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Biomedical subjects

R P Smith

Publications and source records attributed to R P Smith.

At least 19 recordsLinked to original sources
PubMed1992

Characterization of platelet-releasable forms of beta-amyloid precursor proteins: the effect of thrombin.

Activated platelets release a potent inhibitor of factor XIa previously identified as a Kunitz proteinase inhibitor domain-containing form of the beta-amyloid precursor proteins (beta APP). Two carboxy-terminal truncated forms of the beta APP, beta APP-751 and beta APP-770, are shown to be the predominant isoforms secreted by platelets. The release of beta APP from platelets is responsible for the higher concentration of beta APP in serum compared with plasma, and thrombin dose-response data show that release of beta APP is most consistent with alpha granule localization within the platelet. Thrombin induces a limited and specific proteolysis of platelet-secreted beta APP, resulting in loss of a carboxy-terminal fragment. This phenomena is dependent on both thrombin concentration and duration of incubation and is inhibited by the thrombin-specific inhibitor hirudin, characteristics that can be duplicated in a mixture of purified recombinant beta APP-751 and thrombin. A similar effect of thrombin on full-length transmembrane forms of beta APP would result in a membrane-bound remnant containing the intact beta-amyloid protein.

Alternative Splicing↗
PubMed1992

Formation of nitric oxide hemoglobin in erythrocytes co-cultured with alveolar macrophages taken from bleomycin treated rats.

Alveolar macrophages, taken from rats treated with a single intratracheal dose of bleomycin, release reactive nitrogen intermediates in the form of nitric oxide which are cytostatic to murine leukemia L1210 cells. When cultured in the presence of erythrocytes the cytostatic activity of alveolar macrophages was inhibited which corresponded with an increase in nitrosylated hemoglobin content when compared with erythrocytes cultured alone. These results suggest that erythrocytes inhibit alveolar macrophage cytostatic activity by preventing reactive nitrogen intermediates from reaching target cells because the hemoglobin serves as a sink for reactive nitrogen intermediates in the form of nitric oxide.

Animals↗
PubMed1992

Unrecognized association of sleep disorders and depression with chronic pelvic pain.

Assessment of cases of chronic pelvic pain presents a challenging problem, and many physicians overlook the association of sleep disorders and depression with such pain. We examined these linkages in our chronic pelvic pain clinic, using a questionnaire that assists in diagnosis and management of these cases. To date, the cases of 72 patients (both physician- and self-referred) with pelvic pain have been evaluated. Of these patients, 51 of 71 (72%) reported sleep disorders, and 37 of 72 (51%) had clinical depression, as determined by the Beck Depression Inventory. After adjustment for a sleep-related item on the Beck scale, these two measures showed a positive correlation of .355 (P < .01). The scores of pain patients differed significantly from those of a control group of asymptomatic patients on the depression and sleep disorder measures. By being aware and using a simple questionnaire, the clinician may readily identify overlooked factors, such as sleep disorders and depression, when assessing cases of chronic pelvic pain.

Adult↗
PubMed1992

Ventilatory and hematopoietic responses to chronic hypoxia in two rat strains.

