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Biomedical subjects

D Reynolds

Publications and source records attributed to D Reynolds.

At least 37 records · Page 2Linked to original sources
PubMed1999

Conventional and extended-release etodolac for postsurgical dental pain.

This double-masked, parallel-group, randomized study compared the analgesic efficacy and tolerability of a single investigational 1200-mg dose of extended-release etodolac with those of a single 400-mg dose of extended-release etodolac and twice-daily doses of conventional etodolac 200 and 400 mg and placebo given 8 hours apart in 237 patients with moderate or severe postoperative pain following surgical removal of > or = 2 impacted third molars. Both doses of conventional etodolac and the 1200-mg dose of extended-release etodolac were significantly more effective on all summary analgesic measures than placebo (P < 0.05). Conventional etodolac had an onset of analgesic activity within 45 (400 mg) to 60 (200 mg) minutes and an analgesic duration of 5 to 6 hours. Extended-release etodolac 1200 mg had an onset of action within 60 minutes and an analgesic duration of 12 to 24 hours. At hours 2 and 3, conventional etodolac 400 mg was significantly more effective than the other treatments; from hours 6 through 12, extended-release etodolac 1200 mg was significantly more effective than the other treatments (both, P < 0.05). No serious adverse events were observed in this study, with an incidence of side effects in the active etodolac groups no different than that with placebo. Extended-release etodolac 1200 mg has a prolonged analgesic duration and an acceptable side-effect profile in the oral surgery pain model.

Adult↗
PubMed1999

Mutations in autosomal dominant polycystic kidney disease 2 gene: Reduced expression of PKD2 protein in lymphoblastoid cells.

The polycystic kidney disease 2 (PKD2) gene, encoding a 968-amino acid integral membrane protein with six predicted membrane-spanning domains and intracellular NH2 and COOH termini, is mutated in approximately 15% of the cases of autosomal dominant polycystic kidney disease (ADPKD), a common genetic disease frequently resulting in renal failure. For a better understanding of the cause of this disorder, we searched for mutations in the PKD2 gene in two PKD2-linked families characterized by different clinical phenotypes. A common polymorphism, a nonsense mutation, and a frameshift mutation were found. Both mutations are predicted to produce truncated proteins of 314 and 386 amino acids, arrested at the first extracellular loop of the protein. Restriction enzyme analysis of polymerase chain reaction (PCR) and reverse transcriptase (RT)-PCR products, respectively, showed that mutations cosegregated with the disease and mutated alleles were expressed at the messenger RNA level in lymphoblastoid cell lines. However, in these cells, Western blot analysis showed only PKD2 normal protein, and it was expressed at a lower level than that found in cells without the PKD2 mutation. These findings suggest that in lymphoblastoid cells, the truncated protein product of the mutant allele may not be stable.

Aged↗
PubMed1999

PBA increases CFTR expression but at high doses inhibits Cl(-) secretion in Calu-3 airway epithelial cells.

Sodium 4-phenylbutyrate (PBA), a short-chain fatty acid, has been approved to treat patients with urea cycle enzyme deficiencies and is being evaluated in the management of sickle cell disease, thalassemia, cancer, and cystic fibrosis (CF). Because relatively little is known about the effects of PBA on the expression and function of the wild-type CF transmembrane conductance regulator (wt CFTR), the goal of this study was to examine the effects of PBA and related compounds on wt CFTR-mediated Cl(-) secretion. To this end, we studied Calu-3 cells, a human airway cell line that expresses endogenous wt CFTR and has a serous cell phenotype. We report that chronic treatment of Calu-3 cells with a high concentration (5 mM) of PBA, sodium butyrate, or sodium valproate but not of sodium acetate reduced basal and 8-(4-chlorophenylthio)-cAMP-stimulated Cl(-) secretion. Paradoxically, PBA enhanced CFTR protein expression 6- to 10-fold and increased the intensity of CFTR staining in the apical plasma membrane. PBA also increased protein expression of Na(+)-K(+)-ATPase. PBA reduced CFTR Cl(-) currents across the apical membrane but had no effect on Na(+)-K(+)-ATPase activity in the basolateral membrane. Thus a high concentration of PBA (5 mM) reduces Cl(-) secretion by inhibiting CFTR Cl(-) currents across the apical membrane. In contrast, lower therapeutic concentrations of PBA (0.05-2 mM) had no effect on cAMP-stimulated Cl(-) secretion across Calu-3 cells. We conclude that PBA concentrations in the therapeutic range are unlikely to have a negative effect on Cl(-) secretion. However, concentrations >5 mM might reduce transepithelial Cl(-) secretion by serous cells in submucosal glands in individuals expressing wt CFTR.

