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J R Clark

Publications and source records attributed to J R Clark.

At least 19 recordsLinked to original sources
PubMed1999

Comparison of test methods and early toxicity characterization for five dispersants.

The acute toxicities of a commercial dispersant (Corexit 9527) and four experimental dispersant formulations were evaluated using the 96-h mysid (Mysidopsis bahia) test and two rapid screening tests, Microtox and the Mysid IQ Toxicity Test. During 96-h toxicity tests, survival observations were recorded at 3, 6, 9, 12, and 24 h to document mortalities from short-term exposures more consistent with field exposure times and more approximate to exposure times used in Microtox and the Mysid IQ Toxicity Test. At nominal concentrations (6.25 and 12.5 mg/liter) and exposure times (3-24 h) near the upper range of predicted field conditions, mysid mortalities were </=5% for all test materials. Microtox and Mysid IQ Toxicity Test were evaluated for their ability to differentiate test materials compared with that of the 96-h mysid test. Dispersant formulations were ranked by relative toxicities based on LC50 or EC50 values and ranks compared among test methods. Microtox ranked the test materials similar to the 96-h mysid test. Ranks from the Mysid IQ Toxicity Test were dissimilar to those of the other tests. Early mortality observations during 96-h tests did not provide a better basis for comparing results of the rapid screening tests.

Animals↗
PubMed1998

Comparison of the chronic toxicity of piroxantrone, losoxantrone and doxorubicin in spontaneously hypertensive rats.

Comparisons were made of the toxic effects produced in the heart, kidney and small intestine of spontaneously hypertensive rats (SHR) by the administration of 12 consecutive weekly doses of doxorubicin (1 mg/kg), and high, intermediate and low doses of piroxantrone (3, 1.5 and 0.75 mg/kg) and losoxantrone (1, 0.5 and 0.25 mg/kg). Animals receiving saline were used as controls. The toxicities of the three drugs were evaluated by clinical chemistry and hematological determinations, light microscopy and transmission electron microscopy. The severity of the histologic alterations in heart, kidney and small intestine was assessed semiquantitatively. Biochemical and molecular modeling studies were made to evaluate the formation of complexes of Fe(III) with piroxantrone and losoxantrone. The cardiac (myofibrillar loss and dilatation of the sarcoplasmic reticulum) and renal (glomerular vacuolization, tubular damage and laboratory evidence of a nephrotic syndrome) lesions induced by all three agents had similar features. However, the cardiac lesions induced by losoxantrone and doxorubicin were significantly more severe (Billingham scores) than those produced by piroxantrone. The renal lesions induced by piroxantrone and losoxantrone were less severe than those produced by doxorubicin. Similarly losoxantrone and piroxantrone-induced intestinal alterations (denudation of epithelial layer and inflammatory cellular infiltration) were less severe than those occurring after treatment with doxorubicin. Both losoxantrone and piroxantrone were shown to form Fe(III): drug complexes that may cause oxidative damage to various tissues.

Animals↗
PubMed1998

Functional occlusal relationships in a group of post-orthodontic patients: preliminary findings.

This study investigated features of the functional occlusion in a group of 37 patients immediately following two-arch fixed appliance treatment. Study casts were mounted in the retruded axis position on a semi-adjustable articulator and occlusal contacts were recorded with articulating paper in retruded and lateral mandibular positions. The magnitude of the slide between the retruded axis position and the intercuspal position was measured to the nearest 0.5 mm in the antero-posterior, vertical and lateral directions. The results revealed that the majority of subjects had a unilateral contact on initial closure in the retruded axis position, and a slide between this position and the intercuspal position. Most subjects demonstrated canine guidance on the working side in lateral positions. In addition, however, most subjects had contact between the second molars on the non-working side. Based on current concepts of functional occlusion, this group of post-orthodontic patients did not exhibit ideal occlusal relationships. The long-term implications of this finding are unclear, but may be associated with post-orthodontic instability, tooth wear and temporomandibular disorders. A long-term follow-up is planned to attempt to clarify some of these issues.

