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Biomedical subjects

D H Smith

Publications and source records attributed to D H Smith.

At least 19 recordsLinked to original sources
PubMed2003

There is differential loss of pyramidal cells from the human hippocampus with survival after blunt head injury.

The experimental literature has shown that neurons within sub-fields of the hippocampus possess differential sensitivities to cell loss after different types of insult to the brain. In humans, after blunt head injury, differential neuronal responses between sub-fields of the hippocampus up to 72 hours after injury have been documented. But, in only a small part of the literature have data for alterations in real numbers of neurons been provided. In this study the hypothesis was tested that, after severe blunt head injury in humans, the total number of neurons within a defined volume of brain tissue differed between different sub-fields of the hippocampus and between groups of patients with differing post-traumatic survivals. Stereological methods were used to measure total cross-sectional area of sub-fields of the hippocampus taken at the level of the lateral geniculate nucleus and count numbers of neurons within each of the CA1, CA2, CA3, and CA4 sub-fields of the hippocampus in patients. The patients used in this study were categorized as follows: Group 1 (early) had survived for 1 week or less; Group 2 (late) survived 6 months or longer after fatal severe head injury; and Group 3 (controls) consisted of age-matched patients that had no history of head injury or disease prior to death. There was a significant loss in cross-sectional area in sub-fields CA3 and CA4 at 1 week or less after injury and in sub-field CA1 at 6 months and greater survival. There was no change in CA2. There was loss of neurons from within a predefined volume of brain tissue in sub-fields CA1, CA3, and CA4 one week or less after injury. But there was no loss in CA2. There was continued loss of neurons from sub-fields CA1 and CA4 between 1 week and 6 months and greater survival, but there was no loss of neurons in sub-fields CA2 and CA3 within the same period. These novel data show that after human severe head injury there is first an acute loss (1 week or less survival) of pyramidal neurons in all hippocampal sub-fields except CA2. Second, there is an ongoing loss of neurons in sub-field CA1 and, most notably, in sub-field CA4, in patients surviving for more than 6 months. However, in neither group of patients is there loss of neurons from sub-field CA2.

Adolescent↗
PubMed2002

A comparative economic analysis of pegylated liposomal doxorubicin versus topotecan in ovarian cancer in the USA and the UK.

BACKGROUND: Economic information is necessary for rational decision-making in health care. Many European countries require financial impact statements prior to drug approval, and many health care organizations in the USA consider cost-effectiveness when making formulary decisions. We report the findings and discuss the policy implications of an economic evaluation based on an international, randomized controlled trial of salvage therapy for epithelial ovarian cancer, wherein topotecan and pegylated liposomal doxorubicin (PLD) were found to have similar efficacy but differing toxicities. PATIENTS AND METHODS: Direct costs to the payer were estimated for 235 North American and 239 European trial participants who had relapsed or failed platinum-based therapy. Unit costs were obtained from national sources or previously reported economic analyses. Sensitivity analyses were also performed. RESULTS: Total cost per person in the topotecan arm was 12,325 dollars (95% CI 9445 dollars to 15,415 dollars; P >0.05) higher in the USA-based analysis and 2909 dollars (95% CI 779 dollars to 3415 dollars; P <0.05) higher in the UK-based analysis than for PLD. Pegylated liposomal doxorubicin was cost saving over a wide range of assumptions. The main differences (per person) in toxicity management following PLD compared with topotecan in Europe were for blood transfusions (1190 dollars versus 181 dollars, respectively) and hospitalizations (1197 dollars versus 280 dollars, respectively). In North America, differences were mainly for granulocyte colony stimulating factors (1936 dollars versus 419 dollars micro g, respectively), erythropoietin (3493 dollars versus 308 dollars, respectively) and blood transfusions (1346 dollars versus 140 dollars, respectively). CONCLUSIONS: Policy makers who evaluate pharmacoeconomic studies should consider international differences in health care delivery. Cost assessments based on information obtained from one country may not be relevant for policy makers in a different country.

