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Biomedical subjects

D H Smith

Publications and source records attributed to D H Smith.

At least 73 records · Page 4Linked to original sources
PubMed1998

Twofold overexpression of human beta-amyloid precursor proteins in transgenic mice does not affect the neuromotor, cognitive, or neurodegenerative sequelae following experimental brain injury.

By using transgenic mice that overexpress human beta-amyloid precursor proteins (APPs) at levels twofold higher than endogenous APPs, following introduction of the human APP gene in a yeast artificial chromosome (YAC), we examined the effects of controlled cortical impact (CCI) brain injury on neuromotor/cognitive dysfunction and the development of Alzheimer's disease (AD)-like neuropathology. Neuropathological analyses included Nissl-staining and immunohistochemistry to detect APPs, beta-amyloid (Abeta), neurofilament proteins, and glial fibrillary acidic protein, whereas Abeta levels were measured in brain homogenates from mice subjected to CCI and control mice by using a sensitive sandwich enzyme-linked immunosorbent assay. Twenty APP-YAC transgenic mice and 17 wild type (WT) littermate controls were anesthetized and subjected to CCI (velocity, 5 m/second; deformation depth, 1 mm). Sham (anesthetized but uninjured) controls (n = 10 APP-YAC; n = 8 WT) also were studied. Motor function was evaluated by using rotarod, inclined-plane, and forelimb/hindlimb flexion tests. The Morris water maze was used to assess memory. Although CCI induced significant motor dysfunction and cognitive deficits, no differences were observed between brain-injured APP-YAC mice and WT mice at 24 hours and 1 week postinjury. By 1 week postinjury, both cortical and hippocampal CA3 neuron loss as well as extensive astrogliosis were observed in all injured animals, suggesting that overexpression of human APPs exhibited no neuroprotective effects. Although AD-like pathology (including amyloid plaques) was not observed in either sham or brain-inj ured animals, a significant decrease in brain concentrations of only Abeta terminating at amino acid 40 (Abeta x-40) was observed following brain injury in APP-YAC mice (P < 0.05 compared with sham control levels). Our data show that the APP-YAC mice do not develop AD-like neuropathology following traumatic brain injury. This may be because this injury does not induce elevated levels of the more amyloidogenic forms of human Abeta (i.e., Abeta x-42/43) in these mice.

Amyloid beta-Peptides↗
PubMed1998

Brain trauma induces massive hippocampal neuron death linked to a surge in beta-amyloid levels in mice overexpressing mutant amyloid precursor protein.

Although brain trauma is a risk factor for Alzheimer's disease, no experimental model has been generated to explore this relationship. We developed a model of brain trauma in transgenic mice that overexpress mutant human amyloid precursor protein (PDAPP) leading to the appearance of Alzheimer's disease-like beta-amyloid (Abeta) plaques beginning at 6 months of age. We induced cortical impact brain injury in the PDAPP animals and their wild-type littermates at 4 months of age, ie, before Abeta plaque formation, and evaluated changes in posttraumatic memory function, histopathology, and regional tissue levels of the Abeta peptides Abeta1-40 and Abeta1-42. We found that noninjured PDAPP mice had impaired memory function compared to noninjured wild-type littermates (P < 0.01) and that brain-injured PDAPP mice had more profound memory dysfunction than brain-injured wild-type littermates (P < 0.001). Although no augmentation of Abeta plaque formation was observed in brain-injured PDAPP mice, a substantial exacerbation of neuron death was found in the hippocampus (P < 0.001) in association with an acute threefold increase in Abeta1-40 and sevenfold increase in Abeta1-42 levels selectively in the hippocampus (P < 0.01). These data suggest a mechanistic link between brain trauma and Abeta levels and the death of neurons.

Amyloid beta-Peptides↗
PubMed1998

Enduring cognitive, neurobehavioral and histopathological changes persist for up to one year following severe experimental brain injury in rats.

