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Biomedical subjects

D E Smith

Publications and source records attributed to D E Smith.

At least 19 recordsLinked to original sources
PubMed2006

Development and preliminary experience with an ease of extractability rating system for prescription opioids.

One important factor in the abuse potential of an opioid product is the ease with which active drug can be extracted. There are currently no standards for testing or reporting extractability. This article describes the development of an Extractability Rating System for use by the pharmaceutical industry and regulators. Despite several limitations, this effort serves as a call for standardized testing and reporting so that products can be accurately rated, and should help establish goals for drug developers who wish to develop "abuse-resistant" opioid products.

Algorithms↗
PubMed2006

Efavirenz and chronic neuropsychiatric symptoms: a cross-sectional case control study.

OBJECTIVE: The aim of the study was to investigate symptoms of long-term central nervous system (CNS) toxicity in HIV-positive patients treated with efavirenz (EFV). METHODS: We carried out a single-centre, cross-sectional case-control study comparing patients treated with EFV for at least 6 months with a matched control group. Self-administered, standardized questionnaires including the Depression, Anxiety and Stress Scales (DASS), the Cognitive Failures Questionnaire (CFQ) and a questionnaire on unusual dreams, insomnia, fatigue, dizziness, depersonalization and derealization were administered. RESULTS: Data for 32 matched pairs were analysed. Significantly higher total stress scores (P=0.008) were found in the EFV group. Of the patients in this group, 19% also reported severe to extremely severe levels of stress (P=0.014), indicating increased difficulty in relaxing, and being more irritable, impatient, agitated and easily upset. Nineteen per cent of patients treated with EFV also reported severe levels of anxiety (P=0.059) as assessed with the DASS scale. This patient group also reported a higher rate of unusual dreams (P=0.049). No significant differences between groups were found for measures of cognitive impairments, fatigue, dizziness, derealization or depersonalization. CONCLUSION: EFV-treated patients reported higher levels of severe stress and anxiety as well as a higher rate of unusual dreams than patients not treated with EFV. These differences may be an expression of persisting CNS side effects in patients who remain on EFV for a prolonged period.

Adult↗
PubMed2004

Search for the rare decay K(L)-->pi(0)e(+)e(-).

The KTeV/E799 experiment at Fermilab has searched for the rare kaon decay K(L)-->pi(0)e(+)e(-). This mode is expected to have a significant CP violating component. The measurement of its branching ratio could support the standard model or could indicate the existence of new physics. This Letter reports new results from the 1999-2000 data set. One event is observed with an expected background at 0.99+/-0.35 events. We set a limit on the branching ratio of 3.5x10(-10) at the 90% confidence level. Combining with the previous result based on the data set taken in 1997 yields the final KTeV result: BR(K(L)-->pi(0)e(+)e(-))<2.8x10(-10) at 90% C.L.

Journal Article↗
PubMed2003

CO2 snow depth and subsurface water-ice abundance in the northern hemisphere of Mars.

Observations of seasonal variations of neutron flux from the high-energy neutron detector (HEND) on Mars Odyssey combined with direct measurements of the thickness of condensed carbon dioxide by the Mars Orbiter Laser Altimeter (MOLA) on Mars Global Surveyor show a latitudinal dependence of northern winter deposition of carbon dioxide. The observations are also consistent with a shallow substrate consisting of a layer with water ice overlain by a layer of drier soil. The lower ice-rich layer contains between 50 and 75 weight % water, indicating that the shallow subsurface at northern polar latitudes on Mars is even more water rich than that in the south.

Atmosphere↗
PubMed2003

Transport of 5-aminolevulinic acid between blood and brain.

