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D H Smith

Publications and source records attributed to D H Smith.

At least 91 records · Page 5Linked to original sources
PubMed1997

A cost of illness study of allergic rhinitis in the United States.

BACKGROUND: Allergic rhinitis is a common condition, but the burden of this condition on the national economy is not well understood. OBJECTIVE: The purpose of this study was to estimate the national direct and indirect costs of allergic rhinitis. METHODS: Data from the National Medical Expenditure Survey were used to provide estimates of resource utilization, medical expenditures, and lost productivity. With the complex survey design, variance estimates were used to construct confidence intervals for cost estimates of resource utilization and lost productivity. RESULTS: It is estimated that approximately 39 million persons in the United States experienced allergic rhinitis in 1987. However, only 12.3% (4.8 million) sought medical treatment for allergic rhinitis. The total estimated cost of the condition, in 1994 dollars, was $1.23 billion (95% confidence interval, $846 million to $1.62 billion). Direct medical expenses accounted for 94% of total costs. Allergic rhinitis results in approximately 811,000 missed workdays, 824,000 missed school days, and 4,230,000 reduced activity days. CONCLUSION: Allergic rhinitis clearly creates a burden in terms of the number of persons affected, total expenditures, and lost productivity. It also appears that a relatively large proportion of persons with allergic rhinitis were not seeking medical treatment.

Adolescent↗
PubMed1997

Central nervous system resuscitation.

Traumatic injury to the central nervous system induces delayed neuronal death, which may be mediated by acute and chronic neurochemical changes. Experimental identification of these injury mechanisms and elucidation of the neurochemical cascade following trauma may provide enhanced opportunities for treatment with novel neuroprotective strategies.

Animals↗
PubMed1997

Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice.

We constructed two megabase-sized YACs containing large contiguous fragments of the human heavy and kappa (kappa) light chain immunoglobulin (Ig) loci in nearly germline configuration, including approximately 66 VH and 32 V kappa genes. We introduced these YACs into Ig-inactivated mice and observed human antibody production which closely resembled that seen in humans in all respects, including gene rearrangement, assembly, and repertoire. Diverse Ig gene usage together with somatic hypermutation enables the mice to generate high affinity fully human antibodies to multiple antigens, including human proteins. Our results underscore the importance of the large Ig fragments with multiple V genes for restoration of a normal humoral immune response. These mice are likely to be a valuable tool for the generation of therapeutic antibodies.

Amino Acid Sequence↗
PubMed1997

Human African trypanosomiasis in south-eastern Uganda: clinical diversity and isoenzyme profiles.

The spectrum of clinical manifestations of trypanosomiasis in south-eastern Uganda is extremely wide. Isoenzyme characterization of trypanosome strains isolated in this area during recent epidemics of sleeping sickness has shown that particular clinical features of the disease can be related to the zymodeme of the causative parasite. For example, B17, part of the 'busoga' group of isolates and a zymodeme identified from central areas of Busoga during outbreaks of sleeping sickness, is associated with severe early features and a high frequency of presentation with a chancre. Isolates belonging to the 'zambezi' group, most of which came from areas close to the lake shores or close to the River Nile, were more heterogenous and were associated with significantly different clinical features: a more chronic, prolonged illness; more frequent presentation with meningo-encephalitis, and less frequent chancres. The clinical spectrum of infection associated with the parasites currently in circulation indicates that the previous endemicity and the early epidemics could be explained on the basis of existing zymodemes.

Animals↗
PubMed1997

Metabolic quantification of lesion volume following experimental traumatic brain injury in the rat.