Clinical studies have demonstrated that patients sustain prolonged behavioral deficits following traumatic brain injury, in some cases culminating in the cognitive and histopathological hallmarks of Alzheimer's disease. However, few studies have examined the long-term consequences of experimental traumatic brain injury. In the present study, anesthetized male Sprague-Dawley rats (n = 185) were subjected to severe lateral fluid-percussion brain injury (n = 115) or sham injury (n = 70) and evaluated up to one year post-injury for cognitive and neurological deficits and histopathological changes. Compared with sham-injured controls, brain-injured animals showed a spatial learning impairment that persisted up to one year post-injury. In addition, deficits in specific neurologic motor function tasks also persisted up to one year post-injury. Immunohistochemistry using multiple antibodies to the amyloid precursor protein and/or amyloid precursor protein-like proteins revealed novel axonal degeneration in the striatum, corpus callosum and injured cortex up to one year post-injury and in the thalamus up to six months post-injury. Histologic evaluation of injured brains demonstrated a progressive expansion of the cortical cavity, enlargement of the lateral ventricles, deformation of the hippocampus, and thalamic calcifications. Taken together, these findings indicate that experimental traumatic brain injury can cause long-term cognitive and neurologic motor dysfunction accompanied by continuing neurodegeneration.

Amyloid beta-Peptides↗
PubMed1998

Hypertension: where have we gone wrong and how can we fix it?

Hypertension is defined as a disease of elevated systolic and diastolic blood pressure and consequently the goals of treating hypertension have been simply to normalize the blood pressure. However, effective blood pressure control has not resulted in the expected decreases in coronary artery disease. These findings have forced researchers to reexamine the importance of blood pressure in causing coronary artery disease, and to pose the question "Is there more to hypertension than high blood pressure?" Although there are probably several reasons for the poor reduction in the incidence of coronary artery disease in hypertensive patients, one of the most compelling appears to be the realization that hypertension is not simply a disease of numbers, but is a complex inherited syndrome of cardiovascular risk factors, all of which contribute to heart disease in these patients. Included in the hypertension syndrome are abnormalities of lipid profile, insulin resistance, changes in renal function, endocrine changes, obesity, abnormalities of coagulation factors, left ventricular hypertrophy and diastolic dysfunction, and abnormalities of vascular structure and compliance. In many patients, high blood pressure is a late manifestation of this disease process and is preceded by some or all of the associated cardiovascular risk factors. Perhaps where we have gone wrong in the management of hypertension is in the belief that this is simply a disease of numbers. To improve our management, we need to find methods to diagnose these patients early in the course of this disease process, and to treat it as a syndrome rather than as a number.

Arteries↗
PubMed1998

The Dorothy Russell Memorial Lecture. The molecular and cellular sequelae of experimental traumatic brain injury: pathogenetic mechanisms.

The mechanisms underlying secondary or delayed cell death following traumatic brain injury (TBI) are poorly understood. Recent evidence from experimental models of TBI suggest that diffuse and widespread neuronal damage and loss is progressive and prolonged for months to years after the initial insult in selectively vulnerable regions of the cortex, hippocampus, thalamus, striatum, and subcortical nuclei. The development of new neuropathological and molecular techniques has generated new insights into the cellular and molecular sequelae of brain trauma. This paper will review the literature suggesting that alterations in intracellular calcium with resulting changes in gene expression, activation of reactive oxygen species (ROS), activation of intracellular proteases (calpains), expression of neurotrophic factors, and activation of cell death genes (apoptosis) may play a role in mediating delayed cell death after trauma. Recent data suggesting that TBI should be considered as both an inflammatory and/or a neurodegenerative disease is also presented. Further research concerning the complex molecular and neuropathological cascades following brain trauma should be conducted, as novel therapeutic strategies continue to be developed.

Animals↗
PubMed1998

High-field proton magnetic resonance spectroscopy of a swine model for axonal injury.