Butyrates↗
PubMed1999

Butyrate increases apical membrane CFTR but reduces chloride secretion in MDCK cells.

Sodium butyrate and its derivatives are useful therapeutic agents for the treatment of genetic diseases including urea cycle disorders, sickle cell disease, thalassemias, and possibly cystic fibrosis (CF). Butyrate partially restores cAMP-activated Cl(-) secretion in CF epithelial cells by stimulating DeltaF508 cystic fibrosis transmembrane conductance regulator (DeltaF508-CFTR) gene expression and increasing the amount of DeltaF508-CFTR in the plasma membrane. Because the effect of butyrate on Cl(-) secretion by renal epithelial cells has not been reported, we examined the effects of chronic butyrate treatment (15-18 h) on the function, expression, and localization of CFTR fused to the green fluorescent protein (GFP-CFTR) in stably transfected MDCK cells. We report that sodium butyrate reduced Cl(-) secretion across MDCK cells, yet increased apical membrane GFP-CFTR expression 25-fold and increased apical membrane Cl(-) currents 30-fold. Although butyrate also increased Na-K-ATPase protein expression twofold, the drug reduced the activity of the Na-K-ATPase by 55%. Our findings suggest that butyrate inhibits cAMP-stimulated Cl(-) secretion across MDCK cells in part by reducing the activity of the Na-K-ATPase.

Animals↗
PubMed1999

A PDZ-interacting domain in CFTR is an apical membrane polarization signal.

Polarization of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel, to the apical plasma membrane of epithelial cells is critical for vectorial transport of chloride in a variety of epithelia, including the airway, pancreas, intestine, and kidney. However, the motifs that localize CFTR to the apical membrane are unknown. We report that the last 3 amino acids in the COOH-terminus of CFTR (T-R-L) comprise a PDZ-interacting domain that is required for the polarization of CFTR to the apical plasma membrane in human airway and kidney epithelial cells. In addition, the CFTR mutant, S1455X, which lacks the 26 COOH-terminal amino acids, including the PDZ-interacting domain, is mispolarized to the lateral membrane. We also demonstrate that CFTR binds to ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50), an apical membrane PDZ domain-containing protein. We propose that COOH-terminal deletions of CFTR, which represent about 10% of CFTR mutations, result in defective vectorial chloride transport, partly by altering the polarized distribution of CFTR in epithelial cells. Moreover, our data demonstrate that PDZ-interacting domains and PDZ domain-containing proteins play a key role in the apical polarization of ion channels in epithelial cells.

Amino Acid Sequence↗
PubMed1999

Retroversion of the acetabulum. A cause of hip pain.

We describe a little-known variety of hip dysplasia, termed 'acetabular retroversion', in which the alignment of the mouth of the acetabulum does not face the normal anterolateral direction, but inclines more posterolaterally. The condition may be part of a complex dysplasia or a single entity. Other than its retroversion, the acetabulum is sited normally on the side wall of the pelvis, and its articular surface is of normal extent and configuration. The retroverted orientation may give rise to problems of impingement between the femoral neck and anterior acetabular edge. We define the clinical and radiological parameters and discuss pathological changes which may occur in the untreated condition. A technique of management is proposed.

Acetabulum↗
PubMed1999

Development of a finite element model of a transtibial socket liner--an initial study.

A number of computer models of limb loading by lower limb prostheses have been developed to date, however their accuracy and clinical usefulness is somewhat debatable. This paper is the first in a series describing investigations into the behaviour of a transtibial socket under compressive loading. The work focuses upon the socket liner and its role in reducing and redistributing stresses within the socket. This initial study used non-linear finite element analysis to replicate the effect of pressure loading on a polyurethane socket liner in the region of a bony prominence. It is a first step in understanding the load transfer between the residual limb, socket liner and socket of a transtibial prosthesis. The Mooney Rivlin material model [1] was used to simulate the polyurethane socket liner and compression tests in accordance with BS903 [2] were performed to gain the necessary data to calculate the Mooney Rivlin constants. Experimental validation showed that a very accurate, large-strain representation of the material was achieved. Future work will model more complex, three-dimensional geometries.

Artificial Limbs↗
PubMed1998

Exposure-based safety evaluation of recombinant human macrophage colony-stimulating factor (M-CSF) in cynomolgus monkeys.