A reliable and rapid method for quantifying lesion volume following traumatic brain injury (TBI) has vast potential in brain injury research. Staining with 2, 3, 5-triphenyltetrazolium chloride (TTC) provides for demarcation of damaged or infarcted tissue from normal, viable cerebral tissue, in which a red formazan product is formed by reduction during cellular respiration of mitochondrial dehydrogenase enzymes. The present study evaluated the use of TTC staining to quantify the cortical lesion volume in rats undergoing fluid-percussion (FP) brain injury. Male Sprague-Dawley rats (350-450 g, n = 27) were anesthetized (sodium pentobarbital, 60 mg/kg, ip) and subjected to lateral FP brain injury of mild (1.1-1.3 atm, n = 5), moderate (2.0-2.3 atm, n = 9), or high (2.4-2.6 atm, n = 8) severity, while sham (noninjured) animals (n = 5) were anesthetized and surgically prepared without injury. Forty-eight hours after injury animals were sacrificed, brains were stained with TTC, and lesion volumes were calculated. A highly significant correlation was found between cerebral cortical lesion volume (mm3) and severity of brain injury (r = 0.85; p < 0.0001). The mean (+/-SD) lesion volumes were 12.1 (+/-4.5) mm3 following mild injury, 33.8 (+/-8.6) mm3 following moderate injury, and 45.1 (+/-14.0) mm3 following severe injury. A significant difference was observed between all injury groups using a t test with Bonferroni correction (p < 0.05). These results suggest that the TTC staining technique is a useful, rapid, and reproducible method for quantification of lesion volume following lateral FP brain injury.

Animals↗
PubMed1997

Delayed administration of basic fibroblast growth factor (bFGF) attenuates cognitive dysfunction following parasagittal fluid percussion brain injury in the rat.

The present study evaluates the therapeutic effects of delayed administration of bFGF on cognitive dysfunction and histopathological damage following lateral fluid-percussion (FP) brain injury. Male Sprague-Dawley rats were trained to learn a visuospatial task in a Morris Water Maze (MWM) paradigm and then were anesthetized and subjected to either FP brain injury of moderate severity (2.5-2.8 atm, n = 32) or surgery without brain injury (n = 10). Twenty-four hours postinjury, an infusion cannula connected to a mini-osmotic pump was implanted into the area of maximal cortical injury to continuously infuse either bFGF (2.0 g) or vehicle for 7 days. Treatment with bFGF significantly attenuated posttraumatic memory dysfunction in the MWM at 8 days postinjury when compared to vehicle treatment (p < 0.05). The cortical lesion and significant cell loss in the ipsilateral CA3 region of the hippocampus, produced by FP injury, was not affected by bFGF treatment. However, immunohistochemical evaluation of glial fibrillary acidic protein revealed a trend toward increased astrocytosis in the injured cortex of bFGF-treated animals compared to vehicle-treated animals (p < 0.1). These results indicate that bFGF may be efficacious in attenuating cognitive dysfunction associated with traumatic brain injury.

Analysis of Variance↗
PubMed1997

Effects of the novel NMDA antagonists CP-98,113, CP-101,581 and CP-101,606 on cognitive function and regional cerebral edema following experimental brain injury in the rat.

The present study evaluated the effects of two novel N-methyl-D-aspartate (NMDA) receptor blockers and ifenprodil derivatives, CP-101,606 and CP-101,581, and their racemic mixture CP-98,113, on spatial memory and regional cerebral edema following experimental fluid-percussion (FP) brain injury in the rat (n = 66). Fifteen minutes after brain injury (2.5 atm), animals received either (1) CP-98,113 (5 mg/kg, i.p., n = 11), (2) CP-101,581 (5 mg/kg, i.p., n = 13), (3) CP-101,606 (6.5 mg/kg, i.p., n = 12), or (4) DMSO vehicle (equal volume, n = 12); followed by a continuous 24-h subcutaneous infusion of drug at a rate of 1.5 mg/kg/h by means of miniature osmotic (Alzet) pumps implanted subcutaneously. Control (uninjured) animals were subjected to identical anesthesia and surgery without injury and received DMSO vehicle (n = 8); CP-98,113 (5 mg/kg, i.p., n = 3); CP-101,581 (5 mg/kg, i.p., n = 3); or CP-101,606 (6.5 mg/kg, i.p., n = 3). FP brain injury produced a significant cognitive impairment assessed at 2 days postinjury using a well-characterized testing paradigm of visuospatial memory in the Morris Water Maze (MWM) (p < 0.001). Administration of either CP-98,113, CP-101,581, or CP-101,606 had no effect on sham (uninjured) animals, but significant attenuated spatial memory impairment assessed at 2 days postinjury (p = 0.004, p = 0.02, or p = 0.02, respectively). Administration of CP-89,113 but not CP-101,581 or CP-101,606 significantly reduced the extent of regional cerebral edema in the cortex adjacent to the site of injury (p < 0.05) and in the ipsilateral hippocampus (p < 0.05) and thalamus (p < 0.05). These results suggest that excitatory neurotransmission may play a pivotal role in the pathogenesis of memory dysfunction following traumatic brain injury (TBI) and that blockade of the NMDA receptor may significantly attenuate cognitive deficits associated with TBI.

