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Biomedical subjects

J Crowell

Publications and source records attributed to J Crowell.

At least 19 recordsLinked to original sources
PubMed2001

High-performance liquid chromatography-based determination of total isothiocyanate levels in human plasma: application to studies with 2-phenethyl isothiocyanate.

Dietary and pharmacologic isothiocyanates (ITCs) may play a role in reducing the risk of certain cancers. The quantification of ITCs in humans is important both for epidemiological and pharmacokinetic studies. We describe a modification of an HPLC-based assay of urinary ITCs for use with human plasma. The assay utilizes the cyclocondensation reaction of 1,2-benzenedithiol with ITCs present in human plasma, followed by a two-step hexane extraction and analysis by HPLC using UV detection at 365 nm. The method shows linearity and reproducibility with human plasma over a range of 49-3003 nM phenethyl isothiocyanate (PEITC) (r(2) = 0.996 +/- 0.003). A similar degree of linearity was seen with two other biologically occurring conjugates of PEITC: PEITC--N-acetylcysteine (PEITC--NAC) and PEITC--glutathione (PEITC--GSH). The recovery of PEITC assessed on multiple days was 96.6 +/- 1.5% and was 100% for PEITC--GSH and PEITC--NAC. The reproducibility of the assay on multiday samplings showed a mean %CV of 6.5 +/- 0.3% for PEITC, 6.4 +/- 4.3 for PEITC--NAC and 12.3 +/- 3.9 for PEITC--GSH. In clinical studies, mean plasma ITC level of 413 +/- 193 nM PEITC equivalents was determined for a non-dietary-controlled group of 23 subjects. Multiday analysis data from pharmacokinetic plasma sets of 3 subjects taking a single dose of PEITC at 40 mg showed a good CV (range: 16-21%). The applicability of the methodology to pharmacokinetic studies of PEITC in humans is demonstrated.

Chromatography, High Pressure Liquid↗
PubMed2001

How much observational data is enough? An empirical test using marital interaction coding.

Using three different samples of couples (clinic, nondistressed community, and engaged), we found that 15 minutes was sufficient to witness enough behavior to make reliable (i.e., internally consistent) estimations of most Rapid Marital Interaction Coding System (Heyman & Vivian, 1993) code frequencies. Ten minutes is sufficient for many codes of interest. The ease in which "how much time is necessary" calculations can be made should entice behavioral investigators from a variety of content areas to publish such figures. By empirically investigating a factor that in most fields becomes reified through convention, investigators can conduct observational research that is both maximally efficient and maximally scientifically defensible.

Journal Article↗
PubMed2001

Oltipraz concentrations in plasma, buccal mucosa cells, and lipids: pharmacological studies.

Oltipraz is considered one of the most potent cancer chemoprevention agents, as shown in preclinical studies. Its pharmacological effects in humans have been associated with unusual toxicity affecting the fingers and toes. This study was designed to test intermittent dosing schedules using two dosage levels: 500 mg as a single weekly dose and 200 mg as a biweekly dose, each for 30 days. Fifteen men and women were studied in each dosing group. All were heavy smokers considered to be at high risk for developing lung cancer. Plasma, buccal mucosa cell, and lipoprotein concentrations were measured at different intervals corresponding to the time period when most of the adverse effects occur. No serious toxicities were observed using these doses and schedules. The plasma and buccal mucosa cell concentrations of Oltipraz showed substantial interindividual variations at each sampling. Some subjects had no detectable plasma or buccal mucosal cell Oltipraz concentrations. The distribution of Oltipraz incorporation into the lipid fractions and albumin was changed by the administration of different schedules of Oltipraz. The results of this study suggest that the intermittent dosing is well tolerated and does not result in steady state in plasma or buccal mucosa cells. The variation and lack of detectable Oltipraz concentration in plasma, buccal mucosa cells, and lipids may affect both the toxicity and the pharmacological effects when these doses and schedules are used.

