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Biomedical subjects

R A Smith

Publications and source records attributed to R A Smith.

At least 19 recordsLinked to original sources
PubMed2006

The isozyme-specific effects of cyclooxygenase-deficiency on bone in mice.

Prostaglandin E(2) (PGE(2)) plays a critical role in skeletal physiology and bone loss. PGE(2) production is regulated in vivo by at least two cyclooxygenase (COX) isozymes, COX-1 and COX-2. The purpose of this study was to investigate the in vivo effects of the selective deletion of COX-1 or COX-2 on bone mineral density (BMD), bone microarchitecture and bone strength in wild type (WT), COX-1(-/-) and COX-2(-/-) mice. Using a LUNAR PIXImus, BMD was measured in 18 (WT), 18 COX-1(-/-) and 16 COX-2(-/-) mice. COX-1(-/-) mice exhibited significantly higher BMD (0.0506 g/cm(2) +/- 0.0014 g/cm(2)) than either WT (0.0493 g/cm(2) +/- 0.0019, P < or = 0.05) or COX-2(-/-) (0.0473 g/cm(2) +/- 0.0034, P < or = 0.01) mice. COX-2(-/-) mice had significantly lower BMD than WT (P < or = 0.01) or COX-1(-/-) (P < or = 0.01). Flexure stress of the femurs, determined by breaking the bones with three-point bending, correlated with bone density. Although plasma levels of both Ca(2+) and PTH were comparable in wild type and COX-1(-/-) mice, both were elevated in COX-2(-/-) mice consistent with primary hyperparathyroidism. These studies suggest that COX enzymes are important regulators of BMD and bone strength in mice. The beneficial effect of absence of the COX-1 enzyme on skeletal parameters may be secondary to decreases in PGE(2). On the other hand, primary hyperparathyroidism and lower bone magnesium content may account for the lower BMD and impairments in bone strength of COX-2(-/-) mice. Further elucidation of the effects of the COX pathway on bone remodeling may provide important information on potential therapeutic targets for preventing and/or treating osteoporosis.

Animals↗
PubMed2006

Probing proton dynamics in molecules on an attosecond time scale.

We demonstrate a technique that uses high-order harmonic generation in molecules to probe nuclear dynamics and structural rearrangement on a subfemtosecond time scale. The chirped nature of the electron wavepacket produced by laser ionization in a strong field gives rise to a similar chirp in the photons emitted upon electron-ion recombination. Use of this chirp in the emitted light allows information about nuclear dynamics to be gained with 100-attosecond temporal resolution, from excitation by an 8-femtosecond pulse, in a single laser shot. Measurements on molecular hydrogen and deuterium agreed well with calculations of ultrafast nuclear dynamics in the H2+ molecule, confirming the validity of the method. We then measured harmonic spectra from CH4 and CD4 to demonstrate a few-femtosecond time scale for the onset of proton rearrangement in methane upon ionization.

Journal Article↗
PubMed2006

Expression of the mouse fragilis gene products in immune cells and association with receptor signaling complexes.

The mouse genome possesses five genes encoding proteins homologous to human Leu-13. The Leu-13 protein associates with immune cell receptor activation complexes: a monoclonal antibody against Leu-13 induces T and B cells to form homotypic aggregates, inhibits activation-induced proliferation and induces the shedding of L-selectin. The mouse fragilis proteins have not been previously analyzed as components of the immune response. Antibody and nucleic acid reagents were generated that are specific for each of the five fragilis gene products. Expression of some of these genes (fragilis and fragilis3) is wide spread in a variety of mouse immune (and nonimmune) tissues while others (fragilis5) appear to be much more restricted. These proteins have been predicted to span the membrane twice with both amino- and carboxyl-terminal sequences extracellular: we show that a highly conserved loop of the protein between the transmembrane domains is intracellular. The fragilis proteins are associated with tetraspanin proteins CD81 and CD9: B cell activation positions fragilis into lipid rafts along with the CD81, CD19, and CD21. The mouse functional equivalent to human Leu-13 may not be single gene product, but instead may require the contribution of multiple fragilis proteins.

Amino Acid Sequence↗
PubMed2005

Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients.

MECP2 mutations are identifiable in approximately 80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis, but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using multiplex ligation dependent probe amplification or quantitative fluorescent PCR. Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193; p<0.0001). Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.

Adolescent↗
PubMed2005

Vitamin E supplementation of newly arrived feedlot calves.