Animals↗
PubMed1997

High-resolution 1H NMR spectroscopy following experimental brain trauma.

We investigated acute metabolic changes following parasagittal fluid-percussion brain injury in the rat, using high-resolution 1H nuclear magnetic resonance (NMR) spectroscopy. Sixty minutes following brain injury or sham (surgery, no injury) treatment, brains were rapidly removed and the injured and control cortices were isolated (n = 5/group). Isolates of brain cortices were then placed in buffer and studied in a 400-MHz spectrometer with measurements taken every 15 min over a 145-min period. At the initial NMR evaluation (immediately following dissection), we observed significantly lower levels of N-acetyl aspartic acid (NAA) in the injured group compared to the sham group. Surprisingly, a reciprocal increase in the concentration of acetate, a major metabolic product of NAA, was not observed at this timepoint. At subsequent timepoints, a progressive loss of NAA was observed in both injured and sham cortices, presumably due to ischemic conditions of the ex vivo samples. However, this progressive loss of NAA was now accompanied by a commensurate accumulation of acetate. These results suggest that (1) a decrease in the concentration of NAA occurs by 1 h following experimental brain trauma, potentially marking traumatic neural injury; (2) the initial absence of an expected reciprocal increase in acetate concentration may signify rapid utilization of acetate following trauma, potentially for reparative processes; and (3) in contrast to trauma alone, post mortem ischemic conditions may induce an increase in acetate concentrations.

Animals↗
PubMed1997

Progressive atrophy and neuron death for one year following brain trauma in the rat.

Although atrophic changes have been well described following traumatic brain injury (TBI) in humans, little is known concerning the mechanisms or progression of brain tissue loss. In the present study, we evaluated the temporal profile of histopathological changes following parasagittal fluid-percussion (FP) brain injury in rats over 1 year postinjury. Anesthetized 3-4 month-old Sprague-Dawley Rats (n = 51) were subjected to FP brain injury of high severity (2.5-2.9 atm, n = 51) or sham treatment (n = 27). At 1 h, 2 h, 48 h, 1 week, 2 weeks, 1 month, 2 months, 6 months and 1 year after brain injury or sham treatment, these animals were humanely euthanized. Brain sections were analyzed with image-processing techniques to determine the extent of cortical tissue loss and shrinkage of the hippocampal pyramidal cell layer. In addition, cell counting was performed to determine the number of neurons in the dentate hilus of the hippocampus, and glial fibrillary acidic protein (GFAP) immunostaining was used to reveal reactive astrocytosis. Examination of the injured brains revealed substantial and progressive tissue loss with concomitant ventriculomegaly in the hemisphere ipsilateral to injury. The regions with the most notable progressive atrophy included the cortex, hippocampus, thalamus, and septum. Quantitative analysis demonstrated a significantly progressive loss of cortical tissue as well as shrinkage of the hippocampal pyramidal cell layer ipsilateral to injury over 1 year following injury. In addition, reactive astrocytosis in regions of atrophy and progressive bilateral death of neurons in the dentate hilus was observed for 1 year following injury. These results suggest that a chronically progressive degenerative process may be initiated by brain trauma. Thus, there is a temporally broad window within which to introduce novel therapeutic strategies designed to ameliorate the short and long-term consequences of brain trauma.