Adult↗
PubMed2001

Critical wavelength for river meandering.

A fully nonlinear modal analysis identifies a critical centerline wave number q(c) for river meandering that separates long-wavelength bends, which grow to cutoff, from short-wavelength bends, which decay. Exact, numerical, and approximate analytical results for q(c) rely on the Ikeda, Parker, and Sawai [J. Fluid Mech. 112, 363 (1981)] model, supplemented by dynamical equations that govern the river migration and length. Predictions also include upvalley bend migration at long times and a peak in lateral migration rates at intermediate times. Experimental tests are suggested.

Journal Article↗
PubMed2001

Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels.

Diffuse axonal injury (DAI) is one of the most common and important pathologies resulting from the mechanical deformation of the brain during trauma. It has been hypothesized that calcium influx into axons plays a major role in the pathophysiology of DAI. However, there is little direct evidence to support this hypothesis, and mechanisms of potential calcium entry have not been explored. In the present study, we used an in vitro model of axonal stretch injury to evaluate the extent and modulation of calcium entry after trauma. Using a calcium-sensitive dye, we observed a dramatic increase in intra-axonal calcium levels immediately after injury. Axonal injury in a calcium-free extracellular solution resulted in no change in calcium concentration, suggesting an extracellular source for the increased post-traumatic calcium levels. We also found that the post-traumatic change in intra-axonal calcium was completely abolished by the application of the sodium channel blocker tetrodotoxin or by replacement of sodium with N-methyl-d-glucamine. In addition, application of the voltage-gated calcium channel (VGCC) blocker omega-conotoxin MVIIC attenuated the post-traumatic increase in calcium. Furthermore, blockade of the Na(+)-Ca(2+) exchanger with bepridil modestly reduced the calcium influx after injury. In contrast to previously proposed mechanisms of calcium entry after axonal trauma, we found no evidence of calcium entry through mechanically produced pores (mechanoporation). Rather, our results suggest that traumatic deformation of axons induces abnormal sodium influx through mechanically sensitive Na(+) channels, which subsequently triggers an increase in intra-axonal calcium via the opening of VGCCs and reversal of the Na(+)-Ca(2+) exchanger.

Axons↗
PubMed2001

Use of newborn Girardia tigrina (Girard, 1850) in acute toxicity tests.

Acute toxicity tests, exposing Girardia tigrina to potassium dichromate (K(2)Cr(2)O(7)), showed good reproducibility. The 95% confidence intervals among tests were 0.0262+/-0.0141 g for 48-h LC(50) (N=6) and 0.0129+/-0.0078 g for 96-h LC(50) (N=5). The 96-h LC(50) for G. tigrina was below that of oligochaetes and above that of cladocera.

Animals↗
PubMed2001

Giant cell arteritis mimicking a testicular tumour.

Giant cell arteritis involving the testis was identified incidentally upon orchidectomy of a right testicular mass. The mass looked like a malignant process on ultrasound. The patient also had generalised disease and was treated appropriately. Giant cell arteritis involving the bladder, prostate, uterus, and adnexa have been described before. To our knowledge, this is the first described case of giant cell arteritis affecting the testis.

Aged↗
PubMed2001

Notes on a pilgrimage to science: a fly on the wall.

The paper is a set of reflections on the moral culture of modern biology built around the author's experience as a participant observer in two university laboratories. I draw parallels between laboratory culture and organized religion and point out practical problems in conducting scientific research. The notion that good biologists must be atheists is questioned and failures of organized religion are noted. The paper concludes with a suggestion that research ethics should be rooted in laboratory practice and must include vigorous principles of honesty and justice. Those are not requirements imposed from outside but internal requirements of the research community.

Biological Science Disciplines↗
PubMed2001

Contrasting clinical properties and exercise responses in obese and lean hypertensive patients.