Dental Articulators↗
PubMed1997

Calreticulin biosynthesis and processing in human myeloid cells: demonstration of signal peptide cleavage and N-glycosylation.

Calreticulin is a soluble endoplasmic reticulum protein comprising the major storage reservoir for inositol trisphosphate-releasable calcium. Although its highly conserved primary structure and a wide range of functions have been well described, less attention has been paid to its biosynthesis, particularly in human tissues. We report analyses of synthesis, proteolytic processing and glycosylation of human calreticulin. In both HL-60 and PLB-985 myeloid cell lines calreticulin was immunoprecipitated as a single 60-kD species without evidence of precursor forms. However, in vitro cell-free synthesis produced a 62-kD primary translation product, which in the presence of microsomal membranes, was processed by cotranslational signal peptide cleavage to a 60-kD species that comigrated with mature calreticulin produced in myeloid cells. Neither tunicamycin treatment of the cells nor endoglycosidase digestion of calreticulin resulted in any forms other than the 60-kD protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, suggesting that the potential site for N-glycosylation at asparagine-327 was unmodified. However, oxidative derivatization of carbohydrate components with digoxigenin showed that human calreticulin produced in either HL-60 cells or Sf9 insect cells is glycosylated, indicating that glycosylated and nonglycosylated human calreticulin have indistinguishable electrophoretic mobilities. Direct measurement by phenol-H2SO4 confirmed the presence of carbohydrate on recombinant human calreticulin. These data show that human myeloid calreticulin undergoes cotranslational signal peptide cleavage and posttranslational N-linked glycosylation. Although glycosylation of calreticulin has been shown in rat liver and bovine liver and brain, it has been reported to be lacking in other tissues including human lymphocytes.

Animals↗
PubMed1997

Comparison of the structural changes induced by doxorubicin and mitoxantrone in the heart, kidney and intestine and characterization of the Fe(III)-mitoxantrone complex.

Histologic, nick end labeling for apoptosis and electron microscopic studies were made of the heart, kidney and small intestine in spontaneously hypertensive rats (SHR) treated for 12 weeks with doxorubicin (1 mg/kg/week), mitoxantrone (0.5 or 0.25 mg/kg/week) or saline (controls). Semiquantitative scoring showed that the severity of the cardiac lesions produced by doxorubicin was comparable to that resulting from 0.5 mg/kg mitoxantrone, but greater than that induced by 0.25 mg/kg mitoxantrone (to which it is therapeutically equivalent). The nephropathy and the intestinal toxicity produced by doxorubicin were also more severe than those resulting from either dose of mitoxantrone. Apoptosis of cardiac myocytes was not induced by either drug, but involved cardiac dendritic cells in SHR given doxorubicin. Apoptosis in renal tubular epithelium was comparable in SHR given doxorubicin and the higher dose of mitoxantrone. Doxorubicin induced more frequent apoptosis in intestinal epithelium than did the higher dose of mitoxantrone. We also show that mitoxantrone and iron(III) form a strong 2:1 complex, in which the drug may be acting as a tridentate ligand. This complex, like the iron(III)-doxorubicin complex, may be capable of redox cycling and producing reactive oxygen intermediates (ROI) that damage tissue. Decreased formation of ROI by mitoxantrone may account for its reduced cardiotoxicity compared to that of doxorubicin.

Animals↗
PubMed1997

Comparison of the protective effects against chronic doxorubicin cardiotoxicity and the rates of iron (III) displacement reactions of ICRF-187 and other bisdiketopiperazines.