Animals↗
PubMed1997

The circadian pattern of blood pressure: cardiovascular risk and therapeutic opportunities.

It has been known for many years that humans possess internal time clocks that regulate multiple physiologic factors (chronobiology). Epidemiologic studies have demonstrated that the peak incidence of many diseases, including respiratory disease (asthma, allergy), cardiovascular disease (hypotension, angina, myocardial infarction, stroke), as well as several others, tends to occur in a circadian pattern. In particular, studies utilizing ambulatory blood pressure monitoring have demonstrated that blood pressure has a very definite and reproducible circadian pattern over a 24-h period. Blood pressure is highest during the day; lowest during sleep, and then rapidly increases during the period 0400 h to 1200 h. Because recent data have demonstrated a possible cause-effect relationship between increases in blood pressure and angina, effective antihypertensive control in the early morning is desirable. Some once-a-day drugs taken in the morning may lose efficacy in the last few hours of the dosing interval, resulting in increases in blood pressure during the early morning period. In an attempt to ensure peak plasma levels during the early morning period, novel, controlled-onset, extended release-delivery systems have been developed. Studies using these delivery systems have demonstrated that, when dosed at night, these formulations provide maximal plasma levels during the period 0600 h to 1200 h, when blood pressure is physiologically rising at its greatest rate. The use of drugs designed to have peak efficacy at certain desirable times in the circadian pattern is referred to as chronotherapeutics.

Antihypertensive Agents↗
PubMed1997

A national estimate of the economic costs of asthma.

This cost of illness analysis examines national cost and resource utilization by persons with asthma using a single, comprehensive data source, the 1987 National Medical Expenditure Survey. Direct medical expenditures included payments for ambulatory care visits, hospital outpatient services, hospital inpatient stays, emergency department visits, physician and facility payments, and prescribed medicines. Indirect medical costs included costs resulting from missed work or school and days with restricted activity at work. Point estimates and 95% confidence intervals (CI) were calculated and inflated to 1994 dollars. The total estimated cost was $5.8 billion (95% CI, $3.6 to $8 billion). The estimated direct expenditures were $5.1 billion (95% CI, $3.3 to $7.0 billion), and indirect expenditures were valued at $673 million (95% CI, $271 to $1,076 million). Hospitalization accounted for more than half of all expenditures. More than 80% of resources were used by 20% of the population (defined as 'high-cost patients'). The estimated annual per patient cost for those high-cost patients was $2,584, in contrast with $140 for the rest of the sample. Findings from this study indicate that future asthma research and intervention efforts directed at hospitalizations and high-cost patients could help to decrease health care resource use and provide cost savings.

Absenteeism↗
PubMed1997

Characterization of diffuse axonal pathology and selective hippocampal damage following inertial brain trauma in the pig.

Dynamic deformation applied to white matter tracts is a common feature of human brain trauma, and may result in diffuse axonal injury (DAI). To produce DAI in an experimental model, we have utilized nonimpact inertial loading to induce brain trauma in miniature swine. This species was chosen due to its large gyrencephalic brain with substantial white matter domains. Twenty anesthetized (2% isoflurane) miniature swine were subjected to pure impulsive centroidal rotation 110 degrees in the coronal plane in 4 to 6 ms; peak accelerations ranged from 0.6 to 1.7 x 10(5) rad/s2. Seven days following injury, the brains were fixed (4% paraformaldehyde). Histopathologic examination was performed on 40 microns sections stained with cresyl violet (Nissl), antibodies targeting neurofilament (axonal damage), GFAP (astrocytes), and pig IgG (protein extravasation). Widespread multifocal axonal injury was observed in combination with gliosis throughout the brain, most commonly in the root of gyri and at the interface of the gray and white matter. Very little vascular disruption was noted in regions of axonal injury. Neuronal damage was primarily found in the CA1 and CA3 subfields of the hippocampus. These results suggest that this model is clinically relevant and useful for evaluating mechanisms of inertial brain trauma.

Animals↗
PubMed1996

The 1996 Albert Lasker Medical Research Awards. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharide-based vaccines.