The safety of M-CSF was assessed in cynomolgus monkeys in an intravenous dosing regimen. Exposure (AUC0-24) multiples (monkey vs human) were calculated using the no observable adverse effect level (NOAEL) observed in this study and correlated with known M-CSF-induced toxicities in a previous continuous intravenous infusion (civ) study in monkeys. M-CSF was administered by daily intravenous infusion (2 h) to cynomolgus monkeys (2/sex/ group) at 0.1, 0.3, 0.7, and 1.0 mg/kg/day, for 28 consecutive days. Control animals (2/sex) received placebo. The 0.7 mg/kg/day group was held for an additional 4-week recovery period. Criteria evaluated included physical observations, ophthalmoscopy, electrocardiography, body weight, food consumption, clinical pathology, antibody formation, pharmacokinetics, necropsy, organ weights, and histopathology. The only effect previously seen in monkeys after intravenously administered M-CSF occurred in animals in the 0.7 and 1.0 mg/kg/day groups. They exhibited a slight decrease in platelets between days 4 and 12 with subsequent recovery. No effects related to M-CSF administration were evident in macroscopic or microscopic evaluations and there was no evidence of anti-M-CSF antibody production. M-CSF at all dose levels was completely eliminated within each dosing interval with no accumulation. Clearance of M-CSF was enhanced during the first week of dosing, but returned to baseline clearance levels by day 27. This dosing regimen was shown to be remarkably free of toxicities noted in a previous monkey study where M-CSF was given by civ at similar daily doses. At the high dose, which was considered to be the NOAEL, the AUC0-24 was 40-fold greater than the AUC0-24 in clinical trials where 2.0 mg/m2 was administered by a daily 2-h infusion.

Animals↗
PubMed1998

The contributions of Dr. Roswell Park to epilepsy and spinal surgery.

ROSWELL PARK, M.D., (1852-1914) is remembered for founding the world's first cancer institute that now bears his name a century ago, The Roswell Park Cancer Institute, and for an unfortunate association with the mortal wounding of President William McKinley in Buffalo, NY, in 1901. Park's accomplishments as a pioneer American neurosurgeon have been overlooked. After Park was appointed as Chair of Surgery at the University of Buffalo in 1884, he became the first American surgeon to precisely localize and remove a posttraumatic epileptic focus in the absence of external scars in 1886. Park introduced American physicians and surgeons to David Ferrier's research on localization of cerebral cortical function and Victor Horsley's techniques for extirpating epileptic foci. In 1895, Park became the first American surgeon to successfully treat spina bifida. In the same year, he wrote the first American monograph on surgery of the head. Park's case reports of successful operations on patients deemed almost incurable reveal boldness and ingenuity. Park's untimely death truncated a promising career.

Epilepsy↗
PubMed1996

Renal ischemic-reperfusion injury in L-selectin-deficient mice.

L-selectin on leukocyte surfaces mediates cell rolling on endothelium. L-selectin blockade with antibodies attenuated ischemic-reperfusion injury (IRI) in heart and skeletal muscle, but its role in renal IRI is unknown. We evaluated the role of L-selectin in renal IRI using L-selectin-deficient mice. Neutrophil migration to chemically inflamed peritoneum was reduced by 47% (P < 0.01) in L-selectin-deficient mice. Ischemia was induced by bilateral renal pedicle clamping for 30 min. Control and L-selectin groups had similar elevations of serum creatinine (1.8 +/- 0.3 vs. 1.7 +/- 0.2 mg/dl) and blood urea nitrogen (111 +/- 17 vs. 128 +/- 12 mg/dl) 24 h postischemia. Pathological assessment showed comparable degrees of tubular necrosis at 24 h. The postischemic increase in peritubular neutrophils per 10 high-power field was similar in control and L-selectin-deficient groups at 4 (28 +/- 10 vs. 22 +/- 5), 12 (245 +/- 80 vs. 236 +/- 78), and 24 h (130 +/- 12 vs. 156 +/- 18). These data argue against a significant role for L-selectin in renal IRI. Patho-physiological roles of L-selectin in vivo appear to be more complex than in vitro data would suggest.

Animals↗
PubMed1996

Application of a new technology to the design of effective anti-vibration gloves.

Gloves that attenuate vibration above approximately 25 Hz and that exceed the characteristics of standard viscoelastic gloves have been developed using an air bladder system in the palm and fingers of a glove. Testing was performed on a variety of viscoelastic gloves currently marketed to obtain the ratio of energy leaving the handle of a vibrating device and the energy entering the hand. Several simple rectangular air bladders of varying thickness were developed and tested for their vibration attenuating characteristics. A four degree-of-freedom, lumped-parameter model of the vibration response of the human and air bladder was developed using measured hand and bladder parameters. This model, along with subjective criteria, was used to design and fabricate two prototype air bladder gloves. These gloves were tested and found to exceed adopted standard requirements and the characteristics of standard viscoelastic gloves. The prototypes in this study will be further developed, adapted and marketed for practical applications.