Histologic and biochemical studies were carried out to compare the protective activity of various bisdiketopiperazines against the cardiac and renal toxicity induced by doxorubicin in spontaneously hypertensive rats (SHR), a well-established animal model of this disorder, with: (1) the rates of hydrolysis of these agents to form the iron-chelating derivatives (which are considered to cause a decrease in the formation of reactive oxygen intermediates) and (2) the ability of these derivatives to bind iron. SHR were given 12 weekly injections of doxorubicin, 1 mg/kg i.v. either alone or 30 min after the administration of ICRF-154, ICRF-187, ICRF-192, ICRF-197, ICRF-198, ICRF-239 and ADR-559. Semiquantitative grading of the severity of the resulting cardiac and renal lesions showed that ICRF-187, ICRF-154 and ADR-559 were the most protective, whereas ICRF-197 and ICRF-239 provided intermediate degrees of protection, and ICRF-192 and ICRF-198 were not protective. Quantitative measurements in vitro revealed only relatively small differences in the rates of opening of the two diketopiperazine rings of the various agents to form the corresponding iron-chelating diacid diamide derivatives, and in the ability of these various derivatives to remove iron from the iron-doxorubicin complex. Such differences showed no relationship with cardioprotective activity. Some bisdiketopiperazines (including ICRF-154 and ICRF-187) with cardioprotective activity also are inhibitors of DNA topoisomerase II; however, the significance of this relationship remains uncertain, since ADR-925, the open-ring derivative of ICRF-187, does not inhibit DNA topoisomerase II.

Animals↗
PubMed1997

Late developing supernumerary teeth in the mandible.

This paper presents two cases in which supplemental premolars were an incidental finding. Although anomalies of tooth number and form are quite common, both cases demonstrate late forming supernumeraries with one case illustrating their development in a more unusual site. It is not routine practice to screen for late development of teeth during orthodontic treatment. Therefore the possibility of their interference with occlusal development or orthodontic mechanics such as space closure, should always be kept in mind.

Bicuspid↗
PubMed1997

Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for squamous cell carcinoma of the head and neck: long-term results.

PURPOSE: A phase II trial of cisplatin, fluorouracil, and leucovorin (PFL) induction chemotherapy in patients with locally advanced squamous cell carcinomas of the head and neck region (HNCA). PATIENTS AND METHODS: One hundred two patients (stage III/IV, previously untreated) were treated with induction PFL. Patients with resectable primary tumor site lesions and clinical complete response (CR) were offered radiotherapy (RT) without surgery to the primary tumor site. Response, toxicity, local-regional therapy, survival, and preservation of the primary tumor site were assessed. RESULTS: Among 279 courses, the overall response rate was 81%. Nineteen (19%) failed to respond, including three who died during therapy. Sixty-seven (69%) of 97 with assessable primary lesions had a clinical CR at the primary tumor site. Pathologic CR was recorded in 46 of 55 (84%) clinical CR patients who had biopsies performed on the primary tumor site. Toxicities resulted in unexpected hospitalizations in 19% of cases. After definitive local-regional therapy, 84 (82%) were disease-free including 71 (69%) with preserved primary tumor site anatomy. With a median follow-up time of 63 months, the cause-specific, overall (OS), and failure-free survival (FFS) rates at 5 years are 58%, 52%, and 51%. Local failure occurred in 29 of 102 (29%) and the local control rate at 5 years was 68%. CONCLUSION: PFL has significant activity with acceptable toxicity in patients with advanced disease who have a good performance status. Preservation of the primary tumor site could be achieved without apparent loss of local control or survival. Management of neck disease by surgery or RT must be individualized and separate from management of primary tumor. Survival compares favorably with similar trials of induction chemotherapy or chemoradiotherapy.

Adolescent↗
PubMed1997

Pathogenesis and prevention of doxorubicin cardiomyopathy.