Seven hundred fifteen crossbred (primarily British) calves purchased in southern Oklahoma and northern Texas auction barns were received at the Willard Sparks Beef Research Center, Stillwater, OK, and used to study effects of duration (days) of vitamin E feeding during a 42-d receiving period on animal performance, health, and serum cholesterol and vitamin E concentrations. Upon arrival, calves were blocked by load (seven loads), sorted by BW (light, n = 4 pens per load; and heavy, n = 4 pens per load), and assigned randomly to one of four dietary treatments (n = 2 pens per load; 14 pens per treatment). Experimental diets were formulated to provide 2,000 IU.calf(-1).d(-1) of supplemental vitamin E (dl-alpha-tocopherol acetate) for 0 (CON), 7 (E7), 14 (E14), or 28 (E28) d. Vitamin E was delivered in a pelleted supplement that was added to the basal diet in decreasing concentrations as DMI increased (2.0 kg of DMI = 6%; 4.0 kg of DMI = 4%; and 6.0 kg of DMI = 2%). Serum samples were collected on d 0, 14, 28, and 42 for determination of cholesterol, alpha-tocopherol (d 0, 28, and 42), and antibody (IgG) concentrations. Duration of vitamin E supplementation did not affect ADG (0.98 kg/d; P = 0.56) or G:F (0.189; P = 0.87). Serum cholesterol concentrations decreased (day effect; P < 0.001) for all treatments from d 0 (average = 127 mg/100 mL) to 14 (average = 62 mg/100 mL). Serum alpha-tocopherol decreased (day effect; P < 0.001) from d 0 (5.2 microg/mL) to 28 (1.8 microg/mL); however, on d 28, a greater (P < 0.001) serum alpha-tocopherol concentration was observed for E28 (3.4 microg/mL) calves than for CON (1.1 microg/mL), E7 (1.2 microg/mL), or E14 (1.5 microg/mL) calves. Respiratory disease was diagnosed in 64.6% of calves in this study. Medical costs were less (P = 0.08) for calves fed vitamin E for 28 d (4.88 dollars/calf) than for calves fed the control diet (6.29 dollars/calf). Carcass characteristics were not affected (P = 0.19 to 0.88) by dietary treatments. Supplemental vitamin E formulated for 2,000 IU.calf(-1).d(-1) had little influence on performance and overall health status of calves under our experimental conditions; however, the increased serum concentrations of alpha-tocopherol when vitamin E was fed for 28 d suggests that any potential effects of vitamin E on health status might be time-dependent.

Animal Feed↗
PubMed2005

Risk factors, prevention and treatment of hypertension in pregnancy.

Hypertensive diseases in pregnancy are common and are associated with significant maternal and perinatal mortality and morbidity. Risk factors for pre-eclampsia include socio-demographical factors (extremes of reproductive age, socio-economic status, ethnic group), genetic factors, pregnancy factors (multiple pregnancies, primigravidae, previous pre-eclampsia) or personal medical history (obesity, chronic renal disease, chronic hypertension, diabetes mellitus, thrombophilia). These risk factors and Doppler screening can help target interventions such as aspirin and calcium that have been proven to reduce the incidence of pre-eclampsia in high risk women. Expectant management is the mainstay of treatment for pre-eclampsia. Hypertension should be controlled by oral or intravenous antihypertensive agents as necessary. Magnesium sulphate is the agent of choice for both the treatment and prevention of eclampsia. Fluid balance and thromboprophylaxis are also both important elements in the management of severe pre-eclampsia.

Administration, Oral↗
PubMed2004

Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial.

BACKGROUND: Patients with ALS commonly exhibit pseudobulbar affect. METHODS: The authors conducted a multicenter, randomized, double-blind, controlled, parallel, three-arm study to test a defined combination of dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) (AVP-923) for the treatment of pseudobulbar affect in ALS. Q inhibits the rapid first-pass metabolism of DM. The effects of AVP-923 (30 mg of DM plus 30 mg of Q) given twice daily for 28 days were compared with those of its components. Patients were evaluated on days 1, 15, and 29. The primary efficacy variable was the change from baseline in the Center for Neurologic Study Lability Scale (CNS-LS) score. Secondary efficacy variables were laughing/crying episode rates and changes in Visual Analog Scales for Quality of Life (QOL) and Relationships (QOR). Efficacy was evaluated in intention-to-treat subjects who were not poor metabolizers of DM (n = 65 for AVP-923, n = 30 for DM, and n = 34 for Q). Safety was assessed in all randomized subjects (n = 140). RESULTS: AVP-923 patients experienced 3.3-point greater improvements in CNS-LS than DM patients (p = 0.001) and 3.7-point greater improvements than Q patients (p < 0.001). AVP-923 patients exhibited lower overall episode rates, improved QOL scores, and improved QOR scores (p < 0.01 for all endpoints). Adverse effects were mostly mild or moderate; treatment-related discontinuation was 24% for AVP-923, 6% for DM, and 8% for Q. CONCLUSIONS: AVP-923 palliates pseudobulbar affect in ALS. Overall benefits of treatment are reflected in fewer episodes of crying and laughing and improvements in overall quality of life and quality of relationships.