OBJECTIVES: We sought to test whether the differences in activity of the renin-angiotensin and sympathetic nervous systems at rest or during exercise can explain the differing cardiovascular properties and outcomes of lean and obese hypertensive patients. BACKGROUND: Although lean hypertensive patients have fewer metabolic abnormalities than obese hypertensive patients, paradoxically they appear to have a poorer cardiovascular prognosis. METHODS: To evaluate the heightened risks in lean hypertensive patients, this study compared metabolic, neuroendocrine and cardiovascular characteristics at rest and during a standardized treadmill protocol in obese (body mass index [BMI] = 32.5 +/- 0.3 kg/m2, n = 55) and lean (BMI = 24.3 +/- 0.2 kg/m2, n = 66) hypertensive patients. Normotensive obese (n = 21) and lean (n = 55) volunteers served as control subjects. RESULTS: Compared with the lean normotensive subjects, the lean and obese hypertensive patients had greater left ventricular mass index (LVMI) values, but on multivariate analysis, LVMI correlated with plasma renin activity (p < 0.001) and plasma norepinephrine (PNE) (p < 0.01) in the lean but not the obese hypertensive patients. Arterial compliance (stroke volume/pulse pressure ratio) was reduced in the lean hypertensive patients, in whom it correlated (p = 0.033) with PNE. The PNE rose less (22%) in the obese than in the lean (55%) hypertensive patients in response to standing (p < 0.05). Likewise, during treadmill exercise, there were lesser increases in renin (65% vs. 145%, p < 0.01) and epinephrine (200% vs. 500%, p < 0.05) in the obese hypertensive patients. These changes were also less in obese patients than in lean control subjects, indicating attenuated neurohormonal responses to stress in obesity. CONCLUSIONS: Compared with obese hypertensive patients, cardiovascular properties in lean hypertensive patients are more dependent on catecholamines and the renin system. The different neuroendocrine responses to dynamic stimuli in lean and obese patients also might help to explain the disparity in their cardiovascular outcomes.

Adult↗
PubMed2001

A new chronotherapeutic oral drug absorption system for verapamil optimizes blood pressure control in the morning.

A novel verapamil chronotherapeutic oral drug absorption system (CODAS-Verapamil) designed for bedtime dosing and with controlled onset and extended-release properties was evaluated in 257 patients with mild-to-moderate essential hypertension in an 8-week, double-blind, placebo-controlled trial. After bedtime dosing (9 PM to 11 PM, this delivery system delays drug release for 4 to 5 h, and provides the highest concentrations of verapamil between 6 AM and noon. The study results showed that CODAS-verapamil produced its greatest antihypertensive effect during this morning period (6 AM to 12 noon) and also provided effective trough diastolic blood pressure reductions at 200, 300, and 400 mg. Significant trough systolic blood pressure reductions were achieved only with the 300- and 400-mg doses. The nighttime dosing regimen was not associated with excessive blood pressure (BP) reductions during the sleeping hours, when the antihypertensive effect was generally slightly less than that of the 24-h mean reduction. The CODAS-verapamil provides enhanced BP reduction during the morning period when compared with other time intervals of the 24-h dosing period.

Absorption↗
PubMed2001

Valsartan alone or with a diuretic or ACE inhibitor as treatment for African American hypertensives: relation to salt intake.

