Biomedical subjects
D H Smith
Publications and source records attributed to D H Smith.
Headache in mild-to-moderate hypertension and its reduction by irbesartan therapy.
BACKGROUND: Although it is generally acknowledged to be a problem in severe hypertension, headache has not been consistently associated with mild-to-moderate hypertension. PATIENTS AND METHODS: In 7 randomized, double-blind, placebo-controlled trials, which included 2,673 patients with mild-to-moderate hypertension (defined as seated diastolic blood pressure of 95-110 mm Hg), patients were randomized to receive once-daily treatment with irbesartan, an angiotensin II receptor blocker (n= 1,987), or placebo (n=686). The data were pooled and analyzed retrospectively to determine whether the level of hypertension was associated with headache and whether antihypertensive therapy reduced the incidence of headache. RESULTS: Factors found to be predictive of headache incidence were diastolic blood pressure, sex (female), and age (<50 years). In comparison with placebo, the use of irbesartan was associated with a significant reduction in the incidence of headache (P=.003). CONCLUSIONS: These data suggest that mild-to-moderate hypertension is not asymptomatic and that the incidence of headache can be reduced by antihypertensive treatment with a favorable adverse effect profile.
Heat and light in the childhood spanking debate.
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If the WCB can do it, why not others?
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Brain trauma in aged transgenic mice induces regression of established abeta deposits.
Traumatic brain injury (TBI) increases susceptibility to Alzheimer's disease (AD), but it is not known if TBI affects the progression of AD. To address this question, we studied the neuropathological consequences of TBI in transgenic (TG) mice with a mutant human Abeta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter resulting in overexpression of mutant APP (V717F), elevated brain Abeta levels, and AD-like amyloidosis. Since brain Abeta deposits first appear in 6-month-old TG (PDAPP) mice and accumulate with age, 2-year-old PDAPP and wild-type (WT) mice were subjected to controlled cortical impact (CCI) TBI or sham treatment. At 1, 9, and 16 weeks after TBI, neuron loss, gliosis, and atrophy were most prominent near the CCI site in PDAPP and WT mice. However, there also was a remarkable regression in the Abeta amyloid plaque burden in the hippocampus ipsilateral to TBI compared to the contralateral hippocampus of the PDAPP mice by 16 weeks postinjury. Thus, these data suggest that previously accumulated Abeta plaques resulting from progressive amyloidosis in the AD brain also may be reversible.
NPS 1506 attenuates cognitive dysfunction and hippocampal neuron death following brain trauma in the rat.
Although several noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists have been shown to be substantially efficacious in experimental models of brain trauma, side effects associated with this class of compounds have impeded clinical application. Therefore, new noncompetitive NMDA receptor antagonists have been developed, including NPS 1506, that appear to be nontoxic but retain efficacy. In the present study, we evaluated the efficacy of NPS 1506 in a model of parasagittal fluid percussion brain trauma in the anesthetized rat. Administration of 1 mg/kg NPS 1506 at both 10 min and 4 h posttrauma induced no changes in brain temperature, mean arterial pressure, pulse, or arterial blood gasses. At 1 week postinjury, animals treated with the same dosing regimen of NPS 1506 demonstrated a dramatic attenuation of memory dysfunction evaluated by a water maze task (P < 0.02) and had greatly reduced neuron death in the CA3 subfield of the hippocampus (P < 0.01). However, NPS 1506 treatment did not significantly affect the extent of cortical tissue loss following injury. Since memory dysfunction and hippocampal damage are common and potentially related consequences of brain trauma in humans, our results suggest that NPS 1506 treatment may have clinical utility.
Measuring appropriate use of acute beds. A systematic review of methods and results.
A systematic review of the methods used to assess appropriateness of acute bed use and the evidence on the scale of inappropriate use in different patient groups is presented. Issues of generalisability of the findings are also addressed. Criteria based tools are the accepted way of measuring inappropriate days of stay and admissions, although opinion based classification is very common. While a number of tools exist, few have been adequately tested for reliability and validity. The Appropriateness Evaluation Protocol (AEP) is the most commonly used tool, and has been tested more widely. It appears to be both reliable and valid. An estimated 29% of admissions to acute psychiatric may be inappropriate. Regarding days of care after admission, between 24 and 58% of stays were not judged to be appropriate for continued stay on an acute ward. The need for continued acute psychiatric care may become lower as patients experience continued stay in the acute setting. A lack of housing and community support was the most commonly cited reason preventing discharge. Rates of inappropriate use appear to be higher for older patients than for the general population. Wide variation in rates of inappropriate days of stay was found, but it may be safe to assume that inappropriate use is greater than 20% across a wide variety of settings. Reasons for older patients to remain in an acute hospital bed after medically necessary are typically moderate nursing care needs (i.e. long-term care). The estimates of inappropriate use in other groups was found to be highly variable. Before definitive conclusions on the inappropriate use of acute beds can be made, future research needs to take into account the methodological problems discussed here.