Administration, Oral↗
PubMed2000

Focal adhesion kinase (FAK) phosphorylation is not required for genistein-induced FAK-beta-1-integrin complex formation.

It has previously been shown that changes in the activity of focal adhesion kinase (FAK), and its binding to beta-1-integrin, accompany genistein-induced adhesion of prostate cells. Consumption of genistein world wide is associated with a lower incidence of metastatic prostate cancer. Early human clinical trials of genistein are under way to evaluate genistein's potential causal role in this regard. Though an important cell adhesion-associated signaling molecule, FAK's role in regulating prostate cell adhesion was not clear. Elucidation of this process would provide important information relating to both biology and potential clinical endpoints. It was hypothesized that FAK activation and complex formation are temporally related in prostate cells, and can thus be separated. Significant activation of FAK was demonstrated when cells adhered to fibronectin, as compared to poly-L-lysine, thus demonstrating that beta-1-integrin plays a significant role in activating FAK. Neither FAK activation, nor FAK-integrin complex formation, required beta-1-integrin ligand. However, disruption of the cellular cytoskeleton by cytochalasin D prevented FAK activation, but did not block genistein-induced complex formation. In the face of a disrupted cytoskeleton, signaling through FAK could not be restored through either integrin cross linking, or re-establishment of tensile forces via attachment to solid matrix. These studies demonstrate that FAK-beta-1-integrin complex formation does not require FAK activation, suggesting that it is an early event in prostate cell adhesion. An intact cytoskeleton is necessary for FAK activation. The functional importance of beta-1-integrin in prostate cells is demonstrated. Current findings support plans to test genistein in prostate cancer.

Cell Adhesion↗
PubMed1997

Suppression of human colorectal mucosal prostaglandins: determining the lowest effective aspirin dose.

BACKGROUND: A variety of studies have supported the finding that regular intake of aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory agents can affect colorectal cancer carcinogenesis. These agents inhibit the synthesis of prostaglandins. High levels of prostaglandins are observed in colon cancer tissues. PURPOSE: Experiments were planned to determine the lowest dose of aspirin that can markedly suppress the levels of mucosal prostaglandins E2 and F(2alpha) in colorectal mucosa and to determine whether a relationship exists between these levels and plasma levels of both acetylsalicylic acid and its metabolite, salicylic acid. METHODS: Healthy men and women aged 18 years or older participated in the study. The participants took a single, daily dose of aspirin (40.5, 81, 162, 324, or 648 mg) or a placebo for 14 days. Colorectal biopsy specimens were taken at baseline, 24 hours after the first dose of aspirin, and 24-30 hours and 72-78 hours after the last, i.e., fourteenth, daily dose of aspirin. The biopsy specimens were assayed for prostaglandins E2 and F(2alpha) by use of a competitive enzyme immunoassay. Plasma concentrations of acetylsalicylic acid and salicylic acid were determined by use of high-performance liquid chromatography. All P values are two-sided. RESULTS: A total of 65 subjects (10 receiving placebo, groups of 10 each receiving 40.5, 81, 162, or 324 mg of aspirin, and a group of 15 receiving 648 mg of aspirin) completed the protocol. One subject reported unacceptable drug-induced toxic effects and did not complete the protocol; other subjects reported acceptable side effects. The lowest dose to significantly suppress colorectal mucosal prostaglandin E2 concentrations from baseline at 24 hours after the first dose (by 22.6%; P = .002) and at 24-30 hours after the last dose (by 14.2%; P = .021) was 162 mg. At 72-78 hours after the last dose, there was significant suppression for subjects receiving 81 mg (by 23.7%; P = .008). The lowest dose to significantly suppress colorectal mucosal prostaglandin F(2alpha) concentrations from baseline at 24 hours after the first dose (by 18.3%; P = .032) was 324 mg. The lowest dose causing a marked reduction in the level of prostaglandin F(2alpha) at 24-30 hours (by 15.1%; P = .003) and 72-78 hours (by 23.0%; P = .0002) after the last dose was 40.5 mg. No detectable amounts of acetylsalicylic acid or salicylic acid were present in the plasma at any of the biopsy time points. CONCLUSIONS: The lowest doses of aspirin taken daily for 14 days to significantly suppress concentrations of colorectal mucosal prostaglandins E2 and F(2alpha) were 81 and 40.5 mg, respectively. The suppression occurred without detectable amounts of aspirin or salicylic acid in the plasma at the time points studied. On the basis of these observations, we recommend a single, daily dose of 81 mg of aspirin in future studies of this drug as a chemopreventive agent for colorectal cancer.

