two-bottle choice procedure was used, water vs. 0.1 % saccharin with one conditioning trial and three retention trials. (+/-)-Amphetamine and phenylethanolamine induced a significant conditioned taste aversion but PEA did not. (+/-)-Amphetamine and PEA increased spontaneous locomotor activity but phenylethanolamine had no effects on this measure. Measurement of whole brain levels of these drugs revealed that the peak brain elevation of PEA occurred at approximately 10 min whereas the peak elevations of (+/-)-amphetamine and phenylethanolamine occurred at approximately 20 min. The present failure of PEA to elicit conditioned taste aversion learning is consistent with previous reports for this compound. The differential functional aversive stimulus effects of these three compounds are surprising since they exhibit similar discriminative stimulus properties and both (+/-)-amphetamine and PEA are self-administered by laboratory animals. The present data suggest that time to maximal brain concentrations following peripheral injection may be a determinant of the aversive stimulus properties of PEA derivatives.

Amphetamine↗
PubMed2001

Inhibition of K/HCO(3) cotransport in squid axons by quaternary ammonium ions.

Previous squid-axon studies identified a novel K/HCO3 cotransporter that is insensitive to disulfonic stilbene derivatives. This cotransporter presumably responds to intracellular alkali loads by moving K(+) and HCO(3)(-) out of the cell, tending to lower intracellular pH (pH(i)). With an inwardly directed K/HCO(3) gradient, the cotransporter mediates a net uptake of alkali (i.e., K(+) and HCO(3)(-) influx). Here we test the hypothesis that intracellular quaternary ammonium ions (QA(+)) inhibit the inwardly directed cotransporter by interacting at the intracellular K(+) site. We computed the equivalent HCO(3)(-) influx (J(HCO3)) mediated by the cotransporter from the rate of pH(i) increase, as measured with pH-sensitive microelectrodes. We dialyzed axons to pH(i) 8.0, using a dialysis fluid (DF) free of K(+), Na(+) and Cl(-). Our standard artificial seawater (ASW) also lacked Na(+), K(+) and Cl(-). After halting dialysis, we introduced an ASW containing 437 mm K(+) and 0.5% CO(2)/12 mm HCO(3)(-), which (i) caused membrane potential to become transiently very positive, and (ii) caused a rapid pHi decrease, due to CO(2) influx, followed by a slower plateau-phase pH(i) increase, due to inward cotransport of K(+) and HCO(3)(-). With no QA(+) in the DF, J(HCO3) was approximately 58 pmole cm(-2) sec(-1). With 400 mm tetraethylammonium (TEA(+)) in the DF, J(HCO3) was virtually zero. The apparent K(i) for intracellular TEA(+) was approximately 78 mm, more than two orders of magnitude greater than that obtained by others for inhibition of K(+) channels. Introducing 100 mm inhibitor into the DF reduced J(HCO3) to approximately 20 pmole cm(-2) sec(-1) for tetramethylammonium (TMA(+)), approximately 24 for TEA(+), approximately 10 for tetrapropylammonium (TPA(+)), and virtually zero for tetrabutylammonium (TBA(+)). The apparent K(i) value for TBA(+) is approximately 0.86 mm. The most potent inhibitor was phenyl-propyltetraethylammonium (PPTEA(+)), with an apparent K(i) of approximately 91 microm. Thus, trans-side quaternary ammonium ions inhibit K/HCO(3) influx in the potency sequence PPTEA(+) > TBA(+) > TPA(+) > TEA(+) congruent with TMA(+). The identification of inhibitors of the K/HCO(3) cotransporter, for which no inhibitors previously existed, will facilitate the study of this transporter.

Animals↗
PubMed2001

Estimating cohort health expectancies from cross-sectional surveys of disability.

A life history can be regarded as a random process that evolves with age through various states of health before terminating with absorption into the state of death. Health expectancies are the occupation times of the non-absorbing states and their estimation is of interest. A continuing major problem has been the lack of satisfactory longitudinal data on which to base estimates and as a result standard inferential techniques may not be relevant. Supposing only cross-sectional data available, we propose a method that is generally applicable and first estimates a logistic parametrization of the probabilities of the various states. A large sample approximation is obtained for the distribution of age specific log (odds). Parameters are estimated by weighted least squares, and this in turn leads to estimates of cohort health expectancies. A result of Liang and Zeger is used to find standard errors. The method is illustrated by application to Australian data from the health surveys of 1981, 1988 and 1993.