Previous clinical trials have demonstrated the important influence of ethnicity and dietary salt on the antihypertensive efficacy of drugs that block the renin angiotensin system. Angiotensin II receptor blockers are a new therapeutic entity that have not been widely studied in African American hypertensives, either alone, or in combination with other therapies such as diuretics or angiotensin converting enzyme inhibitors. We performed a pilot, prospective, open label, randomized design clinical trial to evaluate the effects of the angiotensin II receptor blocker valsartan (160 mg once a day) on systolic and diastolic blood pressure in hypertensive African Americans (n = 88) on a low salt (100 mEq Na+/day) for 2 weeks and the same diet supplemented by 100 mEq Na+ for 4 weeks. After this evaluation, while continuing the Na+ supplementation, patients were randomized to valsartan 320 mg/day (n = 28), or the addition of hydrochlorothiazide (HCTZ) 12.5 mg/day (n = 30), or benazepril 20 mg/day to the valsartan 160 mg/day for an additional 6 weeks. Valsartan (160 mg/day) lowered blood pressure significantly in African American patients on both low salt (-6.4/-4.8 mm Hg: P < .001) and a high salt diet (-4.9/-3.8 mm Hg: P = .01). The high salt diet attenuated the antihypertensive effect slightly (1.6/1.3 mm Hg, P = not significant). When comparing the efficacy of the three randomized therapeutic regimens while on the Na+ supplement, the valsartan 160 mg/HCTZ 12.5 mg was the most effective therapy with an incremental reduction in blood pressure of -10.5/-6.9 mm Hg (P < .01), compared to valsartan 160 mg/day alone. Doubling the dose of valsartan to 320 mg incrementally lowered blood pressure by -3.8/-3.3 mm Hg (P = not significant). The least effective approach was adding benazepril 20 mg/day to valsartan 160 mg/day with no incremental reduction in systolic blood pressure and diastolic blood pressure reduction of only 1.7 mm Hg (P = not significant). We conclude that in our open label pilot study, the antihypertensive activity of valsartan is not significantly attenuated by supplemented salt diet in hypertensive African Americans. Moreover, adding a low dose of HCTZ appears to be the most effective strategy in enhancing the antihypertensive activity of this angiotensin II receptor blocker in contrast to either doubling the dose or adding an angiotensin converting enzyme inhibitor.

Adult↗
PubMed2001

Pharmacology of cardiovascular chronotherapeutic agents.

Although sudden cardiac death, myocardial infarction, or stroke can occur at any time of day, event rates increase during the waking hours, particularly in the morning. In most people-both normotensive and hypertensive-blood pressure (BP) rises rapidly in the early morning hours, the time when most individuals wake and begin their day. This rise in BP corresponds to increased secretion of catecholamines and increased plasma renin activity. Thus, vascular tone and total peripheral resistance increase in the morning hours, and BP rises as a result. At the same time, heart rate increases. In the late morning or early afternoon, BP reaches its peak. After that, BP declines, falling 15 to 20 mm Hg between about 8 PM and 2 AM, the time when BP is usually lowest. These findings have led to an interest in chronotherapy for hypertension. A major objective of chronotherapy for hypertension is to deliver the drug in higher concentrations during the early-morning post-awakening period, when BP is highest, and in lesser concentrations during the middle of a sleep cycle, when BP is low. Traditional sustained-release pharmacologic agents, which deliver a near-constant drug concentration, were not designed to complement the circadian pattern. There are currently two antihypertensive agents, Verelan PM (verapamil HCl) and Covera HS (verapamil HCl), that provide chronotherapy for hypertension. These drugs use novel delivery systems that provide 24-h BP control while maximizing drug concentrations in the morning and minimizing drug concentrations during sleep.

Antihypertensive Agents↗
PubMed2001

The practice of discounting in economic evaluations of healthcare interventions.

OBJECTIVES: Discounting of costs in health-related economic evaluation is generally regarded as uncontroversial, but there is disagreement about discounting health benefits. We sought to explore the current recommendations and practice in health economic evaluations with regard to discounting of costs and benefits. METHODS: Recommendations for best practice on discounting for health effects as set out by government agencies, regulatory bodies, learned journals, and leading health economics texts were surveyed. A review of a sample of primary literature on health economic evaluations was undertaken to ascertain the actual current practice on discounting health effects and costs. RESULTS: All of the official sources recommended a positive discount rate for both health effects and costs, and most recommended a specific rate (range, 1% to 8%). The most frequently specified rates were 3% and 5%. A total of 147 studies were reviewed; most of these used a discount rate for health of either 0% (n = 50) or 5% (n = 67). Over 90% of studies used the same discount rate for both health and cost. While 28% used a zero rate for both health and cost, in 64% a nonzero rate was used for both. Studies where the health measure was in natural clinical units (direct) were significantly more likely to have a zero discount rate. CONCLUSION: The finding that 28% of studies did not discount costs or benefits is surprising and concerning. A lower likelihood of discounting for benefits when they are in natural units may indicate confusion regarding the rationale for discounting health effects.