Adult↗
PubMed2004

Fast-ion production from short-pulse irradiation of ethanol microdroplets.

We report on the first detailed measurements of ion energy distributions from microdroplet targets under ultrashort (100 fs), intense (10(16) Wcm(-2)) laser irradiation. Protons with kinetic energies of up to 20 keV are produced in a strongly anisotropic microexplosion. Modeling of the incident electromagnetic field indicates strong spatial variations over the surface of the microdroplet. Detailed numerical modeling shows that nonuniform heating on a submicron scale causes temperature inhomogeneities and nonradial pressure gradients, which drive an energetic nonspherical expansion.

Journal Article↗
PubMed2004

How can paediatric epilepsy services best be delivered in secondary care?

OBJECTIVE: To produce practical evidence-based guidelines for the management of paediatric epilepsy in secondary care settings. DESIGN: Question-specific systematic literature review and local service audit. MAIN OUTCOME MEASURES: Grade of recommendation for specific management issues. RESULTS: There is little good quality research to support many existing epilepsy guidelines for secondary care. CONCLUSION: Practical guidelines for the provision of children's epilepsy services can be evidence influenced but until more relevant research is undertaken, not evidence based.

Adolescent↗
PubMed2004

Quantitation and kinetics of CD51 surface receptor expression: implications for targeted delivery.

The CD51 integrin subunit is important in many functions ranging from mediation of adenovirus attachment and internalization to facilitation of angiogenesis. CD51 has also gained interest as an attractive ligand for directed therapy studies, including those for targeted gene delivery. While the function and importance of several CD51-specific targeting molecules have been examined, studies are often carried out without quantitative assessment of the receptor. A lack of this data complicates further mathematical analysis of targeting data and elucidation of the mechanism(s) underlying specific targeting. We performed a quantitative evaluation of CD51 receptors on the surface of HeLa cells, a common cell line utilized in many receptor-based studies, and compared them to other similar and dissimilar cell types. Unstimulated HeLa cells strongly express the CD51 receptor at a level of 212,700 +/- 12,000 (mean +/- SD) antibody binding capacity (ABC) cell(-1) (n = 3). Following irradiation with 3 Gy, receptor expression increases dramatically, peaking at a value of 403,700 +/- 26,400 (n = 4). The utility of this quantitative information is highlighted by the application of our data to targeting studies from the literature. Taken together, the results yield more detailed information than is available with experimental targeting data alone.

Adaptation, Physiological↗
PubMed2004

Number needed to screen: lives saved over 20 years of follow-up in mammographic screening.

OBJECTIVE: To estimate the number needed to screen with mammography to save one life, based on a stated amount of screening activity and long-term follow-up for breast cancer death. SETTING: A randomised controlled trial of mammographic screening for breast cancer, with 77,080 women invited to screening and 55,985 not invited. The invited group was offered screening for seven years. Follow-up continued for a total of just over 20 years. METHODS: Number needed to screen for seven years to save one life over 20 years was calculated by dividing the number screened (not the number invited) by the total number of lives saved. Similarly, we calculated the number of mammographic examinations required to save one life. RESULTS: We estimate that the number of women needed to screen for seven years to save one life over 20 years is 465 (95% CI 324-819). The number of mammographic examinations needed to save one life was 1499 (95% CI 1046-2642). CONCLUSIONS: The number needed to screen to save one life is smaller than has been reported in the past. Mammographic screening is effective in absolute terms as well as relative. Long-term follow-up allowed us to estimate the absolute benefit with greater accuracy.

Adult↗
PubMed2004

Cell-based screening: a high throughput flow cytometry platform for identification of cell-specific targeting molecules.