Aged↗
PubMed2001

2-Bromoethylamine as a potent selective suicide inhibitor for semicarbazide-sensitive amine oxidase.

Semicarbazide-sensitive amine oxidase (SSAO) catalyzes the deamination of methylamine and aminoacetone to produce toxic aldehydes, i.e. formaldehyde and methylglyoxal, as well as hydrogen peroxide and ammonia. An increase of SSAO activity was detected by different laboratories in patients suffering from vascular disorders, i.e. diabetes and myocardial infarction. The enzyme has been suggested to play a role in vascular endothelial damage and atherogenesis. To date, there are no selective SSAO inhibitors. In the present study, 2-bromoethylamine (2-BrEA) was found to be a highly effective and selective inhibitor of SSAO obtained from different sources. The inhibition was irreversible and time dependent. It was competitive when the enzyme was not preincubated with the inhibitor, but became noncompetitive after incubation of the enzyme with 2-BrEA. The aldehyde trapping agent o-phenylenediamine was capable of preventing 2-BrEA-induced inhibition of SSAO activity. An aldehyde product was detected to be an initial product of 2-BrEA after it was incubated with SSAO. The inhibition, therefore, is mechanism-based. The SSAO inhibitory effects of eight structural analogues of 2-BrEA were assessed. It was concluded that a bromine atom at the beta position is quite important for exerting high potency of SSAO inhibition. The inhibition of SSAO activity by 2-BrEA was also demonstrated in vivo. It increased the urinary excretion of methylamine, an endogenous substrate for SSAO, in mice. 2-BrEA can be employed as a very useful tool in the investigation of SSAO.

Amine Oxidase (Copper-Containing)↗
PubMed2001

Enantio-specific induction of apoptosis by an endogenous neurotoxin, N-methyl(R)salsolinol, in dopaminergic SH-SY5Y cells: suppression of apoptosis by N-(2-heptyl)-N-methylpropargylamine.

Endogenous N-methyl(R)salsolinol, which caused parkinsonism in rats by injection in the striatum, was found to induce apoptosis in dopaminergic neuroblastoma SH-SY5Y cells. After 12-h incubation with 500[microM N-methyl(R)salsolinol, almost all the cells died with apoptosis and necrotic cell death was negligible. N-Methyl(R)salsolinol was much more potent to induce apoptosis than the (S)-enantiomer. The mechanism of apoptosis was studied in relation to changes in mitochondrial membrane potential, deltapsi(m), using a fluorescent indicator, JC-1. Red fluorescence of J-aggregates representing hyperpolarized deltapsi(m) was found to decrease significantly within 60 min after incubation with N-methyl(R)salsolinol, but not by the (S)-enantiomer at the same concentration. It suggests that mitochondria may recognize the stereo-chemical structure of N-methyl(R) salsolinol. Aliphatic propargylamines, (R)-N-(2-heptyl)-N-methylpropargylamine and (R)-N-(2-heptyl)propargylamine, were found to prevent deltapsim loss and subsequent apoptosis induced by N-methyl(R)salsolinol. These results suggest that mitochondria play a key role in the induction of apoptosis by the neurotoxin and the prevention by aliphatic propargylamines.

Alkynes↗
PubMed2001

Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol.

An endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, was found to induce apoptosis in human dopaminergic SH-SY5Y cells by step-wise activation of apoptotic cascade; collapse in mitochondrial membrane potential, DeltaPsim, activation of caspases, and fragmentation of DNA. Recently, accumulation of gylceraldehyde-3-phosphate dehydrogenase (GAPDH) in nuclei was proposed to play an important role in apoptosis. In this paper, involvement of GAPDH in apoptosis induced by N-methyl(R)salsolinol was studied. The isoquinoline reduced DeltaPsim within 3 h, as detected by a fluorescence indicator, JC-1, then after 16 h incubation, GAPDH accumulated in nuclei by detection with immunostaining. To clarify the role of GAPDH in apoptotic process, a stable cell line of Bcl-2 overexpressed SH-SY5Y cells was established. Overexpression of Bcl-2 prevented the decline in DeltaPsim and also apoptotic DNA damage induced by N-methyl(R)salsolinol. In Bcl-2 transfected cells, nuclear translocation of GAPDH was also completely suppressed. In addition, a novel antiparkinsonian drug, rasagiline, prevented nuclear accumulation of GAPDH induced by N-methyl(R)salsolinol in control cells. These results suggest that GAPDH may accumulate in nuclei as a consequence of signal transduction, which is antagonized by anti-apoptotic Bcl-2 protein family and rasagiline. The results are discussed in concern to intracellular mechanism underlying anti-apoptotic function of rasagiline analogues.