A miniature swine model for diffuse brain injury has recently been developed that replicates the inertial loading conditions associated with rotational acceleration during automotive accidents. The swine model induces diffuse axonal pathology without macroscopic injury such as contusions and hematomas, thus affording a unique opportunity to study axonal injury with noninvasive techniques such as magnetic resonance imaging (MRI) and spectroscopy (MRS). In the present study, we evaluated this diffuse injury model with proton MRS, in vivo, using a high-field (4.0-T) MR scanner, since MRS has been demonstrated as a sensitive probe for detecting neurochemical abnormalities. Our study examined a region of the swine brain at timepoints before and after brain injury. Spectroscopic results indicate that N-acetylaspartate/creatine is diminished by at least 20% in regions of confirmed axonal pathology, whereas conventional MRI did not detect any abnormalities. These findings suggest that MRS has high sensitivity in diagnosing microscopic pathology following diffuse brain injury.

Animals↗
PubMed1998

Magnetic resonance spectroscopy of diffuse brain trauma in the pig.

The acute metabolic events linked to the evolution of selective axonal pathology in the white matter following diffuse brain injury have not previously been evaluated due to the paucity of relevant experimental models. Here, we utilized a new model of inertial brain injury in the pig that selectively damages axons in the white matter, and applied proton and phosphorous magnetic resonance spectroscopy (MRS) to noninvasively monitor the temporal course of metabolic changes following trauma. Evaluating four pigs with MRS prior to injury, within 1 h and 3 and 7 days postinjury, we found that widespread axonal injury was produced in the absence of changes in pH, PCr/Pi, or the concentrations of ATP, and lactate. However, we did observe an acute 60% loss of intracellular Mg2+ levels, which gradually resolved by 7 days postinjury. In addition, we found that the levels of the neuron marker, N-acetylaspartate (NAA), acutely dropped 20% and remained persistently decreased for at least 7 days postinjury. Moreover, the changes in Mg2+ and NAA were found with MRS in the absence of abnormalities with conventional magnetic resonance imaging (MRI). These results show that (1) profound alterations in intracellular metabolism occur acutely following diffuse axonal pathology in the white matter, but in the absence of indicators of ischemia, and (2) axonal pathology may be evaluated with high sensitivity utilizing noninvasive MRS techniques.

Adenosine Triphosphate↗
PubMed1998

Human African trypanosomiasis: an emerging public health crisis.

There is a dramatic resurgence of human African trypanosomiasis (HAT) in sub-Saharan Africa. T.b. gambiense is spreading epidemically in large areas of Central Africa, especially the Southern Sudan, Congo-Zaire, Angola, Uganda and the Central African Republic. Devastating epidemics of T.b. rhodesiense have occurred in south-eastern Uganda. The causes of the re-emergence of sleeping sickness as a public health problem include widespread civil disturbance and war, declining economies, reduced health financing and the dismantling of disease control programmes. Despite the inevitably fatal outcome without treatment, HAT is often given low priority by donors and national governments. The advances made in diagnosis, treatment and vector control have not been sufficiently implemented. To limit the human impact in some of the poorest communities in Africa, endemic countries will require external support to implement strategies for disease control. Donor agencies, NGOs and mission organisations could play an important role in supporting control efforts. National authorities will need to control and co-ordinate these efforts with assistance from WHO and the international community.

Africa South of the Sahara↗
PubMed1998

A randomized controlled trial of a drug use review intervention for sedative hypnotic medications.