Targeting of drugs and genes to specific cell types is an emerging paradigm in the treatment of many medical conditions. However, targeting structures such as peptides are susceptible to rapid inactivation in vivo. To address this problem, novel targeting molecules can now be rapidly synthesized using a combinatorial approach. Methods to screen the large libraries created in this process are often lacking or compatible only with solution-based screening. This report describes a high-throughput cell-based method utilizing flow cytometry, capable of rapidly screening large libraries of molecules simultaneously for biological functionality and stability. In this method, each library molecule is attached to a microsphere exhibiting a unique set of optical properties, or "fingerprint", conferring modularity and multiplex capability. We investigated the multiplex capability of our flow cytometric method to determine its capacity for high-throughput screening. Current instrumentation in our laboratory allows the screening of at least 75 unique compounds in a single well, a number comparable to available solution-based assays. In state-of-the-art configuration, however, this methodology can support the screening of up to 1875 compounds per well, achieving high-throughput potential in a single multiwell plate. We also investigated the binding capability of targeted microspheres to adherent target cells. These microspheres exhibited a 12-fold increase in binding over control, untargeted microspheres. Competitive inhibition experiments with soluble ligand confirmed the specificity of microsphere binding. Overall, the methodology proposed here is capable of quickly and effectively screening large libraries of targeting molecules using instrumentation readily available to the greater research community.

Antibodies, Monoclonal↗
PubMed2004

Effects of dietary energy and starch concentrations for newly received feedlot calves: I. Growth performance and health.

Crossbred calves (n = 572; initial BW = 186 +/- 27 kg) purchased from northern Texas, Arkansas, and southeast Oklahoma auction markets were delivered to the Willard Sparks Beef Research Center, Stillwater, OK, and used to study the effects of dietary energy and starch concentrations on performance and health of newly received feedlot calves during a 42-d receiving period. On arrival, calves were assigned randomly to one of two dietary energy levels (0.85 or 1.07 Mcal NEg/kg DM) and one of two dietary starch levels (34 or 48% of ME from starch) in a 2 x 2 factorial arrangement of treatments. Cattle were weighed and serum samples were collected on d 0, 7, 14, 28, and 42. Individual animal records of morbidity were kept for all cases of respiratory and other disease. Nasal swabs were collected from each morbid animal and cultured for upper-respiratory pathogens. There were no energy x starch level interactions for performance or health response variables. Daily gain (1.14 kg/d) and gain efficiency (ADG:DMI = 0.179) were not affected by increasing dietary energy or starch concentrations. Calves fed low-energy diets consumed (P < 0.05) more DM. No difference (P = 0.54) was detected in morbidity for calves fed high-energy (62.4% calves treated) compared with low-energy (65.8% calves treated) diets; however, calves fed the high-starch diets had numerically (P = 0.11) greater morbidity than calves fed low-starch diets (68.8 vs. 59.4% calves treated, respectively). There were no energy or starch effects on Mannheimia haemolytica or Pasteurella multocida antibody titers; however, day effects (P < 0.02) occurred. On d 7, 14, and 28, calves had antibody titers for P. multocida that were greater (P < 0.05) than titers on d 0. In addition, calves had greater antibody titers to M. haemolytica on d 7 and 14 than on d 0. Nasal swabs revealed that calves fed the high-energy diets tended (P = 0.06) to have a lower percentage of morbid calves with P. multocida during the first antimicrobial treatment and a lower percentage of Haemophilus somnus isolates during the first (P = 0.01) and second (P = 0.06) antimicrobial treatments than calves fed the low-energy diets. Although animal performance was not influenced, the present data suggest that feeding the high-energy diet decreased the percentage of P. multocida and H. somnus pathogens in calves that received one or more antimicrobial treatments.

Animal Feed↗
PubMed2004

Effects of dietary energy and starch concentrations for newly received feedlot calves: II. Acute-phase protein response.

Two hundred forty five market-stressed bull and steer calves (205 +/- 14 kg) were received in January and September 2001 to determine the response of acute-phase proteins to dietary energy and starch concentrations and to determine whether acute-phase proteins could be used as a diagnostic or prognostic tool for calves affected by bovine respiratory disease. On arrival, calves were randomly assigned to one of two dietary energy levels (0.85 or 1.07 Mcal of NEg/kg of DM) and one of two dietary starch levels (34 or 48% of dietary ME from starch; n = 5 pens/treatment). All calves were weighed, and plasma and serum samples were collected from a subset of animals (n = 6 calves/pen; 30 calves/treatment) on d 0, 7, 14, 28, and 42 of the receiving period. This subset of calves (n = 120) was used for all subsequent analyses. Concentrations of fibrinogen (Fb), haptoglobin (Hp), and serum amyloid-A (SaA) were determined. In addition, samples were collected from the subset of calves when they received medical treatment and 7 d following treatment to measure serum concentrations of Hp and SaA. Serum concentrations of Fb, Hp, and SaA did not differ among dietary treatments, but decreased (P < 0.03) as day of the receiving period increased. Fibrinogen (P < 0.001) and the ratio of Fb:total blood protein were greater (P < 0.003) in calves treated multiple times than in calves never treated or treated once for bovine respiratory disease. In addition, on d 0 and 7, Hp concentration increased (antimicrobial treatment x day interaction, P < 0.03) as the number of antimicrobial treatments increased, and was greater on d 14 and 28 in calves treated multiple times than in calves never treated or treated once. Haptoglobin concentration was greater (P < 0.05) in calves on medical treatment days compared with recovery days (7 d after medical treatment). Although diet seemed to have little effect on acute-phase protein response, these results suggest that haptoglobin may be useful as a diagnostic tool to make management decisions regarding treatment protocols for calves with bovine respiratory disease.