Cryptococcal infection in an HIV-positive Ugandan population.
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Comparison of protein A gene sequencing with pulsed-field gel electrophoresis and epidemiologic data for molecular typing of methicillin-resistant Staphylococcus aureus.
The epidemiologic relatedness of methicillin-resistant Staphylococcus aureus (MRSA) isolates is currently determined by analysis of chromosomal DNA restriction patterns by pulsed-field gel electrophoresis (PFGE). We have evaluated an alternative typing system (MicroSeq StaphTrack Kit; Perkin-Elmer Biosystems) based on the sequence analysis of the chromosomally encoded polymorphic repeat X region of the S. aureus protein A (spa) gene. A total of 69 clinical MRSA isolates were divided into 18 groups according to the number and nucleotide sequences of the spa repeats. Molecular typing results obtained both by spa sequencing and from the PFGE patterns were concordant except for one group, which contained 20 isolates recovered over a 2-year period from hospitalized patients at the Mayo Clinic. Although the spa typing patterns were indistinguishable for those isolates, PFGE analysis yielded seven related but distinguishable patterns. Further coagulase gene sequence analysis subtyped those 20 strains into four groups which followed distinct temporal and geographic distributions. During a 2-year epidemic period there were up to 7 fragment changes in PFGE patterns among epidemiologically related isolates, suggesting that PFGE may be unsuitable for long-term typing of strains involved in epidemics. Although more limited than PFGE in discriminatory power, spa sequencing analysis could be used as a screening method for typing of MRSA strains because of the shorter turnaround time, ease of use, and the inherent advantages of sequence analysis, storage, and sharing of information.
Identification of coryneform bacterial isolates by ribosomal DNA sequence analysis.
Identification of coryneform bacteria to the species level is important in certain circumstances for differentiating contamination and/or colonization from infection, which influences decisions regarding clinical intervention. However, methods currently used in clinical microbiology laboratories for the species identification of coryneform bacteria are often inadequate. We evaluated the MicroSeq 500 16S bacterial sequencing kit (Perkin-Elmer Biosystems, Foster City, Calif.), which is designed to sequence the first 527 bp of the 16S rRNA gene for bacterial identification, by using 52 coryneform gram-positive bacilli from clinical specimens isolated from January through June 1993 at the Mayo Clinic. Compared to conventional and supplemented phenotypic methods, MicroSeq provided concordant results for identification to the genus level for all isolates. At the species level, MicroSeq provided concordant results for 27 of 42 (64.3%) Corynebacterium isolates and 5 of 6 (83.3%) Corynebacterium-related isolates, respectively. Within the Corynebacterium genus, MicroSeq gave identical species-level identifications for the clinically significant Corynebacterium diphtheriae (4 of 4) and Corynebacterium jeikeium (8 of 8), but it identified only 50.0% (15 of 30) of other species (P < 0.01). Four isolates from the genera Arthrobacter, Brevibacterium, and Microbacterium, which could not be identified to the species level by conventional methods, were assigned a species-level identification by MicroSeq. The total elapsed time for running a MicroSeq identification was 15.5 to 18.5 h. These data demonstrate that the MicroSeq 500 16S bacterial sequencing kit provides a potentially powerful method for the definitive identification of clinical coryneform bacterium isolates.
Immediate coma following inertial brain injury dependent on axonal damage in the brainstem.
OBJECT: Immediate and prolonged coma following brain trauma has been shown to result from diffuse axonal injury (DAI). However, the relationship between the distribution of axonal damage and posttraumatic coma has not been examined. In the present study, the authors examine that relationship. METHODS: To explore potential anatomical origins of posttraumatic coma, the authors used a model of inertial brain injury in the pig. Anesthetized miniature swine were subjected to a nonimpact-induced head rotational acceleration along either the coronal or axial plane (six pigs in each group). Immediate prolonged coma was consistently produced by head axial plane rotation, but not by head coronal plane rotation. Immunohistochemical examination of the injured brains revealed that DAI was produced by head rotation along both planes in all animals. However, extensive axonal damage in the brainstem was found in the pigs injured via head axial plane rotation. In these animals, the severity of coma was found to correlate with both the extent of axonal damage in the brainstem (p < 0.01) and the applied kinetic loading conditions (p < 0.001). No relationship was found between coma and the extent of axonal damage in other brain regions. CONCLUSIONS: These results suggest that injury to axons in the brainstem plays a major role in induction of immediate posttraumatic coma and that DAI can occur without coma.
Multiplex polymerase chain reaction-based analysis of T-cell receptor gamma gene rearrangements for the determination of T-lymphocyte clonality.