Little is known about the movement of 5-aminolevulinic acid (delta-aminolevulinic acid; ALA) between blood and brain. This is despite the fact that increases in brain ALA may be involved in generating the neuropsychiatric symptoms in porphyrias and that systemic administration of ALA is currently being used to delineate the borders of malignant gliomas. The current study examines the mechanisms involved in the movement of [(14)C]ALA across the blood-brain and blood-CSF barriers in the rat. In the adult rat, the influx rate constant (K(i)) for [(14)C]ALA movement into brain was low ( approximately 0.2 microl/g per min), was unaffected by increasing plasma concentrations of non-radioactive ALA or probenecid (an organic anion transport inhibitor) and, therefore, appears to be a diffusional process. The K(i) for [(14)C]ALA was 3-fold less than that for [(14)C]mannitol, a molecule of similar size. This difference appears to result from a lower lipid solubility rather than saturable [(14)C]ALA transport from brain to blood. The K(i) for [(14)C]ALA for uptake into the neonatal brain was 7-fold higher than in the adult. However, again, this was unaffected by increasing plasma ALA concentrations suggesting a diffusional process. In contrast, at the blood-CSF barrier, there was evidence of carrier-mediated [(14)C]ALA transport from blood to choroid plexus and blood to CSF. Both processes were inhibited by administration of non-radioactive ALA and probenecid. However, experiments in choroid plexus epithelial cell primary cultures indicated that transport in these cells was polarized with [(14)C]ALA uptake from the apical (CSF) side being about 7-fold greater than uptake from the basolateral (blood) side. In total, these results suggest that the brain is normally fairly well protected from changes in plasma ALA concentration by the very low blood-brain barrier permeability of this compound and by a saturable efflux mechanism present at the choroid plexus.

Aminolevulinic Acid↗
PubMed2001

Seasonal variations of snow depth on Mars.

Using topography collected over one martian year from the Mars Orbiter Laser Altimeter on the Mars Global Surveyor (MGS) spacecraft, we have measured temporal changes in the elevation of the martian surface that correlate with the seasonal cycle of carbon dioxide exchange between the surface and atmosphere. The greatest elevation change (1.5 to 2 meters) occurs at high latitudes ( above 80 degrees ), whereas the bulk of the mass exchange occurs at lower latitudes (below 75 degrees N and below 73 degrees S). An unexpected period of sublimation was observed during northern hemisphere autumn, coincident with dust storms in the southern hemisphere. Analysis of MGS Doppler tracking residuals revealed temporal variations in the flattening of Mars that correlate with elevation changes. The combined changes in gravity and elevation constrain the average density of seasonally deposited carbon dioxide to be 910 +/- 230 kilograms per cubic meter, which is considerably denser than terrestrial snow.

Atmosphere↗
PubMed2001

The bacteriophage straight phi29 portal motor can package DNA against a large internal force.

As part of the viral infection cycle, viruses must package their newly replicated genomes for delivery to other host cells. Bacteriophage straight phi29 packages its 6.6-microm long, double-stranded DNA into a 42 x 54 nm capsid by means of a portal complex that hydrolyses ATP. This process is remarkable because entropic, electrostatic and bending energies of the DNA must be overcome to package the DNA to near-crystalline density. Here we use optical tweezers to pull on single DNA molecules as they are packaged, thus demonstrating that the portal complex is a force-generating motor. This motor can work against loads of up to 57 pN on average, making it one of the strongest molecular motors reported to date. Movements of over 5 microm are observed, indicating high processivity. Pauses and slips also occur, particularly at higher forces. We establish the force-velocity relationship of the motor and find that the rate-limiting step of the motor's cycle is force dependent even at low loads. Notably, the packaging rate decreases as the prohead is filled, indicating that an internal force builds up to approximately 50 pN owing to DNA confinement. Our data suggest that this force may be available for initiating the ejection of the DNA from the capsid during infection.

Bacillus Phages↗
PubMed2001

Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction.

The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction. MyD88 is one such protein that contains a TIR domain. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling; however, our understanding of how TLR-4 signals is incomplete. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome. Mal activates NF-kappaB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. Mal can form homodimers and can also form heterodimers with MyD88. Activation of NF-kappaB by Mal requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TIR domain. A dominant negative form of Mal inhibits NF-kappaB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-kappaB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.

Adaptor Proteins, Signal Transducing↗
PubMed2001

An ethics core curriculum for Australasian medical Schools.