Adult↗
PubMed1997

Prevalence of hepatitis C virus genotypes in southern Italy.

HCV is ubiquitous. In 50% of all cases it causes chronic hepatitis that often evolves into liver cirrhosis and hepatocellular carcinoma. Recently HCV has been classified in 5 genotypes by Okamoto. The purpose of this study is to evaluate the prevalence of 5 genotypes in Campania, a region of southern Italy, where the prevalence of anti-HCV antibodies ranges from 0.87 to 4%, and to evaluate the correlation between the HCV genotypes and the severity of histological damage. One-hundred- and-thirty-five anti-HCV positive patients were enrolled and tested by PCR to identify HCV-RNA. One-hundred-and-twenty-four patients resulted HCV-RNA positive. Genotyping was performed as described by Okamoto et al. with minor modifications of the specific primer to type III proposed by Silini et al. Eight patients were negative for all genotypes. Eight patients were positive for type I(1a), 61 for type II(1b), 39 for type III(2a), 11 for type IV(2b) and 1 for type V(3a). In 4 cases two different genotypes were present in the same sample [II(1b)-IV(2b), III(2a)-II(1b) twice, III (2a)-IV(2b)]. Histological evaluation of liver damage showed: CPH (22 cases), minimal CAH (56), severe CAH (31) and liver cirrhosis (15). There was no statistically significant correlation between the 5 genotypes and the severity of histological damage. Data on the prevalence of genotype II (1b) in Italy are similar to those reported for other European countries. The prevalence of genotypes in southern Italy is similar to that reported in the population of northern Italy.

Adult↗
PubMed1997

Intraventricular interferon-alpha stops seizures in Rasmussen's encephalitis: a case report.

A 3.5-year-old girl had epilepsia partialis continua of the right side. Clinical and laboratory findings were consistent with Rasmussen's encephalitis. Treatment with high-dose methylprednisolone led to temporary control of seizures, but for 2 years, the seizures remained refractory to phenobarbital, phenytoin, lorazepam, carbamazepine, valproic acid, vigabatrin, gabapentin, and lamotrigine. A 6-week course, and later a 6-month course, of intraventricular interferon-alpha almost totally suppressed the seizures. Although moderately hemiparetic, the child has reasonable neurologic function with mild speech delay. She is receiving her third course of treatment, and seizures remain completely controlled.

Child, Preschool↗
PubMed1996

Subchronic toxicity of triethylenetetramine dihydrochloride in B6C3F1 mice and F344 rats.