Active Transport, Cell Nucleus↗
PubMed2001

Isolated subscapularis tear from minimal trauma in a recreational athlete: a case report.

A 49-year-old male recreational weight lifter suffered an isolated partial tear of the subscapularis muscle after minimal trauma. His history was atypical for development of a subscapularis tear, which made his case more difficult to evaluate and subsequently treat. His recovery was uncomplicated and was facilitated by a physical therapy program to enhance rotator cuff strength and proprioception. This report includes a brief review of the literature on the etiology and management of these tears. This case emphasizes the importance of an appropriate physical examination and judicious use of imaging techniques so that uncommon disorders, even those with unusual presentations, can be diagnosed and managed to obtain good outcomes.

Humans↗
PubMed2001

Inhibition of rat liver microsomal CYP1A2 and CYP2B1 activity by N-(2-heptyl)-N-methyl-propargylamine and by N-(2-heptyl)-propargylamine.

(R)-N-(2-Heptyl)-N-methyl-propargylamine (R-2HMP) and (R)-N-(2-heptyl)-propargylamine (R-2HPA) are analogs of R-deprenyl. R-Deprenyl, a selective monoamine oxidase B inhibitor, is a mechanism-based inactivator of purified CYP2B1. The aim of the present study was to determine whether R-2HMP and R-2HPA behaved like deprenyl with respect to inhibiting cytochrome P450 (CYP450) enzyme activity. The activities of CYP1A2 and CYP1A1 were assessed by measuring the deethylation of 7-ethoxyresorufin by liver microsomes obtained from control and beta-naphthoflavone-treated female Wistar rats, respectively. CYP2B1 activity was assessed by measuring depentylation of 7-pentoxyresorufin by liver microsomes obtained from phenobarbital-treated rats. The activity of CYP1A1 was unaffected by 100 microM concentrations of R-deprenyl, R-2HMP, or R-2HPA. In contrast, the activities of CYP1A2 and CYP2B1 were significantly decreased. In general, the percentage of CYP1A2 activity remaining in the presence of 100 microM of one of these propargylamines ranged from 45 to 56%, whereas 10% or less of CYP2B1 activity remained. No marked differences between the various propargylamines were observed. The IC(50) values for the inhibition of CYP2B1 activity by R-deprenyl, R-2HMP, and R-2HPA were found to be 2.6, 8.5, and 3.6 microM, respectively. The S-enantiomers of deprenyl, 2HMP, and 2HPA also inhibited the activity of microsomal CYP2B1. R-2HMP, R-2HPA, and S-2HPA were found to be mechanism-based inactivators of CYP2B1 activity. The inactivation constants k(inact) and K(I) were found to be as follows: R-deprenyl, 1.3 microM and 0.32 min(-1); R-2HMP, 0.8 microM and 0.08 min(-1); R-2HPA, 0.5 microM and 0.36 min(-1); and S-2HPA, 0.24 microM and 0.18 min(-1).

Animals↗
PubMed2000

Long-term outcome of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in high-risk beta-thalassemia.