Acute-Phase Proteins↗
PubMed2004

Estimates of diffuse phosphorus sources in surface waters of the United States using a spatially referenced watershed model.

The statistical watershed model SPARROW (SPAtially Referenced Regression On Watershed attributes) was used to estimate the sources and transport of total phosphorus (TP) in surface waters of the United States. We calibrated the model using stream measurements of TP from 336 watersheds of mixed land use and spatial data on topography, soils, stream hydrography, and land use (agriculture, forest, shrub/grass, urban). The model explained 87% of the spatial variability in log transformed stream TP flux (kg yr(-1)). Predictions of stream yield (kg ha(-1) yr(-1)) were typically within 45% of the observed values at the monitoring sites. The model identified appreciable effects of soils, streams, and reservoirs on TP transport. The estimated aquatic rates of phosphorus removal declined with increasing stream size and rates of water flushing in reservoirs (i.e. areal hydraulic loads). A phosphorus budget for the 2.9 million km2 Mississippi River Basin provides a detailed accounting of TP delivery to streams, the removal of TP in surface waters, and the stream export of TP from major interior watersheds for sources associated with each land-use type.

Agriculture↗
PubMed2003

Escherichia coli O157 in feedlot cattle feces and water in four major feeder-cattle states in the USA.

The prevalence of Escherichia coli O157 was determined in 10662 fecal samples, 2130 water and 1132 water tank-sediment samples collected during the summer months in 2001 from 711 pens in 73 feedlots located in Kansas, Nebraska, Texas, or Oklahoma, USA. Overall, 10.2% of fecal samples were positive for E. coli O157, with 52% of the pens and 95.9% of the feedlots having at least one positive fecal sample. There were no differences among states or months in the fecal prevalences. Water or water tank-sediment was positive in 13.1% of the water tanks, and 60.3% of feedlots had at least one positive tank. Cattle were more likely to be shedding E. coli O157 in pens with positive water tanks, and water was more likely to be positive when E. coli O157 was detected in the sediment.

Animals↗
PubMed2003

The relative contributions of screen-detected in situ and invasive breast carcinomas in reducing mortality from the disease.

We aimed to quantify the benefits of detecting ductal carcinoma in situ (DCIS) and of downwards stage-shifting within invasive tumours in mammographic screening. Using data from the Swedish Two-County Trial of breast cancer screening, we examined the 20-year death rates from invasive tumours of stage II or worse, invasive tumours of stage I and DCIS. We then used these rates and their respective incidences in invited (active study population, ASP) and control (passive study population, PSP) arms of the trial, to estimate the numbers of deaths avoided by downward stage-shifting the larger stage II or worse tumours to stage I and the stage I cancers to DCIS. We also studied the association between the mortality reduction achieved and the proportion of DCIS cases detected in the randomised trials of breast cancer screening. In the Swedish Two County Trial, 141 breast cancer deaths were avoided in the ASP compared with the PSP at approximately 20 years of follow-up. Of these, 65% (91/141) were avoided as a result of stage-shifting from invasive stage II or worse to invasive stage I, and 5% (7/141) as a result of stage-shifting from invasive stage I to DCIS. If we assumed that 10% of stage II or worse tumours avoided were shifted not to stage I, but to DCIS, the estimated number of deaths prevented by shifting from invasive disease to in situ was 17, which is 12% of all deaths prevented. When the results of all the randomised trials of breast cancer screening were reviewed, there was no clear association between the percentage of DCIS cases diagnosed and the observed mortality reduction. We conclude that compared with downward stage-shifting of invasive tumours, detection of DCIS plays a small part in saving lives from breast cancer. Treatment decisions in DCIS, as in invasive carcinoma, should take full account of histopathological, clinical and radiological attributes of the tumour.

Adult↗