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Biomedical subjects

P Frost

Publications and source records attributed to P Frost.

At least 37 records · Page 2Linked to original sources
PubMed2001

Physical exposure assessment in monotonous repetitive work--the PRIM study.

OBJECTIVES: A program called the Project on Research and Intervention in Monotonous Work (PRIM) was initiated in 1994 as a prospective cohort study of work-related musculoskeletal disorders. The group-based exposure assessment strategy, focusing on task-related exposure and used to obtain baseline measures of physical exposures, is reported in this paper. METHODS: Monotonous, repetitive worktasks were evaluated at 19 factories. Tasks with an estimated similarity in physical exposure were aggregated before 103 exposure groups were formed. Subjects from the exposure groups were randomly sampled for measurements, and task-related exposure levels were quantified by 43 single exposure items using a real-time video-based observation method that allowed computerized estimates of repetitiveness, body postures, force, and velocity. In combination with questionnaire-based data on task distribution, the duration of exposure was calculated at the individual level. RESULTS: The video-based observational method and the large number of exposure variables enabled the establishment of detailed quantitative exposure profiles in 103 task-based exposure groups. However, methodological problems associated with the use of grouped exposure assessment were revealed. Despite efforts to optimize group homogeneity, the within-group variance was larger than the between-group variance for several shoulder postural variables. CONCLUSIONS: A task-based exposure-assessment strategy can be successful in solving some of the main problems associated with the assessment of physical workplace exposures. The large within-group variance in exposure to nonneutral shoulder postures may eventually require individual assessment or the inclusion of groups with maximal contrast in exposure or both.

Adult↗
PubMed2001

A new antiestrogen, 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride (ERA-923), inhibits the growth of tamoxifen-sensitive and -resistant tumors and is devoid of uterotropic effects in mice and rats.

PURPOSE: Tamoxifen is an antiestrogen used in women who have estrogen receptor (ER)-alpha-positive breast cancer. Unfortunately, resistance to tamoxifen is common in women with metastatic disease and side effects, including increased risk of endometrial cancer, exist. Here we describe the activity of a new selective ER modulator, ERA-923, in preclinical models focused on these limitations. EXPERIMENTAL DESIGN: The ability of ERA-923, 4-OH tamoxifen, or raloxifene to inhibit estrogen-stimulated growth was evaluated in cell-based and xenograft assays with tumor cells that are sensitive or resistant to tamoxifen. Uterine effects of selective ER modulators were compared in rodents. RESULTS: ERA-923 potently inhibits estrogen binding to ER-alpha (IC(50), 14 nM). In ER-alpha-positive human MCF-7 breast carcinoma cells, ERA-923 inhibits estrogen-stimulated growth (IC(50), 0.2 nM) associated with cytostasis. In vitro, a MCF-7 variant with inherent resistance to tamoxifen (10-fold) or 4-OH tamoxifen (>1000-fold) retains complete sensitivity to ERA-923. Partial sensitivity to ERA-923 exists in MCF-7 variants that have acquired profound tamoxifen resistance. In tumor-bearing animals, ERA-923 (10 mg/kg/day given p.o.) inhibits 17beta-estradiol-stimulated growth in human tumors derived from MCF-7, EnCa-101 endometrial, or BG-1 ovarian carcinoma cells, including a MCF-7-variant that is inherently resistant to tamoxifen. Raloxifene is inactive in the MCF-7 xenograft model. Unlike tamoxifen, droloxifene, or raloxifene, ERA-923 is not uterotropic in immature rats or ovariectomized mice. Consistent with this, tamoxifen, but not ERA-923, stimulates the growth of EnCa-101 tumors. CONCLUSIONS: In preclinical models, ERA-923 has an improved efficacy and safety compared with tamoxifen. Clinical trials with ERA-923 are in progress.

Animals↗
PubMed2000

Chemical pathology

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Journal Article↗
PubMed2000

Enhanced detection of mutations in BRCA1 exon 11 using restriction endonuclease fingerprinting-single-strand conformation polymorphism.