A review is presented of the various types of cardiotoxicity associated with the clinical use of doxorubicin, a highly effective antineoplastic agent of the anthracycline family. Acute toxicity is related to rapid intravenous administration of the drug and is manifested by vasodilatation, hypotension and cardiac arrhythmias. Subacute toxicity is very uncommon. It develops early in the course of therapy and is characterized by myocarditis and pericarditis. Chronic toxicity is the most common form of doxorubicin-induced cardiac toxicity. It is manifested by chronic dilated cardiomyopathy, which develops late in the course of therapy or shortly after its termination. Morphologic changes are characteristic and consist of myofibrillar loss and cytoplasmic vacuolization (which is due to dilatation of the sarcoplasmic reticulum) of the myocytes. The damaging effects of reactive oxygen species, generated by the interaction of doxorubicin with iron, play a critically important role in the pathogenesis of the chronic cardiotoxicity. Other factors related to this toxicity include inhibition of DNA topoisomerase II, stimulation of certain immune responses and a diversity of other biochemical effects on various cellular organelles. Doxorubicin induces apoptosis in a variety of cell types, but not in cardiac myocytes. The chronic cardiotoxicity of doxorubicin is significantly attenuated by chelation of iron by ICRF-187 (dexrazoxane). A greatly delayed type of doxorubicin cardiotoxicity has been recently found to occur in survivors of childhood cancers who were treated with doxorubicin without any immediate adverse effects, but develop chronic cardiomyopathy at periods of time ranging up to 15 years later. The pathogenesis of this type of toxicity remains to be determined.

Antibiotics, Antineoplastic↗
PubMed1996

Doxorubicin-induced apoptosis in spontaneously hypertensive rats: differential effects in heart, kidney and intestine, and inhibition by ICRF-187.

The occurrence of apoptosis in heart, kidney and small intestine was investigated in spontaneously hypertensive rats (SHR) treated with doxorubicin (1 mg/kg/week for 6, 9 and 12 weeks) with and without pretreatment with the iron chelator ICRF-187 [(+)1.2-bis(3.5-dioxopiperazinyl-l-yl)propane] (25 mg/kg, i.p., given 30 min before doxorubicin). Animals receiving either ICRF-187 alone or saline were used as controls. Cells undergoing apoptosis were identified ultrastructurally and by staining using the nick-end labeling method. The results obtained by counting cells with positive nick-end labeling showed that, when given in cumulative doses of 9 and 12 (but not 6) mg/kg, doxorubicin induced significant toxicity in the heart, kidneys and intestine in association with apoptosis in epithelial cells of the intestinal mucosa and renal tubules but not in cardiac myocytes. At these doses nick end labeling in the heart was confined to occasional endothelial cells, interstitial dendritic cells and macrophages. The frequency of doxorubicin-induced apoptosis in renal and intestinal epithelial cells was decreased by pretreatment of the SHR with ICRF-187. Our data support the concept that the chronic cardiomyopathy induced by doxorubicin is not mediated by apoptosis of the cardiac myocytes.

Animals↗
PubMed1996

Docetaxel: an active drug for squamous cell carcinoma of the head and neck.

PURPOSE: We conducted a phase II study designed to evaluate the activity, safety, and tolerability of docetaxel (Taxotere: Rhône-Poulenc Rorer Pharmaceuticals Inc, Collegeville, PA) in patients with advanced, incurable, or recurrent squamous cell carcinoma of the head and neck (SCCHN) who had not received prior palliative chemotherapy. PATIENTS AND METHODS: Thirty-one patients with measurable, locoregional, or metastatic SCCHN were treated with docetaxel, administered at a dose of 100 mg/m2 as a 1-hour intravenous (i.v.) infusion once every 21 days on an outpatient basis. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic administration of growth factors or antiemetics was not permitted. RESULTS: Thirty-one patients were treated. Twenty-nine patients were assessable for response and 30 for toxicity. Four of 31 patients (13%) achieved complete response (CR), nine (29%) achieved partial response had stable disease (SD) and seven (23%) experienced progression of disease (PD). The major response rate was 42% (95% confidence interval [CI], 24% to 60%). The median duration of responses was 5 months (range, 2 to 14). The principal toxicity was leukopenia, which occurred with rapid onset and brief duration. Sixteen patients (53%) experienced nadir fever, and 13 required dose reduction. Hypersensitivity reactions occurred in four patients. Grade 3 peripheral neuropathy occurred in two patients; grade 2 or 3 fatigue occurred in six (20%) and 10 (33%), respectively. Minimal edema (grade 1) occurred in five patients (17%). Clinically significant mucositis, diarrhea, or dermatitis were not observed. CONCLUSION: Docetaxel has major activity against SCCHN. It appears to be well tolerated in this group of patients and can be safely administered on an outpatient basis. Premedication with dexamethasone, cimetidine, and diphenhydramine is associated with a reduced incidence of significant edema, hypersensitivity reactions, and dermatologic toxicities.

