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Biomedical subjects

D B Smith

Publications and source records attributed to D B Smith.

At least 181 records · Page 10Linked to original sources
PubMed1988

Depression of gelsolin levels and detection of gelsolin-actin complexes in plasma of patients with acute lung injury.

Actin is the major protein of muscle and nonmuscle cells and is one of the most abundant body proteins. Physiologic or pathologic cell death may therefore result in the liberation of large amounts of this fibrous protein into the extravascular space. The potential for long actin filaments to increase plasma viscosity and change the rheology of the microvasculature are potentially obviated by the presence of 2 recently recognized plasma actin-binding proteins, vitamin-D-binding protein, and plasma gelsolin. As part of our initial evaluation of this newly recognized physiologic system in humans, we measured levels of gelsolin in plasma samples from patients with extensive lung injury. Gelsolin levels were depressed in 25 of 25 patients with the adult respiratory distress syndrome (ARDS), a disease characterized by massive cellular injury, as determined by either of 2 functional assays for gelsolin. Mean total gelsolin concentration of 20 patients with ARDS was 89.2 +/- 33 micrograms/ml (normal levels, approximately 240 micrograms/ml; p less than 0.001) and the mean free gelsolin concentration 69.6 +/- 29 micrograms/ml (normal levels, approximately 240 micrograms/ml; p less than 0.001). Gelsolin concentrations of 6 patients with bacterial pneumonias were also depressed, but to a lesser degree (mean total level, 117 +/- 21 micrograms/ml). Direct demonstration of the presence of actin in these plasmas (but not in normal plasmas) was performed by precipitating actin directly with DNase-Sepharose beads, or indirectly with antigelsolin-Sepharose beads, as confirmed with immunoblotting. Actin was found in 18 of 19 patients using DNase beads and in 7 of 19 using antigelsolin beads.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1988

Circulating actin-gelsolin complexes following oleic acid-induced lung injury.

Plasma gelsolin is one of two extracellular proteins that bind actin, a major body protein, with high affinity. The authors performed a series of experiments to determine whether tissue injury leads to actin release and the formation of circulating actin-gelsolin complexes. Two functions of plasma gelsolin, filament-nucleating and filament-severing activity, were used to measure total and free gelsolin concentrations, respectively. Both gelsolin and gelsolin-actin complexes nucleate actin assembly, whereas only free gelsolin severs actin filaments. Therefore, nucleation reflects the total gelsolin concentration, severing, the free gelsolin concentration, and the difference, gelsolin-actin complexes. Injection of F-actin in the rat caused a reduction in the free, but not total, gelsolin levels, consistent with the formation of circulating actin-gelsolin complexes. Oleic acid (50 mg/kg) administered intravenously in rats, a treatment that causes acute hemorrhagic pulmonary necrosis, caused the free gelsolin concentration to fall to a greater extent than the total gelsolin concentration, which indicated the presence of circulating actin-gelsolin complexes. Lower doses (9-27 mg/kg) in rabbits caused a qualitatively similar but smaller change in the free gelsolin level. Plasma gelsolin was immunoprecipitated at times when actin-gelsolin complexes were present, as determined functionally, and bound actin was demonstrated by immunoblotting with an anti-actin antiserum. These studies show that considerable amounts of actin are released into the extracellular space during acute lung injury and that circulating actin-gelsolin complexes can be detected in the peripheral blood.

Actins↗
PubMed1988

Decreased plasma gelsolin levels in patients with Plasmodium falciparum malaria: a consequence of hemolysis?

Mammalian plasma contains a high-affinity actin-binding protein, plasma gelsolin, that severs actin filaments. Destruction of erythrocytes could result in the release of erythrocyte cytoskeletal actin into the plasma where it could bind to gelsolin. If the clearance of actin-gelsolin complexes exceeds its synthesis, lowering of the plasma gelsolin concentration might follow. To test this hypothesis, we measured plasma gelsolin levels in patients with falciparum malaria, a disease where at least part of the hemolysis takes place in the intravascular space and that is usually not accompanied by dysfunction of other organs. Two functional gelsolin assays showed that the mean plasma gelsolin concentration of 18 Nigerian children with Plasmodium falciparum malaria was less than 50% (P less than .001) of healthy Nigerian control subjects tested at the same time. Patients with pneumonia and febrile seizures also had depressed gelsolin levels, which indicates that factors other than hemolysis can lower gelsolin concentrations. Gelsolin levels were measured in 11 patients from The Gambia with P falciparum malaria before and approximately 3 weeks after treatment. In all cases the gelsolin level increased after treatment. To confirm the hypothesis that hemolysis can result in a lowering of plasma gelsolin levels, hemolysis was induced in rabbits, either acutely (by the injection of human serum) or subacutely (by the administration of phenylhydrazine). A fall in plasma gelsolin levels was seen, the rate of fall differing with the extent of hemolysis. Affinity adsorption of plasma from animals undergoing acute hemolysis with Sepharose beads coupled to the actin-binding protein DNase I, followed by immunoblotting of adherent proteins with antiactin antiserum demonstrated the presence of actin in circulating rabbit plasma. These studies suggest that under some conditions components of the red cell cytoskeleton are exposed to plasma proteins and that accelerated clearance of actin-gelsolin complexes may explain in part the depressed plasma gelsolin levels seen in patients with falciparum malaria.

Actins↗
PubMed1988

Sneddon's disease presenting with visual loss and dementia.

A 51-year-old woman with Sneddon's disease presented with transient right hemifield loss of vision and transient right-sided weakness. Over the preceding decade she had experienced a slow decline in mental function. She also had hypertension, migraine, and a mixed seizure disorder. She had skin changes typical for generalized livedo reticularis but she did not have Raynaud's phenomenon or winter ulcerations. Her disease was not understood until the stroke-related symptoms were associated with the skin abnormalities. We review the neuro-ophthalmic manifestations of Sneddon's disease and add data from our case to the growing body of fact that suggests that Sneddon's disease may be an immunologically mediated vasculopathy.