OBJECTIVES: Drug use review is used by both the public and private sector to influence prescribing behavior and patient drug use. Past interventions mailed to prescribers have had mixed results. The objective was to evaluate the effect of a one-time, mailed intervention on subsequent use of sedative hypnotic medication. METHODS: An experimental design was used. The intervention contained guidelines for the use of sedative hypnotics, a prescriber profile detailing sedative hypnotic prescribing, and a patient profile. Clustering of patients and their shared prescribers was done to avoid contamination bias and statistical problems associated with a lack of independence of observations. Subjects were 189 Washington State Medicaid recipients who had received at least one tablet per day of a sedative hypnotic medication for 1 year and their prescribing physicians or (when information about the physician was lacking) the dispensing pharmacy. RESULTS: A significant reduction in the use of targeted sedative hypnotic medications was measured in the intervention group (-27.6%) versus the control group (-8.5%). In the intervention group, 9.4% of patients began a new prescription for a benzodiazepine not targeted by the drug use review, whereas no control patients had new use of nontarget benzodiazepines. CONCLUSIONS: The intervention achieved a statistically significant decrease in targeted drug use, and the amount of reduction is likely to have decreased the risk of fractures associated with benzodiazepine use. This study adds to the recent evidence that mailed drug use review interventions can have a desirable impact on patient drug use.

Adult↗
PubMed1998

Comparison of phenotypic and genotypic techniques for identification of unusual aerobic pathogenic gram-negative bacilli.

Rapid and accurate identification of bacterial pathogens is a fundamental goal of clinical microbiology, but one that is difficult or impossible for many slow-growing and fastidious organisms. We used identification systems based on cellular fatty acid profiles (Sherlock; MIDI, Inc., Newark, Del.), carbon source utilization (Microlog; Biolog, Inc., Hayward, Calif.), and 16S rRNA gene sequence (MicroSeq; Perkin-Elmer Applied Biosystems Division, Foster City, Calif.) to evaluate 72 unusual aerobic gram-negative bacilli isolated from clinical specimens at the Mayo Clinic. Compared to lengthy conventional methods, Sherlock, Microlog, and MicroSeq were able to identify 56 of 72 (77.8%), 63 of 72 (87.5%), and 70 of 72 (97.2%) isolates to the genus level (P = 0.002) and 44 to 65 (67.7%), 55 of 65 (84.6%), and 58 of 65 (89.2%) isolates to the species level (P = 0.005), respectively. Four Acinetobacter and three Bordetella isolates which could not be identified to the species level by conventional methods were identified by MicroSeq. In comparison to the full 16S rDNA sequences, the first 527 bp provided identical genus information for all 72 isolates and identical species information for 67 (93.1%) isolates. These data show that MicroSeq provides rapid, unambiguous identification of clinical bacterial isolates. The improved turnaround time provided by genotypic identification systems may translate into improved clinical outcomes.

Carbon↗
PubMed1998

Interviews with elderly patients about side effects.

Fifty older persons were interviewed about their medicines, side effects, and their responses to statements describing side effects. Participants were taking nearly 4 drugs each and knew what those medicines were and why they were taking them. Participants knew much less about the potential side effects and almost nothing about potential drug interactions. They wanted to know all the side effects, and indicated that if their doctors told them about all the side effects, they would still follow the doctors' prescription. However, fewer than 1 in 3 of their doctors were doing so. Responses to hypothetical statements about a high blood pressure medication showed that positive statements were more reassuring than negative statements. Responses to statements about side effects were more driven by the nature of the side effect than by its likelihood. Overall, participants did not find side-effect information strongly discouraging.

Journal Article↗
PubMed1998

Proton magnetic resonance spectroscopy for detection of axonal injury in the splenium of the corpus callosum of brain-injured patients.