Hilltop (H) and Madison (M) strains of Sprague-Dawley rats exhibit strikingly different susceptibilities to the effects of chronic altitude exposure. The H rats develop greater polycythemia, hypoxemia, and pulmonary hypertension. We studied ventilation, pulmonary gas exchange, tissue oxygenation, and hematologic adaptations in the two rat strains during a 50-day exposure to a simulated altitude (HA) of 5,500 m (18,000 ft). There were no strain differences among the variables we studied under sea level (SL) conditions. Within the first 14 days of hypoxic exposure, the only significant strain differences were that erythropoietin (EPO) rose much higher and erythroid activity was greater in the H rats, even though arterial Po2 and PCo2 (Pao2 and PaCo2, respectively), renal venous PO2 (Prvo2), and ventilation (VE) were equivalent in the two strains during this time. By day 14 at HA, the H rats had significantly higher erythroid activity, hematocrit (Hct), and EPO levels, significantly lower PaO2 and PrvO2, but equivalent VE and PaCO2. These changes persisted for the remainder of the exposure, except that the Hct continued to rise and the increase was greater in H rats. Despite the greater O2-carrying capacity of H rats in the later stages of hypoxic exposure, PaO2 and PrvO2 were significantly lower in H rats. There were no strain differences at either SL or HA in ventilatory responses to hypercapnia or hypoxia, in blood O2 affinity or 2,3-diphosphoglycerate, in extrarenal production of EPO, or in EPO clearance. We conclude that early in the hypoxic exposure the H rats produce more EPO at apparently equivalent levels of hypoxia, and this is the first step in the pathogenesis of the maladaptation to HA manifest by H rats. We find no consistent evidence that differences in VE contribute to the variable susceptibility to hypoxia in the two rat strains.

Altitude Sickness↗
PubMed1992

Diversity of tick species biting humans in an emerging area for Lyme disease.

BACKGROUND: Although most tick bites in humans in areas of the northeastern United States in which Lyme disease is highly endemic are due to Ixodes dammini, no study documents the frequency of I. dammini bites in low-prevalence or emerging areas for Lyme disease. Data on the proportion of tick bites in humans that are due to I. dammini in a region may have implications for public health policy and clinical management. METHODS: A statewide survey of the tick species that parasitized humans in Maine was conducted during 1989 and 1990. Tick submissions from throughout the state were elicited through media announcements. All ticks that had been removed from humans were identified, and data were collected that included bite seasonality and geography and demographics of tick bite victims. RESULTS: Of 709 ticks submitted, only 17% were I. dammini. Ixodes cookei, a vector for Powassan encephalitis, accounted for 34% of bites, and Dermacentor variabilis accounted for 45%. Other tick species were occasionally implicated. CONCLUSIONS: The likelihood that a tick bite was due to I. dammini was lower in Maine than in areas in the northeastern United States in which Lyme disease is highly endemic. Other tick vectors, associated with diseases other than Lyme disease, were more frequently implicated. Regional tick bite surveys may prove useful in assessing the risk of Lyme disease following a tick bite.

Adolescent↗
PubMed1992

Recreational propane inhalation in an adolescent male.

Propane inhalation may be widespread, yet only a few cases have been reported. The victims were usually found dead, and only one other report describes firsthand the sought-after effects. We report on a 17 year-old male with a six month history of repeated inhalation. The patient manifested no pathophysiologic signs, but the ready availability of propane may result in an increase in its abuse. This activity carries considerable risk for trauma and/or sudden death. Our patient was able to recruit others to the practice by finding ways to avoid some of the unique, inherent deterrents.

Adolescent↗
PubMed1992

Nitric oxide hemoglobin in patients receiving nitroglycerin as detected by electron paramagnetic resonance spectroscopy.

Blood specimens were obtained from 30 adult patients admitted to a coronary care unit after the decision to use nitroglycerin had been made by their physicians. The samples were drawn before nitroglycerin administration, within 1 hour after starting nitroglycerin, after several hours of therapy, and more than 4 hours after discontinuing therapy. One patient was admitted twice, accounting for 31 sets of blood specimens. A positive identification of nitric oxide-hemoglobin (NOHb), with electron paramagnetic resonance (EPR) spectroscopy could be made in the blood of 10 of the subjects after they had been receiving nitroglycerin for several hours (third blood sample). In seven subjects this third blood sample was not drawn, and they were dropped from the study. A final positive finding of NOHb was made in 10 of 24 patients. NOHb has not been identified previously in human subjects given nitroglycerin, and a significant dose-response relationship was observed between nitroglycerin and NOHb. We ascribe our inability to detect NOHb in all subjects before nitroglycerin (basal levels) and after nitroglycerin in 14 subjects to concentrations that were below the limits of detection of the technique as used. Subtraction of the EPR signal for plasma ceruloplasmin was necessary to detect the NOHb EPR signals. Thus we have shown EPR spectroscopy to be a highly specific and sensitive method for detecting and quantifying NOHb in human subjects. Further refinements in the technique to improve sensitivity are possible.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Acute neurotoxicity of sodium azide and nitric oxide.