The development of Haemophilus influenzae type b (Hib) conjugate vaccines has led to the virtual elimination of systemic infections caused by that pathogen, has provided insights into the pathogenesis of and immunity to other capsulated bacteria, and has contributed to the development of new vaccines. Meningitis, a common and serious infection of children, and other infections caused by Hib have been virtually eliminated in countries that have achieved widespread vaccination with Hib conjugates, including the United States, Canada, the United Kingdom, Iceland, Scandinavia, France, and Germany. Hib conjugates have also been shown to be highly effective in developing countries. The principles derived from the use of these vaccines, along with studies of other capsulated pathogens, should allow the rapid inclusion of new polysaccharide-based conjugates into routine vaccination schedules of infants, and should help to realize further reductions in serious systemic infectious diseases.

Animals↗
PubMed1996

Thymocyte cell fate alteration by high levels of CD8alpha is independent of CD8-lck association.

CD8 expression on the surface of developing thymocytes is essential for the positive selection and maturation of CD8 single positive T cells. CD8 is physically associated with the cytoplasmic tyrosine kinase, p56lck and, in addition to increasing the avidity between the TCR and MHC/peptide complex, may transduce intracellular signals. Here we address the extent to which the requirement for CD8 in thymocyte selection depends on its capacity to signal vs its contribution to avidity. We have previously reported that elevated levels of CD8alpha can alter the fate of developing 2C TCR+ thymocytes from positive to negative selection in H-2b mice. We show here that the fate of 2C TCR thymocytes overexpressing a mutant form of CD8alpha that does not bind to p56lck is the same as that of thymocytes overexpressing the wild-type CD8alpha-chain. This finding demonstrates that, for a TCR-MHC system in which the level of CD8alpha is the deciding factor in cell fate, negative selection does not require increased CD8-dependent signaling through p56lck. We have also found that highly elevated levels of CD8alpha expression (10-fold) block thymocyte maturation in both CD8alpha single and CD8alpha/HY TCR double transgenic mice. Although these may be additional examples of CD8alpha overexpression altering cell fate from positive to negative selection, we present arguments in favor of the interpretation that high levels of CD8alpha actually may block positive selection.

Animals↗
PubMed1996

Calpain inhibitor AK295 attenuates motor and cognitive deficits following experimental brain injury in the rat.

Marked increases in intracellular calcium may play a role in mediating cellular dysfunction and death following central nervous system trauma, in part through the activation of the calcium-dependent neutral protease calpain. In this study, we evaluated the effect of the calpain inhibitor AK295 [Z-Leu-aminobutyric acid-CONH(CH2)3-morpholine] on cognitive and motor deficits following lateral fluid percussion brain injury in rats. Before injury, male Sprague-Dawley rats (350-425 g) were trained to perform a beam-walking task and to learn a cognitive test using a Morris water maze paradigm. Animals were subjected to fluid percussion injury (2.2-2.4 atm; 1 atm = 101.3 kPa) and, beginning at 15 min postinjury, received a continuous intraarterial infusion of AK295 (120-140 mg/kg, n = 15) or vehicle (n= 16) for 48 hr. Sham (uninjured) animals received either drug (n = 5) or vehicle (n = 10). Animals were evaluated for neurobehavioral motor function at 48 hr and 7 days postinjury and were tested in the Morris water maze to evaluate memory retention at 7 days postinjury. At 48 hr, both vehicle- and AK295-treated injured animals showed significant neuromotor deficits (P< 0.005). At 7 days, injured animals that received vehicle continued to exhibit significant motor dysfunction (P< 0.01). However, brain-injured, AK295-treated animals showed markedly improved motor scores (P<0.02), which were not significantly different from sham (uninjured) animals. Vehicle-treated, injured animals demonstrated a profound cognitive deficit (P< 0.001), which was significantly attenuated by AK295 treatment (P< 0.05). To our knowledge, this study is the first to use a calpain inhibitor following brain trauma and suggests that calpain plays a role in the posttraumatic events underlying memory and neuromotor dysfunction.

Animals↗