Air↗
PubMed1995

Steroid elution improves the stimulation threshold in an active-fixation atrial permanent pacing lead. A randomized, controlled study. Model 4068 Investigators.

BACKGROUND: Prior work suggests that the addition of a steroid-eluting reservoir to a passive-fixation permanent pacemaker lead improves the stimulation threshold; however, no large randomized study has addressed this tissue. Over the last several years, there has been an increase in enthusiasm for the use of active-fixation permanent pacemaker leads for various reasons in spite of the generally accepted notion that active-fixation leads have higher stimulation thresholds. METHODS AND RESULTS: This multicenter, randomized, controlled study examined the difference in performance between a standard active-fixation atrial lead (Medtronic model 4058) and a steroid-eluting lead (Medtronic model 4068). Stimulation thresholds were obtained in a four-point strength-duration fashion. Evaluations of sensing and impedance were performed as well. These evaluations were performed at implantation, at weeks 1 through 4, and at weeks 6, 12, 24, and 52. Stimulation thresholds were significantly better in the steroid lead than in the nonsteroid lead at each measurement point from 1 week to 12 months. The mean 1.6-V stimulation threshold at 12 months was 0.19 +/- 0.2 ms in the steroid lead and 0.41 +/- 0.30 ms in the control lead. No acute peaking was observed with the steroid lead, whereas significant peaking was observed with the control lead. There was no difference in long-term sensing or impedance. CONCLUSIONS: Inclusion of a steroid-eluting reservoir in an active-fixation permanent pacing lead improved stimulation thresholds in both the subacute and chronic periods and therefore should extend pulse-generator longevity.

Aged↗
PubMed1995

Prevalence of antibodies to Toxoplasma gondii in swine in Illinois in 1992.

A serologic survey that tested for antibodies to Toxoplasma gondii was conducted, using the modified direct agglutination test, on 6,965 serum samples collected from swine in 179 herds in Illinois in 1992. In breeding swine, results for 1,057 of 5,080 (20.8%) sera tested were positive. In growing/finishing swine, results for 59 of 1,885 (3.1%) sera tested were positive, which was substantially lower than the seroprevalence rate estimated in a serosurvey of pigs from abattoirs in Illinois in 1983 and 1984. Data in the survey reported here were summarized for herds having at least 28 samples/herd. Among all herds, the median, mean, and maximum seroprevalence rates were 6.7, 16.1, and 96.8%, respectively, for breeding swine in 172 herds, and 0.0, 2.8, and 20.0%, respectively, for growing/finishing pigs in 44 herds. Among the 172 herds with breeding swine, 61 (35.5%) had no seropositive pigs. Among the 44 herds with growing/finishing swine, 28 (63.6%) had no seropositive pigs. A logistic regression model was used to estimate that the cumulative risk of T gondii infection for swine in herds containing seropositive pigs was 9.0% by 6 months of age for a herd that had the median seroprevalence rate. In contrast, for pigs in herds in the upper quartile of seroprevalence rates, risk of infection by 6 months of age was estimated to be greater than 20%. Analysis of these data would suggest that overall prevalence of T gondii infection in pigs from Illinois is low; nevertheless, there is a small proportion of farms for which the rate of T gondii infection in swine is moderately high.

Age Factors↗
PubMed1995

Pharmacokinetics and pharmacodynamics of the monoamine oxidase B inhibitor mofegiline assessed during a phase I dose tolerance trial.

The safety, pharmacokinetics, and pharmacodynamics of single oral doses of up to 48 mg and daily (for 28 days) doses of up 24 mg mofegiline were investigated in healthy male volunteers. Plasma pharmacokinetics indicated rapid absorption and elimination: time to reach maximum concentration occurred at about 1 hour; half-life ranged from 1 to 3 hours. Maximal plasma concentration and area under the plasma concentration-time curve increased and oral clearance decreased disproportionately with dose. Mofegiline rapidly and markedly inhibited platelet monoamine oxidase B (MAOB) activity, which returned to baseline within 14 days. Urinary excretion of phenylethylamine increased proportionately with doses up to 24 mg. No changes in urinary elimination of catecholamines, blood pressure, heart rate, or ECG were observed. A classic maximum tolerated dose was not achieved in these studies. However, the 48 mg single dose and the 24 mg multiple daily dose far exceeded the dose (1 mg) that was associated with > 90% platelet MAOB inhibition.

Administration, Oral↗