Triethylenetetramine dihydrochloride (trien-2HCl; CAS No. 38260-01-04), a chelating agent used to treat Wilson's disease patients who are intolerant of the drug of choice, was tested for subchronic toxicity in B6C3F1 mice and F344 rats. Mice and rats received trien-2HCl in the drinking water at concentrations of 0, 120, 600, or 3000 ppm for up to 92 days. Twenty mice and 18 rats of each sex were assigned to each dose group fed either a cereal-based (NIH-31) or a purified (AIN-76A) diet, both containing nutritionally adequate levels of copper. An additional control group of rats and mice received a Cu-deficient AIN-76A diet. This low copper diet resulted in Cu-deficiency symptoms, such as anemia, liver periportal cytomegaly, pancreatic atrophy and multifocal necrosis, spleen hematopoietic cell proliferation, and increased heart weight, together with undetectable levels of plasma copper in rats but not in mice. Trien-2HCl lowered plasma copper levels some-what (at 600 and 3000 ppm) in rats fed the AIN-76A diet, but did not induce the usual signs of copper deficiency. Trien-2HCl caused an increased frequency of uterine dilatation at 3000 ppm in rats fed AIN-76A diet that was not noted in females fed the Cu-deficient diet. Trien-2HCl toxicity occurred only in mice in the highest dose group fed an AIN-76A diet. Increased frequencies of inflammation of the lung interstitium and liver periportal fatty infiltration were seen in both sexes, and hematopoietic cell proliferation was seen in the spleen of males. Kidney and body weights were reduced in males as was the incidence of renal cytoplasmic vacuolization. There were no signs of copper deficiency in mice exposed to trien-2HCl. The only effect of trien-2HCl in animals fed the NIH-31 diet was a reduced liver copper level in both rat sexes, noted at 3000 ppm.

Administration, Oral↗
PubMed1993

Development of chemopreventive agents for lung and upper aerodigestive tract cancers.

The lung and upper aerodigestive tract (oral cavity, larynx, pharynx, upper esophagus) will harbor the greatest proportion (approximately 20%) of estimated new cancer cases in 1992. The estimated mortality rate is even higher (32%), which is reflected in a 5-year survival rate of only 7% and 12% for esophageal and lung cancer, respectively. Tobacco use appears to remain the major cause of aerodigestive cancers despite efforts at primary prevention--cessation of exposure. Another strategy to decrease this public health problem is secondary prevention or chemoprevention. Cancer chemoprevention is defined as intervention with chemical agents before invasion to halt or slow the carcinogenic process; potential agents may include minor dietary constituents and pharmaceuticals. The main objective of the Division of Cancer Prevention and Control (DCPC), National Cancer Institute, is to develop promising chemopreventive drugs for use in humans. The testing of cancer chemopreventives for efficacy in the clinic differs from that of cancer treatment drugs. Chemopreventive drug trials involve healthy target populations, and the endpoints are reduced cancer incidence or mortality, or increased latency, with no to minimal toxicity. The lung and upper aerodigestive tract represent a unique opportunity for intervention in this setting. Even with cessation of tobacco exposure, the risk of cancer in the entire epithelium remains high for years due to the "field cancerization" effect. Some of the first chemopreventive trials made use of this system due to the availability of a study population with a tissue at demonstrably high risk for malignant progression. Much of the evidence for chemopreventive efficacy is in the oral cavity because of the well-defined epithelial neoplastic progression, the existence of well-established preclinical models, and relative ease of tissue monitoring and sampling. In one of the first randomized trials, Hong and co-workers demonstrated that 13-cis-retinoic acid prevents the appearance of second primary tumors in patients previously treated for squamous cell carcinomas of the oral cavity and upper respiratory tract. Even using a high risk population, chemoprevention trials involve large sample sizes, lengthy duration and follow-up, and high cost. To circumvent these problems, the use of intermediate biomarkers as surrogate endpoints is being explored. Intermediate biomarkers are defined as biological alterations in tissue (histological, genetic, biochemical, proliferative, differentiation-related) occurring prior to cancer development. In the oral cavity, studies using modulation of a histological intermediate biomarker, dysplastic leukoplakia, as the endpoint have demonstrated response to a retinoid.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Ultrastructural effects of PCMS on mycelial-yeast transition in Histoplasma capsulatum.