Benchmarking↗
PubMed2001

A new strategy to produce sustained growth of central nervous system axons: continuous mechanical tension.

Although a primary strategy to repair spinal cord and other nerve injuries is to bridge the damage with axons, producing axons of sufficient length and number has posed a significant challenge. Here, we explored the ability of integrated central nervous system (CNS) axons to grow long distances in response to continuous mechanical tension. Neurons were plated on adjacent membranes and allowed to integrate, including the growth of axons across a 50-microm border between the two membranes. Using a microstepper motor system, we then progressively separated the two membranes further apart from each other at the rate of 3.5 microm every 5 min. In the expanding gap, we found thick bundles comprised of thousands of axons that responded to this tensile elongation by growing a remarkable 1 cm in length by 10 days of stretch. This is the first evidence that the center portion of synapsed CNS axons can exhibit sustained "stretch-induced growth." This may represent an important growth mechanism for the elongation of established white matter tracts during development. We also found by doubling the stretch rate to 7 microm/5 min that the axon bundles could not maintain growth and disconnected in the center of the gap by 3 days of stretch, demonstrating a tolerance limit for the rate of axonal growth. We propose that this newfound stretch-induced growth ability of integrated CNS axons may be exploited to produce transplant materials to bridge extensive nerve damage.

Animals↗
PubMed2001

Amino-terminal domain exchange redirects origin-specific interactions of adeno-associated virus rep78 in vitro.

The unique ability of adeno-associated virus type 2 (AAV) to site-specifically integrate its genome into a defined sequence on human chromosome 19 (AAVS1) makes it of particular interest for use in targeted gene delivery. The objective underlying this study is to provide evidence for the feasibility of retargeting site-specific integration into selected loci within the human genome. Current models postulate that AAV DNA integration is initiated through the interactions of the products of a single viral open reading frame, REP, with sequences present in AAVS1 that resemble the minimal origin for AAV DNA replication. Here, we present a cell-free system designed to dissect the Rep functions required to target site-specific integration using functional chimeric Rep proteins derived from AAV Rep78 and Rep1 of the closely related goose parvovirus. We show that amino-terminal domain exchange efficiently redirects the specificity of Rep to the minimal origin of DNA replication. Furthermore, we establish that the amino-terminal 208 amino acids of Rep78/68 constitute a catalytic domain of Rep sufficient to mediate site-specific endonuclease activity.

Base Sequence↗
PubMed2001

The costs of treating COPD in the United States.

STUDY OBJECTIVES: COPD affects millions of people in the United States. The purpose of this study was to describe the medical resource use and costs incurred by persons with COPD in the United States in 1987. DESIGN: Data for this study were derived from the 1987 National Medical Expenditure Survey. A societal perspective was adopted for this analysis. PATIENTS OR PARTICIPANTS: All persons > or = 40 years old with resource use or expenditures for chronic bronchitis, emphysema, or nonspecific chronic airway obstruction were included in this study. RESULTS: Mean per-person direct medical expenditures among persons with COPD were $6,469 (1987 US dollars), about 25% of which was COPD related. Approximately 68% of direct medical expenditures in persons with COPD were for inpatient hospitalization. CONCLUSIONS: COPD causes a large societal burden of illness that is expected to increase. This study provides a valuable foundation and historical measure against which to compare other estimates.

Adult↗
PubMed2000

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.

Adult↗