Determination of the frequency of mutations at hprt or other loci in human lymphocytes provides a useful biomarker for human exposure to mutagens. One problem, however, is distinguishing between unique mutants and sibling mutants arising as progeny of an earlier mutant cell. We have developed a multiplex polymerase chain reaction (PCR)-based method to analyze T-cell receptor (TCR) gamma gene rearrangements for determination of T-cell clonality in mutational spectrum analysis. PCR primers for different subgroups of the V gene segment of the TCR gamma gene were selected at different sites in the TCR gamma gene so that the size of PCR products could define which V subgroup was involved in rearranged TCR gamma genes; gamma genes involving different V and J subgroups could be determined directly by PCR. Mutant T-lymphocytes with rearranged TCR gamma genes containing the same V and J subgroups were analyzed using PCR-based denaturing polyacrylamide gel electrophoresis. All of the 161 hprt mutant clones analyzed contained rearranged TCR gamma genes. Rearrangements among all subgroups of the V and J gene segments of the TCR gamma gene could be detected. VgammaI and Jgamma1/2 subgroups were involved in 69 and 71% of rearranged TCR gamma genes, respectively. This PCR-based analysis of TCR gamma gene rearrangements provides a simple and comprehensive method for identifying the clonality of mutant T-lymphocytes in human hprt mutant lymphocyte assay and mutational spectrum analysis.
Narrowing the margin of error.
The patient had been feeling remarkably well 24 hours post-operatively. She remained on intravenous feeding and medication, although she was ambulatory. That afternoon, she realized something was wrong. She was experiencing an overall, generalized weakness, difficulty breathing, and wheezing. In response to her breathing problems, she had used her Serevent (once in the morning) and albuterol inhalers (every four hours), but had achieved no relief. It wasn't until 10:00 p.m. that evening, when she questioned whether or not she had received her dose of prednisone that day which she had been on prior to surgery, that the problem was identified. Despite a detailed history of medication changes, which had been recorded and reported to the anesthesia department prior to surgery, the prednisone dose had been missed.
Asthma: an analysis of high-cost patients.
OBJECTIVE: To examine characteristics of asthma patients who accounted for 80 percent of national expenditures in 1994 dollars. STUDY DESIGN: Data were extracted from a comprehensive data source, the 1987 National Medical Expenditure Survey (NMES) of approximately 35,000 individuals. PATIENTS AND METHODS: Persons of interest were identified using any occurrence of the ICD-9 code 493 or subcategories. Population weighting factors were used to estimate the population in the United States who sought care for the treatment of asthma. Two groups were identified: a high-cost group, which accounted for 80 percent of the direct medical expenditures, and a low-cost group, which represented 20 percent of expenditures. All analyses were performed using SUDAAN software, which takes into account the complex sampling design used in NMES. RESULTS: Individuals who rated their health as poor or fair were more likely to be in the high-cost group, as compared with those who rated their health as good or excellent (p < .0009). Persons who reported having Medicare, other government, or private insurance were more likely to be in the high-cost group as compared to those with Medicaid and self-pay (p = .01). A person was more likely to be in the high-cost group if he or she used four or more different medications to treat asthma (p < .0001). CONCLUSIONS: Persons with asthma are more likely to have greater medical expenditures if they use four or more medications and have deteriorated health status. Managed care organizations and public programs may find these characteristics useful in targeting asthma prevention and management programs.
Dose response and safety of telmisartan in patients with mild to moderate hypertension.
This randomized, double-blind, double-dummy, placebo-controlled, parallel-group study evaluated the dose-response relationship of telmisartan in 207 patients with mild to moderate hypertension (diastolic blood pressure [DBP] 100 to 114 mmHg). After a 28-day placebo run-in period, patients were randomized to 28 days of once-daily, double-blind, double-dummy treatment with telmisartan 40, 80, or 120 mg; enalapril 20 mg; or placebo. Blood pressure (BP) was manually recorded for 12 hours after the first dose and after 24 hours at baseline (Day 0), Day 1, and Day 28 of double-blind treatment. Pharmacokinetic and pharmacodynamic parameters were assessed from telmisartan plasma concentrations. All doses of telmisartan and enalapril significantly reduced BP compared with placebo (p < or = 0.01). Mean +/- SE reductions in supine DBP after 28 days of treatment ranged between 7.9 +/- 1.3 mmHg and 9.8 +/- 1.3 mmHg in the telmisartan groups, 9.6 +/- 1.3 mmHg with enalapril, and 1.5 +/- 1.3 mmHg with placebo. Mean +/- SE reductions in supine systolic blood pressure (SBP) were between 10.0 +/- 2.2 mmHg and 15.5 +/- 2.2 mmHg with telmisartan versus 10.2 +/- 2.1 mmHg with enalapril; placebo increased supine SBP by 3.5 +/- 2.1 mmHg. The BP reductions after 4 weeks of treatment with telmisartan were no different from those achieved with enalapril. No significant linear trend in BP reduction was evident among telmisartan doses. Reductions in SBP and DBP were maintained over the 24-hour period at Day 28. Treatment did not affect supine heart rate. Trough/peak DBP ratios were > or = 85% for all telmisartan doses versus 65% for enalapril. High interpatient variability in telmisartan plasma concentrations was observed. For example, mean +/- SD values for Cmax were 159 +/- 104 ng/mL for telmisartan 40 mg, 693 +/- 606 ng/mL for telmisartan 80 mg, and 1635 +/- 1406 ng/mL for telmisartan 120 mg. Plasma concentration-effect analyses indicated that the antihypertensive effects of telmisartan 40, 80, and 120 mg are at the plateau region of the concentration-response curve. All active treatments were well tolerated, with tolerability profiles similar to placebo, and telmisartan did not produce any clinically relevant first-dose effects. These data confirm the antihypertensive efficacy and placebo-like tolerability of telmisartan.