The Yeast phase of Histoplasma capsulatum has stringent growth requirements. Transition from mycelium to yeast takes place only in the presence of cysteine and can be blocked by the -SH groups inhibitor p-chloromercury-phenylsulfonic acid (PCMS). Ultrastructural studies show lysis and degeneration of PCMS treated mycelium grown at 37 degrees C for 24 hours. Only 50% of PCMS treated mycelium appear degenerate when grown at 34 degrees C for 24 hours. The remaining cells have normal morphology with only slight changes in the cell wall structure. The effect of PCMS is permanent and hereditary. Mice injected with PCMS treated mycelium do not develop disease and are resistant to virulent strains of H. capsulatum when challenged.

4-Chloromercuribenzenesulfonate↗
PubMed1990

[Ultrastructural study of the yeast-mycelium transition in Histoplasma capsulatum. II. Changes at 34 degrees C].

The ultrastructural changes which occur during the mycelium to yeast transition in Histoplasma capsulatum induced by a temperature shift from 25 degrees C to 34 degrees C are described and compared to those observed after a temperature shift from 25 degrees C to 37 degrees C. 24 hours after the temperature shift to 34 degrees C only 8% of the cells are lysed. However, many mitochondria have lost their characteristic elongated form and have become rounded. Vesicular cristae which are no longer oriented parallel to the long axis of the mitochondria are also observed. In contrast a temperature shift from 25 degrees C to 37 degrees C induces lysis of 70% of the cells; mitochondria are rarely observed in the remaining cells. These ultrastructural changes can be correlated with the uncoupling of oxidative phosphorylation and the production of heat shock proteins.

Fungal Proteins↗
PubMed1989

Mycelium-yeast transition in Histoplasma capsulatum. Early ultrastructural changes.

The ultrastructural changes which occur during the first 24 h of mycelium to yeast transition have been studied in the dimorphic fungus Histoplasma capsulatum. A temperature shift controls mycelial to yeast transition. During the first 24 h respiratory rate, ATP and cytochrome concentration fall to very low levels. Ultrastructural observations showed that the plasma membrane became undulated and the cell wall lost its characteristic fibrous outer layer. At 8 h the ordered lamellar structure of the mitochondria was no longer apparent. 24 h after the temperature shift 70% of the cells were lysed. The remaining cells contained many cytoplasmic membrane structures; mitochondria were rarely observed. These changes are considered to be the morphological expression of the physiological events characteristic of stage one in mycelial to yeast transition.

Histoplasma↗
PubMed1989

[Intranuclear particles in chronic non-A, non-B hepatitis: what diagnostic significance?].

Intranuclear particles of 23-27 nm diameter have been repeatedly demonstrated in the nuclei of hepatocytes of patients with non-A, non-B hepatitis and of experimentally infected chimpanzees; however, their specificity has been challenged since they have also been observed in other pathological conditions and in healthy volunteers. We have conducted an ultrastructural study of liver biopsies from 10 patients with chronic active non-A, non-B hepatitis. The intranuclear particles, which were observed in all patients, were classified according to the aggregation patterns described by De Vos. Eight patients (80%) had particles of type 2. A reevaluation our proceeding data on Delta hepatitis demonstrated that no particles of type 2 were present. These results support the hypothesis that only type 2 particles are markers of non-A, non-B hepatitis.

Adult↗
PubMed1989

Prevalence of intranuclear particles in liver pathologies.

An ultrastructural study of the prevalence of electron dense 23-27 nm intranuclear particles was carried out on liver biopsies from patients with NANB chronic active hepatitis (CAH), Delta + CAH, HBsAg + CAH, nonviral liver pathologies and in one healthy volunteer. The particles were classified according to aggregation pattern and were found to be correlated with NANB CAH and Delta + CAH. No particles were observed in nonviral liver pathologies. A close antigenic relationship has been shown between the cytoplasmic alterations observed in NANB and delta hepatitis in chimpanzees. Our data indicate that there is a structural similarity between the intranuclear particles seen in both Delta and NANB hepatitis, thus reinforcing the hypothesis that the NANB and Delta agents are closely related.

Adult↗