Sodium azide is a chemical of rapidly growing commercial importance with a high acute toxicity and an unknown mechanism of action. Although it has some chemical properties and biological effects in common with cyanide, its lethality does not appear to be due to inhibition of cytochrome oxidase. Unlike cyanide it is a potent vasodilator and inhibitor of platelet aggregation presumably by virtue of its conversion to nitric oxide in vivo and in isolated preparations of blood vessels and thrombocytes. It is not clear whether the high toxicity of azide is due to nitric oxide or to the parent anion. Of a number of possible azide antagonists tested in intact mice only phenobarbital in both anesthetic and subanesthetic doses afforded statistically significant protection against death. Diazepam, phenytoin, and an anesthetic dose of a ketamine/xylazine combination had no effect. Major motor seizures are sometimes seen in human azide poisoning, and these are a regular feature of azide poisoning in laboratory rodents. Solutions of nitric oxide given systemically to mice produced no signs of toxicity, but doses 1,000-fold lower placed in the cerebroventricular system of rats produced brief but violent tonic convulsive episodes. A dose of 0.61 mmol/kg azide as given systemically regularly produced convulsions whereas a dose of 6 mumol/kg given icv produced seizures in rats. The icv convulsive dose of azide was 50-fold larger than the icv dose of nitric oxide. These results suggest that azide lethality is due to enhanced excitatory transmission in the central nervous system perhaps after its conversion to nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Antimicrobial effect of clindamycin in combination with aztreonam or aminoglycosides against Klebsiella spp.

The antimicrobial effect of clindamycin combined with aztreonam or an aminoglycoside (gentamicin, tobramycin or amikacin) was studied against 84 strains of Klebsiella pneumoniae and 18 strains of K. oxytoca with an agar dilution technique. Clindamycin concentrations of 1-20 mg/l and an inoculum of 10(4) cuf/spot were used. Anaerobic incubation of agar plates was associated with an increase in the MIC of aminoglycosides and no change or a decrease in the MIC of aztreonam. Lower concentrations of clindamycin (1-2 mg/l) were associated with a decrease in the MIC of aztreonam for 18% and an increase in the MIC of aminoglycosides for between 7% and 44% of the strains, depending upon the precise concentration used. However, higher concentrations of clindamycin (10-20 mg/l) were associated with a decrease in the MIC of aztreonam for between 36 and 87% and an increase in the MIC of aminoglycosides for between 13 and 64% of the isolates. These observations could be important when treatment plans for mixed aerobic/anaerobic infections including mixed Klebsiella spp. are considered.

Aminoglycosides↗
PubMed1991

Comparative in-vitro susceptibilities of Pseudomonas aeruginosa, Xanthomonas maltophilia, and Pseudomonas spp. to sparfloxacin (CI-978, AT-4140, PD131501) and reference antimicrobial agents.

The susceptibility of sparfloxacin, a new broad spectrum fluoroquinolone, was determined for 72 clinical isolates of Pseudomonas aeruginosa, 15 Xanthomonas maltophilia, and 19 Pseudomonas spp. The activity of sparfloxacin was compared with that of ciprofloxacin and other reference antibiotics. Sparfloxacin was the most active antibiotic tested against X. maltophilia (MIC90 1 mg/l) and the most active quinolone against P. cepacia and P. putrifaciens. Ciprofloxacin, however, demonstrated greater activity than sparfloxacin against P. fluorescens and P. stutzeri. P. aeruginosa was most susceptible to ciprofloxacin with an MIC90 of 2 mg/l, compared with an MIC90 of 8 mg/l for sparfloxacin and ofloxacin. Although cross-resistance between quinolones was noted, cross-resistance between antibiotic classes was not seen. Aminoglycoside-resistant and aminoglycoside-susceptible P. aeruginosa strains were equally susceptible to sparfloxacin. Kill curves showed sparfloxacin to be rapidly bactericidal against P. aeruginosa at 1 x MIC. Sparfloxacin demonstrated greater bactericidal activity than ciprofloxacin at 1 x and 2 x their MICs. Unlike ciprofloxacin and gentamicin, sparfloxacin showed sustained bactericidal activity at greater than or equal to 1 MIC for 24 h.