Teaching ethics incorporates teaching of knowledge as well as skills and attitudes. Each of these requires different teaching and assessment methods. A core curriculum of ethics knowledge must address both the foundations of ethics and specific ethical topics. Ethical skills teaching focuses on the development of ethical awareness, moral reasoning, communication and collaborative action skills. Attitudes that are important for medical students to develop include honesty, integrity and trustworthiness, empathy and compassion, respect, and responsibility, as well as critical self-appraisal and commitment to lifelong education.

Australia↗
PubMed2001

Selective radioprotection of hepatocytes by systemic and portal vein infusions of amifostine in a rat liver tumor model.

PURPOSE: The tolerance of the liver to radiation is too low to permit an effective dose to be delivered to patients who have diffuse intrahepatic cancer. In this study we evaluated whether systemic or portal venous administration of the aminothiol compound, amifostine, could protect the normal liver from the effects of ionizing radiation without compromising tumor cell kill in a rat liver tumor model. METHODS AND MATERIALS: Rats implanted with liver tumors were infused with 200 mg/kg amifostine over 15 min via the femoral or portal vein. The livers were irradiated with a single 6-Gy fraction 15-20 min after the termination of amifostine infusion. Protection of the liver was assessed by an in vitro hepatocyte micronucleus assay and tumor protection by an in vivo-in vitro clonogenic survival assay. Tissue levels of the active metabolite, free WR-1065, were determined in the tumor and in the normal liver using a specific HPLC assay with electrochemical detection. RESULTS: After a 6-Gy fraction, the frequency of hepatocyte micronuclei after administration of saline, systemic amifostine, and portal venous amifostine was 18.7+/-1%, 6.8+/-1%, and 9.9+/-2%, respectively, corresponding to a radiation equivalent effect of 6 Gy +/- 0.5, 1.8 Gy +/- 0.3, and 2.5 Gy +/- 1.3, respectively. Both amifostine conditions showed considerably less radiation effect than saline-treated controls (p < 0.01); the two amifostine conditions did not differ (p = 0.3). The surviving fraction of tumor cells was not affected by amifostine treatment and was 0.03+/-0.02 and 0.05+/-0.03 for systemic and portal venous delivery and 0.06+/-0.02 for control animals (ANOVA analysis showed no significant difference of the means p = 0.34). Portal venous delivery produced significantly less WR-1065 in the tumor compared to systemic administration (54 microM +/- 36 vs. 343 microM +/- 88, respectively, p = 0.03). CONCLUSIONS: Both systemic and portal venous administration of amifostine effectively protect hepatocytes from ionizing radiation without compromising tumor cell kill in a clinically relevant animal model. These findings suggest that amifostine may be a selective normal tissue radioprotectant in liver cancer and that regional/portal infusions may be preferable to systemic dosing.

Amifostine↗
PubMed2001

Laser altimetry of small-scale features on 433 Eros from NEAR-Shoemaker.

During the Near Earth Asteroid Rendezvous (NEAR)-Shoemaker's low-altitude flyover of asteroid 433 Eros, observations by the NEAR Laser Rangefinder (NLR) have helped to characterize small-scale surface features. On scales from meters to hundreds of meters, the surface has a fractal structure with roughness dominated by blocks, structural features, and walls of small craters. This fractal structure suggests that a single process, possibly impacts, dominates surface morphology on these scales.

Journal Article↗
PubMed2001

Maharishi Vedic vibration technology on chronic disorders and associated quality of life.

There is a growing interest for more effective, innovative programs to address the chronic illness suffered by approximately 40 percent of the U.S. population. The purpose of this study was to evaluate the effects of a new Maharishi Vedic Medicine program-the Maharishi Vedic Vibration Technology-on the quality of life of individuals with chronic disorders. A total of 213 individuals took part in the study (mean age=48.55 years; average length of time of chronic illness=18.42 years). Results showed that over three sessions, the average self-reported improvement in chronic illness was 40.97 percent. Conditions related to neck pain improved the most (51.25%), followed by respiratory ailments (48.00%), digestive problems (46.90%), mental health, including anxiety and depression (46.34%), arthritis (41.57%), insomnia (37.38%), back pain (36.32%), headaches (35.83%), cardiovascular conditions (22.31%), and eye problems (21.19%). Findings also showed significant reductions in frequency of discomfort or pain (p<.000001), intensity of discomfort (p<.000001), and disabling effects of the discomfort in daily activity (p<.000001), in addition to overall improvement in mental health (p<.000001) and vitality (p<.000125). Possible mechanisms of action are presented.