Adult↗
PubMed1996

Antibiotics and upper respiratory infection: do some folks think there is a cure for the common cold.

BACKGROUND: Symptomatic treatment is the only recommended therapy for the uncomplicated "common cold." The purpose of this study was to examine the use of antibiotics and other prescription medications for the common cold in a Medicaid population seen in ambulatory care settings. METHODS: A cross-sectional sample of Kentucky Medicaid claims from July 1, 1993, through June 30, 1994, was analyzed. Subjects were patients seen in an ambulatory setting for the common cold, defined as acute nasopharyngitis. A total of 1439 individuals were seen for 2171 separate outpatient and emergency department encounters for the common cold. Outpatient visits accounted for 99% (2144) of the encounters. RESULTS: Patients in 35% (752) of the encounters did not fill a prescription for medication, 6% (129) filled a prescription for an antihistamine or other symptomatic medication, and 60% (1290) filled a prescription for an antibiotic for the common cold. Nineteen different antibiotics, 54% of which were amoxicillin, were prescribed for the common cold. Less than 2% of the encounters had a secondary diagnosis of either acute sinusitis or otitis media. These encounters were not more likely than the total sample to receive antibiotics. Adults were more likely than children to receive an antibiotic (P<.001), and urban physicians were more likely than rural physicians to prescribe antibiotics (P=.02). A conservative estimate of the annual cost of antibiotic prescribing for the common cold in the United States was $37.5 million. CONCLUSIONS: A majority of persons receiving medical care for the common cold are given prescriptions for an unnecessary antibiotic. Unchecked, this practice may lead to greater antibiotic resistance and unnecessary use of health care resources. Future research should focus on the ability to institute behavioral changes for treatment of the common cold in both closed systems (eg, managed care) and open systems (eg, general community of physicians).

Adolescent↗
PubMed1994

The utility of electronic mail as a medium for patient-physician communication.

OBJECTIVE: To examine patients' knowledge, use, and attitudes regarding electronic mail communication with their family physicians. DESIGN: Mail survey. SETTING: A university-based family practice center. PARTICIPANTS: Adult patients (18 years and older) of full-time faculty physicians at a university-based family practice center who had seen their physicians at lease once in the 10-month period between July 1, 1992, and April 30, 1993 (N = 4094). Subjects were eligible for participation if both they and their physicians had an electronic mail address at the University of Kentucky, Lexington (n = 117). INTERVENTION: None. MAIN OUTCOME MEASURES: Patient-reported knowledge, use, and attitudes regarding the utility of electronic mail as a means of patient-physician communication. RESULTS: The response rate to the survey was 74% (n = 87). Patient-physician communication via electronic mail was positively perceived by patients for whom electronic mail was accessible Patient-physician communication via electronic mail was perceived to increase speed, convenience, and access to medical care. Electronic mail communication was perceived to be good for simple and nonurgent problems, such as refilling prescriptions, communicating laboratory results, and making appointments. Ninety percent of the patients who had corresponded with their physicians via electronic mail used the medium to discuss a medical problem. CONCLUSIONS: Although electronic mail is not presently in wide use for patient-physician communication, there is great potential for its widespread acceptance.

Attitude↗