OBJECT: This study was conducted to determine whether proton magnetic resonance spectroscopy (MRS) is a sensitive method for detecting diffuse axonal injury, which is a primary sequela of traumatic brain injury (TBI). Diffuse axonal injury is characterized by selective damage to white matter tracts that is caused in part by the severe inertial strain created by rotational acceleration and deceleration, which is often associated with motor vehicle accidents. This axonal injury is typically difficult to detect by using conventional imaging techniques because it is microscopic in nature. The splenium was selected because it is a site vulnerable to shearing forces that produce diffuse axonal injury. METHODS: The authors used proton MRS to evaluate the splenium, the posterior commissure of the corpus callosum, in normal control volunteers and in patients with TBI. Proton MRS provided an index of neuronal and axonal viability by measuring levels of N-acetyl aspartate (NAA). CONCLUSIONS: A majority of mildly brain injured patients, as well as those more severely injured, showed diminished NAA/creatine (Cr) levels in the splenium compared with normal control volunteers. The patients displaying lowered NAA/Cr in the splenium were also likely to exhibit lowered NAA/Cr in lobar white matter. Also, the levels of NAA/Cr in the splenium of normal volunteers were higher compared with those found in lobar white matter. Decreases in NAA/Cr levels in the splenium may be a marker for diffuse injury. A proton MRS examination may be particularly useful in evaluating mildly injured patients with unexplained neurological and cognitive deficits. It is concluded that MRS is a sensitive tool in detecting axonal injury.

Acceleration↗
PubMed1998

Principal findings from the Washington State cognitive services demonstration project.

In addition to dispensing, pharmacists are ideally positioned to provide cognitive services that are targeted at optimizing drug therapy through identification and resolution of drug therapy problems. The Washington Cognitive Activities and Reimbursement Effectiveness project sought to determine: (1) if pharmacists would respond to a financial incentive by performing more cognitive services, and (2) the effect on drug cost of cognitive services they performed.

Attitude of Health Personnel↗
PubMed1997

Remacemide hydrochloride reduces cortical lesion volume following brain trauma in the rat.

We evaluated the therapeutic effects of remacemide hydrochloride, an N-methyl-D-aspartate (NMDA) receptor-associated ionophore blocker with sodium channel blocking activity, on cortical lesion volume and memory dysfunction following parasagittal fluid-percussion brain injury in the anesthetized rat. We found that intravenous (i.v.) administration 15 min following injury of remacemide hydrochloride at both 25 and 10 mg/kg significantly reduced posttraumatic cortical lesion volume (P < 0.05), measured at 48 h postinjury using a tetrazolium salt tissue staining technique. However, neither of these doses nor the dosing regimen of 25 mg/kg i.v. 15 min postinjury plus a subcutaneous infusion over 24 h of 20 mg/kg remacemide hydrochloride improved posttraumatic memory function determined by a Morris water maze paradigm.

Acetamides↗
PubMed1997

Insulin-like growth factor-1 (IGF-1) improves both neurological motor and cognitive outcome following experimental brain injury.

We evaluated the efficacy of insulin-like growth factor-1 (IGF-1) in attenuating neurobehavioral deficits following lateral fluid percussion (FP) brain injury. Male Sprague-Dawley rats (345-425 g, n = 88) were anesthetized and subjected to FP brain injury of moderate severity (2.4-2.9 atm). In Study 1, IGF-1 (1.0 mg/kg, n = 9) or vehicle (n = 14) was administered by subcutaneous injection at 15 min postinjury and similarly at 12-h intervals for 14 days. In animals evaluated daily for 14 days, IGF-1 treatment attenuated motor dysfunction over the 2-week period (P < 0.02). In Study 2, IGF-1 (4 mg/kg/day, n = 8 uninjured, n = 13 injured) or vehicle (n = 8 uninjured, n = 13 injured) was administered for 2 weeks via a subcutaneous pump implanted 15 min postinjury. IGF-1 administration was associated with increased body weight and mild, transient hypoglycemia which was more pronounced in brain-injured animals. At 2 weeks postinjury (P < 0.05), but not at 48 h or 1 week, brain-injured animals receiving IGF-1 showed improved neuromotor function compared with those receiving vehicle. IGF-1 administration also enhanced learning ability (P < 0.03) and memory retention (P < 0.01) in brain-injured animals at 2 weeks postinjury. Taken together, these data suggest that chronic, posttraumatic administration of the trophic factor IGF-1 may be efficacious in ameliorating neurobehavioral dysfunction associated with traumatic brain injury.

Animals↗