Adolescent↗
PubMed2001

A double blind randomized controlled trial of Maharishi Vedic vibration technology in subjects with arthritis.

To explore ancient Vedic medical techniques, one hundred and seventy-six subjects with arthritis participated in a controlled study through the non-pharmacologic approach known as the Maharishi Vedic Vibration Technology (MVVT). Using a double-blinded and randomized experimental design, the findings showed significant reductions of pain and stiffness, and improvement in range of motion in the study sample. One hundred percent relief of symptoms was the most commonly reported category of improvement due to treatment. For the group as a whole, differences in mean response of treatment and control conditions with respect to relief of pain, limitation of motion, and reduction in stiffness were highly significant: t values ranged from a low of 5.609 in stiffness to a high of 20.950 in pain, p = 0.000009 to <10-49 respectively. Analysis by sub-categories of peripheral arthritis, painful conditions of the spine, and rheumatoid arthritis likewise produced significant results. Mechanisms of action were proposed, drawing on Maharishi Vedic Science, developments in quantum field theory, and specifically the theories of chaos and self-organizing systems as they relate to physiological functioning. The instantaneous relief of pain and improvement in function in such a high proportion of subjects with chronic arthritis is unparalleled in modern medical science

Arthralgia↗
PubMed2001

Ancient geodynamics and global-scale hydrology on Mars.

Loading of the lithosphere of Mars by the Tharsis rise explains much of the global shape and long-wavelength gravity field of the planet, including a ring of negative gravity anomalies and a topographic trough around Tharsis, as well as gravity anomaly and topographic highs centered in Arabia Terra and extending northward toward Utopia. The Tharsis-induced trough and antipodal high were largely in place by the end of the Noachian Epoch and exerted control on the location and orientation of valley networks. The release of carbon dioxide and water accompanying the emplacement of approximately 3 x 10(8) cubic kilometers of Tharsis magmas may have sustained a warmer climate than at present, enabling the formation of ancient valley networks and fluvial landscape denudation in and adjacent to the large-scale trough.

Atmosphere↗
PubMed2001

PEPT2-mediated uptake of neuropeptides in rat choroid plexus.

PURPOSE: The peptide transporter PEPT2 was recently shown to be functionally active in rat choroid plexus, suggesting that it may play a role in neuropeptide homeostasis in the cerebrospinal fluid. This study, therefore, examined the role of PEPT2 in mediating neuropeptide uptake into choroid plexus. METHODS: Whole-tissue rat choroid plexus uptake studies were performed on GlySar in the absence and presence of neuropeptides and on carnosine. RESULTS: The neuropeptides NAAG, CysGly, GlyGln, kyotorphin, and carnosine inhibited the uptake of radiolabeled GlySar at 1.0 mM concentrations. In contrast, TRH, [D-Arg2]-kyotorphin, glutathione, and homocarnosine did not inhibit GlySar uptake. Kyotorphin, an analgesic, was a competitive inhibitor of GlySar with a Ki of 8.0 microM. The direct uptake of carnosine was also shown to be mediated by PEPT2 in isolated choroid plexus (Km = 39.3 microM; Vmax = 73.9 pmol/mg/min). Radiolabeled carnosine uptake was inhibited by 1.0 mM concentrations of GlySar or carnosine but not homocarnosine, L-histidine, or beta-alanine. CONCLUSIONS: These findings indicate that PEPT2 mediates the uptake of a diverse group of neuropeptides in choroid plexus, and suggests a role for PEPT2 in the regulation of neuropeptides, peptide fragments, and peptidomimetics in cerebrospinal fluid.

Animals↗