Anti-Bacterial Agents↗
PubMed1991

Synergy with cefsulodin or piperacillin and three aminoglycosides or aztreonam against aminoglycoside resistant strains of Pseudomonas aeruginosa.

Fifty-one strains of Pseudomonas aeruginosa, with resistance to one or more amino-glycosides, were tested for synergy with cefsulodin or piperacillin plus amikacin, tobramycin, gentamicin or aztreonam by the agar dilution technique. Cefsulodin plus any one of the three aminoglycosides regardless of the degree of resistance to the aminoglycoside was synergistic against P. aeruginosa for two thirds of the isolates. In contrast, synergy rates with piperacillin were much less uniform. The highest rate of synergy with piperacillin (90.0%) was observed with gentamicin for the gentamicin resistant strains. The lowest rate of synergy was observed with piperacillin plus amikacin (32.2%) for isolates with moderate resistance to amikacin. Synergy for strains with moderate resistance to amikacin was observed more commonly with cefsulodin than with piperacillin. Synergy for strains with a known mechanism of resistance to amikacin was more common with cefsulodin regardless of the mechanism of resistance. Cefsulodin or piperacillin in combination with aztreonam was rarely synergistic (less than 12%).

Aminoglycosides↗
PubMed1991

Isolation and characterization of a transposon-induced cytotoxin-deficient mutant of Pseudomonas aeruginosa.

In order to provide a better system for investigating the role of cytotoxin in pathogenesis, we mutated wild-type Pseudomonas aeruginosa PA158 by introducing a transposon. The resulting pool of mutants was screened for cytotoxin-deficient strains. One mutant strain, PA114F5, was compared with PA158. Except for cytotoxin production and antibiotic resistance (specified by the transposon), the two strains appear isogenic. This mutant strain should be useful in further clarifying the role of cytotoxin in pathogenesis.

Cytotoxins↗
PubMed1991

In vitro activity of sparfloxacin and six reference antibiotics against gram-positive bacteria.

The in vitro activity of sparfloxacin, a new fluoroquinolone, was assessed against 234 gram-positive bacterial isolates by agar dilution (10(4) CFU/spot). Sparfloxacin activity was compared with that of ciprofloxacin and five other antibiotics. Sparfloxacin was the most active drug tested against methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (MIC90, 0.125-0.25 mg/l). Sparfloxacin was also the most active drug tested against Enterococcus faecalis (MIC90, 1 mg/l) and showed equal activity against gentamicin-susceptible and gentamicin-resistant (MIC greater than 2,000 mg/l) enterococci. Sparfloxacin was the most active quinolone tested against Streptococcus pneumoniae and S. pyogenes (MIC90, 1 mg/l). Most Corynebacterium jeikeium showed exquisite susceptibility to sparfloxacin (MIC, 0.06-0.25 mg/l). For MRSA, time-kill curves showed sparfloxacin to be rapidly bactericidal at the MIC of the organism. Sparfloxacin showed greater and more sustained bactericidal activity than ciprofloxacin and vancomycin at 1x and 2x the MIC. Reduction in the activity of sparfloxacin occurred with decreased agar pH (from 7.0 to 6.0) and increased bacterial inoculum. Sparfloxacin showed superior activity compared to reference drugs against most gram-positive bacteria.

Anti-Bacterial Agents↗
PubMed1991

Canine seroprevalence and the distribution of Ixodes dammini in an area of emerging Lyme disease.