Cerebrovascular Disorders↗
PubMed1988

Cancer in men.

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Humans↗
PubMed1987

Clinical pharmacology of oral and intravenous 4-demethoxydaunorubicin.

The clinical pharmacology of 4-demethoxydaunorubicin (4-DMDNR) was studied in 28 patients with advanced breast cancer, using a sensitive reverse-phase HPLC technique. All patients had normal renal and hepatic function. The serum levels of 4-DMDNR after a single i.v. bolus injection followed a triple exponential decay curve (T 1/2 alpha = 9.6 min, T 1/2 beta = 3.2 h and T 1/2 gamma = 34.7 h) and conformed to a three-compartment model. Comparison of the area under the curve (AUC) and urinary excretion for the oral and i.v. routes suggests an oral bioavailability of approximately 24%. In patients treated with a schedule of weekly oral administration for periods of up to 12 months there was no significant alteration in either AUC or elimination half-life for the parent drug or its principal metabolite 13-OH4DMDNR. Moreover, there was no evidence of accumulation of the metabolite although measurable amounts were present 7 days after administration of 4-DMDNR.

Administration, Oral↗
PubMed1987

Immunoscintigraphy with 99mTc labelled F(ab')2 fragments of an anti melanoma monoclonal antibody (225.28S) in patients with metastatic malignant melanoma.

Immunoscintigraphy was performed in 25 patients with malignant melanoma using a 99mTc labelled monoclonal antibody (225.28S). In four cases, imaging was repeated following treatment with recombinant gamma interferon. In 11 cases, tissue samples of metastatic lesions were investigated for the expression of melanoma associated antigens by immunohistochemical techniques. Overall, 59% of known lesions were detected by imaging. The highest rates of detection were in bone, liver and lymph nodes and the lowest in lung, stomach and bowel. Six lesions were detected which had not shown up on routine clinical and radiological examination. There was no evidence of enhanced or induced HMW-MAA expression following interferon treatment. This technique has been found to be useful in staging patients and has been free from side effects.

Adult↗
PubMed1987

Infiltrating lobular carcinoma of the breast: response to endocrine therapy and survival.

The records of 480 patients who received systemic therapy for advanced breast cancer in the University Hospital of South Manchester from 1975 to 1983 were examined. There were 264 with infiltrating duct carcinomas (IDC) and 33 with infiltrating lobular carcinomas (ILC) for whom the response to endocrine therapy was known. There were 92 responses (35%) among the IDC patients and 9 (27%) among the ILC patients. Sixty-seven per cent of IDC patients tested had steroid hormone receptor positive tumours compared to 90% for ILC (P less than 0.001). Comparison of survival from diagnosis, disease free interval and survival from relapse showed no significant differences between the two groups. Thus despite almost all ILC patients having hormone receptor positive tumours their survival was similar to that of IDC patients. This appears to be due to a lower than expected response rate to endocrine therapy. This is a further indication of the different biological characteristics of these two histological sub-types of breast carcinoma.

Breast Neoplasms↗
PubMed1987

A phase II study of oral weekly 4-demethoxydaunorubicin in advanced breast cancer.

Thirty-eight patients with advanced breast cancer were treated with oral 4-demethoxydaunorubicin in a continuous weekly schedule at a dose of 15 mg/m2/week. Subjective toxicity consisted of mild nausea (grade 1) in 52% with more severe GI side effects (grade 2) in 15%. Three patients developed grade 1 alopecia and there were no episodes of cardiac failure. Significant neutropenia (grade 2/3) only occurred in patients with marrow involvement or widespread bone disease. There was one CR and 5 PRs, an overall response rate of 15.7% (95% confidence limits 6-31%). In addition 6 patients had disease stabilization for at least 6 months. Fourteen patients progressing on 4-demethoxydaunorubicin have received adriamycin 60 mg/m2 21 days. There have been 5 PRs in this group indicating possible non-cross-resistance between these two agents.

Adult↗
PubMed1987

Results of a nationwide Veterans Administration Cooperative Study comparing the efficacy and toxicity of carbamazepine, phenobarbital, phenytoin, and primidone.

In 1985 a 5-year multicenter Veterans Administration Cooperative Study was completed that compared the efficacy and toxicity of phenobarbital, carbamazepine, phenytoin, and primidone in a double-blind prospective study design. A total of 622 patients, either previously untreated or undertreated, were entered into the study. Strict exclusion criteria limited confounding factors such as drug or alcohol abuse. Results showed that each of the four drugs used as monotherapy were similarly effective in the treatment of generalized tonic clonic seizures, but carbamazepine was significantly more effective in the treatment of complex partial seizures as measured by 100% control. When the results for all four drugs were combined, the data showed that approximately 80% of the patients were adequately managed on monotherapy. Differences in toxicity were the most significant factor that discriminated between these four drugs. Both carbamazepine and phenytoin were associated with significantly lower incidences of intolerable side effects than were primidone or phenobarbital. A behavioral toxicity battery was performed whenever possible prior to administration of any antiepileptic drug and at 1, 3, 6, and 12 months after initiation of monotherapy. Significant differences in performance on all subtests of the battery were found between patients with epilepsy and a control group matched by age, sex, and education. When the differential effects of all four drugs on behavioral toxicity were compared, few statistically significant differences emerged. However, carbamazepine consistently produced fewer adverse effects on tests of attention/concentration and motor performance than did the other three antiepileptic drugs.

Adult↗