Traumatic brain injury in young, amyloid-beta peptide overexpressing transgenic mice induces marked ipsilateral hippocampal atrophy and diminished Abeta deposition during aging.
Traumatic brain injury (TBI) is an epigenetic risk factor for Alzheimer's disease (AD). To test the hypothesis that TBI contributes to the onset and/or progression of AD-like beta-amyloid peptide (Abeta) deposits, we studied the long-term effects of TBI in transgenic mice that overexpress human Abeta from a mutant Abeta precursor protein (APP) minigene driven by a platelet derived (PD) growth factor promoter (PDAPP mice). TBI was induced in 4-month-old PDAPP and wild type (WT) mice by controlled cortical impact (CCI). Because Abeta begins to deposit progressively in the PDAPP brain by 6 months, we examined WT and PDAPP mice at 2, 5, and 8 months after TBI or sham treatment (i.e., at 6, 9, and 12 months of age). Hippocampal atrophy in the PDAPP mice was more severe ipsilateral versus contralateral to TBI, and immunohistochemical studies with antibodies to different Abeta peptides demonstrated a statistically significant reduction in hippocampus and cingulate cortex Abeta deposits ipsilateral versus contralateral to CCI in 9-12 month-old PDAPP mice. Hippocampal atrophy and reduced Abeta deposits were not seen in hippocampus or cingulate cortex of sham-injured PDAPP mice or in any WT mice. These data suggest that the vulnerability of brain cells to Abeta toxicity increases and that the accumulation of Abeta deposits decrease in the penumbra of CCI months after TBI. Thus, in addition to providing unique opportunities for elucidating genetic mechanisms of AD, transgenic mice that recapitulate AD pathology also may be relevant animal models for investigating the poorly understood role that TBI and other epigenetic risk factors play in the onset and/or progression of AD.
High tolerance and delayed elastic response of cultured axons to dynamic stretch injury.
Although axonal injury is a common feature of brain trauma, little is known of the immediate morphological responses of individual axons to mechanical injury. Here, we developed an in vitro model system that selectively stretches axons bridging two populations of human neurons derived from the cell line N-Tera2. We found that these axons demonstrated a remarkably high tolerance to dynamic stretch injury, with no primary axotomy at strains <65%. In addition, the axolemma remained impermeable to small molecules after injury unless axotomy had occurred. We also found that injured axons exhibited the behavior of "delayed elasticity" after injury, going from a straight orientation before injury to developing an undulating course as an immediate response to injury, yet gradually recovering their original orientation. Surprisingly, some portions of the axons were found to be up to 60% longer immediately after injury. Subsequent to returning to their original length, injured axons developed swellings of appearance remarkably similar to that found in brain-injured humans. These findings may offer insight into mechanical-loading conditions leading to traumatic axonal injury and into potential mechanisms of axon reassembly after brain trauma.
Immediate in vivo response of the cortex and the blood-brain barrier following dynamic cortical deformation in the rat.
Although it is known that the brain can be injured by mechanical forces initiated at the moment of impact during trauma, it is not clear how the physical response of the brain dictates the injury patterns that occur in experimental models of traumatic brain injury. In this study, we investigated the mechanical response of the brain to a technique that creates a focal injury in the rat brain. Using a transient vacuum pulse applied to the exposed cortical surface, we found that the displacement of the cortex and the extent of in vivo blood-brain barrier breakdown were related significantly to the vacuum pressure level. The relationship between the response of the cortex and injury pattern points towards a new opportunity for control of the distribution and extent of injury patterns in animal models through a precise understanding of the model biomechanics, as well as potential improvements in means of preventing traumatic brain injury.