This study evaluates the relative usefulness of canine serosurveys to predict risk of exposure in an area of emerging Lyme disease by comparing the distribution of canine seroprevalence with that of vector ticks. From 16 veterinary clinics throughout the State of Maine, 828 canine sera were obtained during the heartworm-testing months of April and May 1989 and measured for anti-Borrelia antibodies by enzyme-linked immunosorbent assay. In the same year, 1605 ticks, including 585 Ixodes dammini, were collected from pets, humans, small mammals, and deer. Thirty-six dogs were seropositive, 28 of which had not traveled to endemic areas. Eighty-nine percent of all seropositive dogs were from towns within 20 miles (32 km) of the coast; the great majority lived within 5 miles (8 km) of tidewater (odds ratio =4.45, P = .002). Positivity varied from 17% in a southern coastal clinic to 0% in four northern clinics. Of 585 I. dammini identified, all but 5 (99.1%) were also from towns within 20 miles of the coast. Comparison of I. dammini submissions with those of another commonly found tick, Ixodes cookei, corroborated this predominantly coastal distribution. Canine seropositivity generally coincided with this coastal range. These data predicted areas of risk for human Lyme disease, although the prevalence of reported cases remained low.

Animals↗
PubMed1991

The effects of age and renal impairment on the pharmacokinetics of co-administered lisinopril and hydrochlorothiazide.

The pharmacokinetics of combined lisinopril and hydrochlorothiazide have been studied following single and multiple oral doses to 'young' (reference), elderly and renally impaired hypertensive patients. Tablets containing the fixed combination of lisinopril 20 mg and hydrochlorothiazide 12.5 mg were administered as a single dose followed by daily administration for 6-8 days. Serum concentration and haemodynamic measurements were made at intervals up to 48 hours after the first and last doses. The serum profiles of both drugs were comparable with observations from previous studies, showing higher concentrations in the elderly and in the renally impaired patients. Similar differences have been reported for such patient groups when the drugs were administered separately, indicating an absence of pharmacokinetic interaction. Both drugs accumulated by about 30% on multiple daily dosing. There were no differences between the patient groups in the extent of accumulation. The combination of lisinopril and hydrochlorothiazide produced the expected hypotensive response, minimum BP values being recorded 4 and 6 hours after treatment. The higher concentrations in the elderly and renally impaired patients were not associated with a greater reduction in BP. The pharmacokinetic behaviour of lisinopril and hydrochlorothiazide given together to elderly and renally impaired hypertensive patients suggests that a fixed dose combination is appropriate and that no changes to the dosage regimen additional to those used for the individual agents are necessary.

Adult↗
PubMed1991

Chemicals reacting with various forms of hemoglobin: biological significance, mechanisms, and determination.

The clinical chemistry of various forms of hemoglobin occupies a large fraction of the total activities of hospital and forensic science laboratories. Some of the potential pitfalls are reviewed here along with an account of the accidental discovery of two novel chemical forms. Human or mouse red blood cells were exposed to excess sodium nitrite to convert the intracellular pigment to methemoglobin. When these were subsequently incubated in Krebs-Ringer-phosphate-glucose medium, pH 7.4 at 37 degrees C under nitrogen and in the presence of various concentrations of methylene blue, a blood pigment was generated in high yield which had unique properties. In lysates, the pigment was stable in air, and it could be maintained in liquid nitrogen for as long as a year without deterioration. The pigment had properties different from those of oxyhemoglobin, deoxyhemoglobin, methemoglobin, or carboxyhemoglobin. After separation by isoelectric focusing, the pigment gave a strong signal on electron paramagnetic resonance (EPR) spectroscopy. The other forms of hemoglobin given above are EPR-silent. The pigment was eventually identified as the nitrosylated valency hybrid species, (alpha 2+ beta 3+)2(NO)2. The corresponding species, (alpha 3+ beta 2+)2(NO)2, has similar properties. These species apparently owe their unusual stability in air to the presence of the oxidized subunits in the same tetramer.

Animals↗