The optimal regimen of intravenous deferoxamine for iron overload in high-risk homozygous beta-thalassemia is unknown because only short-term follow-up has been described in small patient groups. We report the outcome over a 16-year period of a continuous 24-hour deferoxamine regimen, with dose adjustment for serum ferritin, delivered via 25 indwelling intravenous lines for 17 patients. Treatment indications were cardiac arrhythmias, left ventricular dysfunction, gross iron overload, and intolerability of subcutaneous deferoxamine. Cardiac arrhythmias were reversed in 6 of 6 patients, and the left ventricular ejection fraction improved in 7 of 9 patients from a mean (+/- SEM) of 36 +/- 2% to 49 +/- 3% (P =.002, n = 9). The serum ferritin fell in a biphasic manner from a pretherapy mean of 6281 +/- 562 microg/L to 3736 +/- 466 microg/L (P =.001), falling rapidly and proportionally to the pretreatment ferritin (r(2) = 0.99) for values >3000 microg/L but falling less rapidly below this value (at 133 +/- 22 microg/L/mo). The principal catheter-related complications were infection and thromboembolism (1. 15 and 0.48 per 1000 catheter days, respectively), rates similar to other patient groups. Only one case of reversible deferoxamine toxicity was observed (retinal) when the therapeutic index was briefly exceeded. An actuarial survival of 61% at 13 years with no treatment-related mortality provides evidence of the value of this protocol. (Blood. 2000;95:1229-1236)

Actuarial Analysis↗
PubMed2000

Pyridoxal supplementation reduces cell proliferation and DNA synthesis in estrogen-dependent and -independent mammary carcinoma cell lines.

In previous studies, decreased growth of tumor cells by vitamin B-6 treatment has been attributed to modulation of steroid hormone action. Therefore, the growth-inhibiting properties of pyridoxal (PL) supplementation were studied in estrogen receptor-positive, MCF-7 and T-47D, and estrogen receptor-negative, BT-20, breast cancer cell lines. Cell counting and [3H]thymidine incorporation into DNA were used to assess growth, and analysis of pS2 expression was used to determine whether PL supplementation affected estrogen action. Treatment with 100 or 300 mM PL resulted in dose-dependent decreases in total cell numbers in the absence (26-85% and 72-98%, respectively) and presence (38-42% and 88-98%, respectively) of estradiol in all cell lines studied compared with control cells cultured without PL supplementation. Similar decreases in DNA synthesis were observed in response to PL supplementation. Incorporation of [3H]thymidine into DNA of cells cultured with 100 or 300 microM PL was decreased by 30-90% and 96-99%, respectively, in the absence and by 32-40% and 82-99%, respectively, in the presence of estradiol. Northern analysis showed that expression of the estrogen-sensitive gene pS2 was not affected by either concentration of PL. These results indicate that PL supplementation regulates breast cancer cell growth in vitro via a mechanism that appears to be steroid independent.

Antineoplastic Agents↗
PubMed2000

Metabolism and pharmacokinetics, in the rat, of (R)-N-(2-Heptyl)Methyl-propargylamine (R-2HMP), a new potent monoamine oxidase inhibitor and antiapoptotic agent.

(R)-N-(2-Heptyl)-N-methylpropargylamine (R-2HMP) is a monoamine oxidase inhibitor and putative antiapoptotic agent analogous to (R)-deprenyl. In the rat, the major amine metabolites of R-2HMP have been identified as (R)-N-2-heptylmethylamine (R-2HMA), (R)-N-2-heptylpropargylamine (R-2HPA), and (R)-2-heptylamine (R-2HA). After R-2HMP was administered s.c. to male Wistar rats, it was observed that the greatest concentration was of the original drug followed in decreasing order by R-2HMA, R-2HPA, and R-2HA in brain, liver, and plasma at all times after administration. The greatest concentrations of the three metabolites were found in brain followed by liver and plasma, and the peak concentrations occurred between 15 and 30 min after administration. After oral administration, the liver contained the greatest concentrations of drug and metabolites, and, again, the peak concentrations occurred at about 15 min. In all cases, depropargylation appears to occur at a faster rate than demethylation. After s.c. administration, R-2HMP and its metabolites exhibited biexponential redistribution and elimination losses. Half-lives of the compounds in brain for the redistribution phase were: R-2HMP, 10 min; R-2HMA, 11 min; R-2HPA, 16 min; and R-2HA, 15 min.

Administration, Oral↗
PubMed1999

Femoral neck stress fracture presenting as gluteal pain in a marathon runner: case report.

A case is described of a 50-year-old man with a femoral neck stress fracture presenting as gluteal pain. An operative pinning procedure of the femoral neck was performed for stabilization. Femoral neck stress fractures are often misdiagnosed early in their presentation. The signs and symptoms can mimic those of more commonly seen disorders. Appropriate physiatric history and physical examination, along with indicated studies, will help prevent misdiagnosis and potentially serious complications associated with musculoskeletal pathology.

Athletic Injuries↗
PubMed1999

Inversion of selectivity of N-substituted propargylamine monoamine oxidase inhibitors following structural modifications to quaternary salts.

A number of N-substituted-propargylamines are well known mechanism-based MAO inhibitors. Clorgyline and deprenyl in fact represent archetypal MAO-A and MAO-B inhibitors respectively. In the present study several ring-substituted deprenyl structural analogues were synthesized and alterations of selectivity and potency towards MAO-A and MAO-B activities were found. When deprenyl and its structural analogues were further modified to their corresponding quaternary ammonium salts. i.e. by attaching either an extra propargyl or a methyl group to the nitrogen atom, the potency of inhibition of MAO-B activity was drastically reduced and inhibition of MAO-A activity substantially increased. Such a complete inversion of selectivity may be related to a hydrophilic and electrophilic region seemingly present only in the MAO-A but not in the MAO-B molecule. The results also suggest that at least three sites are required for the selectivity and mechanism-based action of an inhibitor towards MAO.

Amino Acid Sequence↗
PubMed1999

Patient satisfaction with nursing care in a rural and an urban emergency department.

This descriptive study was designed to describe and compare the level of patient satisfaction and explore differences and relationships of demographic variables with patient satisfaction in two emergency department patient populations in Victoria, Australia. The sample consisted of 103 rural and urban emergency patients. Tests for differences demonstrated that urban patients were more satisfied with nurse teaching behaviours (P = 0.017), with female patients at the urban hospital more satisfied with nurse caring behaviours (P = 0.026). An item, 'The nurse performed his/her duties with skill' scored highest and had the lowest variability. Qualitative analysis of two open-ended questions regarding what respondents liked best about the experience and what could have made the experience better, produced four and six themes, respectively. Conclusions indicated the need for more research comparing rural and urban emergency patients and patients of different cultures.

Adolescent↗
PubMed1999

Patient satisfaction with emergency department triage nursing care: a multicenter study.

This descriptive, correlational study examines relationships between (1) individual patient and nurse characteristics and (2) patient satisfaction with triage nursing care, patient satisfaction with the triage nurse, and patient's intention to return to a specific Emergency Department. The convenience sample consisted of Urgent/Delayed patients (N = 378) triaged in an urban academic medical center, a public hospital in a small city, and a Catholic hospital in a small city. Analysis of variance revealed significantly higher levels of patient satisfaction at the academic medical center, whereas higher levels of intent to return were reported by subjects from the Catholic-affiliated hospital. Educational preparation of the triage nurse was identified as a significant predictor of both patient satisfaction with triage nursing care and loyalty to a specific.

Adult↗
PubMed1999

Litter effects on caries in rats and implications for experimental design.

The purpose of this study was to obtain quantitative estimates of litter effects on caries development in rats and to examine the implications for design of rat caries experiments. Twelve female Sprague-Dawley rats, aged 60 days, were bred with 4 male rats. Nine of the 12 dams had litters in close proximity. The litters were culled to 10 pups. One pup from each litter was placed with each of the other dams for nursing, leaving 2 pups from each litter with the birth dam. This design allowed the litter effect to be separated into a prenatal component, reflecting the shared genetic makeup and in utero environment of littermates, and a postnatal component reflecting a shared environment from shortly after birth to weaning. Pups were infected with Streptococcus sobrinus and fed Diet 2000 and 10% (w/v) sucrose water for 5 weeks. There was no significant evidence of a postnatal litter effect for smooth surface caries (p = 0.37) or sulcal caries (p = 0.43). The prenatal litter effect was significant for both smooth surface caries and sulcal caries (p<0. 01). When litter effects are present, the statistical power of caries studies is improved if animals from the same litter are divided evenly among experimental groups. In addition, if litter effects are present but not allowed for in data analysis, incorrect statistical inferences may be drawn. Based on our results and other reports of litter effects, we recommend planning for litter effects in the design and analysis of rat caries studies.

Animals↗