A novel approach to mutation screening in the large exon 11 (comprising 3427 bp) of the human BRCA1 gene is presented. Restriction endonuclease fingerprinting single-strand conformation polymorphism (REF-SSCP) is based on repeated detection of DNA sequence variants in different restriction endonuclease fragments, and we evaluated the method using blood samples from 25 Norwegian patients with hereditary breast/ovarian cancer. We compared REF-SSCP to constant denaturant gel electrophoresis (CDGE) and to the protein truncation test (PTT). REF-SSCP detected 12 different DNA variants. Four of these were not detected by CDGE, and only one variant detected by CDGE was missed by REF-SSCP. PTT detected 4 of these 13 variants. REF-SSCP was subsequently applied to a second patient series (Swedish, n=20). A total of 14 different DNA variants were detected by REF-SSCP, 6 of which were truncating mutations (PTT detected only 4). Nonsense and frameshift mutations that are putative breast/ovarian cancer mutations, were detected in 7 of the 25 Norwegian and 9 of the 20 Swedish patients.

Breast Neoplasms↗
PubMed2000

Combinatorial chemoprevention of intestinal neoplasia.

A combination of two drugs afforded remarkable protection from intestinal neoplasia in APC(Min/+) mice, a murine model of human familial adenomatous polyposis (FAP). One of the drugs was sulindac, a prototypical non-steroidal anti-inflammatory drug with established chemopreventative activity. The second drug was EKI-569, a newly developed, irreversible inhibitor of the epidermal growth factor receptor kinase. Although 100% of the untreated APC(Min/+) mice developed approximately 20 polyps, nearly half the mice treated with these two agents developed no polyps at all. These results suggest a powerful strategy for the chemoprevention of human colonic neoplasia.

Adenomatous Polyposis Coli↗
PubMed2000

Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor.

UNLABELLED: Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. BACKGROUND: We have previously demonstrated an essential role for increased epidermal growth factor receptor (EGFR) activity in mediating renal cyst formation and biliary epithelial hyperplasia in murine models of autosomal recessive polycystic kidney disease (ARPKD). This study was designed to determine whether or not treatment with a newly developed inhibitor of EGFR tyrosine kinase activity (EKI-785) would reduce renal and biliary abnormalities in murine ARPKD. METHODS: Balb/c-bpk/bpk (BPK) litters were treated with EKI-785, an EGFR-specific tyrosine kinase inhibitor. Animals were treated by intraperitoneal injection beginning at postnatal day 7 and were treated until postnatal day 24 or 48. EKI-785's effectiveness was measured by a reduction in the renal cystic index, an increased life span, and maintenance of normal renal function. RESULTS: Treatment of BPK mice with EKI-785 resulted in a marked reduction of collecting tubule (CT) cystic lesions, improved renal function, decreased biliary epithelial abnormalities, and an increased life span. Untreated cystic animals died of renal failure at postnatal day 24 (P-24) with a CT cystic index of 4.8, a maximal urine osmolarity of 361 mOsm, and moderate to severe biliary abnormalities. Cystic animals treated with EKI-785 to postnatal day 48 (P-48) were alive and well with normal renal function, a reduced CT cystic index of 2.0 (P < 0.02), a threefold increased in maximum urinary concentrating ability (P < 0.01), and a significant decrease in biliary epithelial proliferation/fibrosis (P < 0.01). CONCLUSION: This study demonstrates that EKI-785 has therapeutic effectiveness in improving histopathologic abnormalities and decreasing mortality in murine ARPKD.

Animals↗
PubMed2000

The neuroimmune-endocrine axis: pathophysiological implications for the central nervous system cytokines and hypothalamus-pituitary-adrenal hormone dynamics.

Cytokines are molecules that were initially discovered in the immune system as mediators of communication between various types of immune cells. However, it soon became evident that cytokines exert profound effects on key functions of the central nervous system, such as food intake, fever, neuroendocrine regulation, long-term potentiation, and behavior. In the 80's and 90's our group and others discovered that the genes encoding various cytokines and their receptors are expressed in vascular, glial, and neuronal structures of the adult brain. Most cytokines act through cell surface receptors that have one transmembrane domain and which transduce a signal through the JAK/STAT pathway. Of particular physiological and pathophysiological relevance is the fact that cytokines are potent regulators of hypothalamic neuropeptidergic systems that maintain neuroendocrine homeostasis and which regulate the body's response to stress. The mechanisms by which cytokine signaling affects the function of stress-related neuroendocrine systems are reviewed in this article.

Adrenal Glands↗
PubMed2000

The quality of false memory over time: is memory for misinformation "remembered" or "known"?

The conscious quality of eyewitness memory for misinformation after different retention intervals was investigated in two experiments. Participants viewed computer-projected slides depicting a crime (encoding phase), read a narrative containing misinformation, and took a recall test about the original event. Remember/know judgments were made for each response. A "remember" judgment indicated that the participant vividly recalled seeing a detail in the encoding phase. A "know" judgment indicated that the participant believed that a detail was presented but did not vividly remember it. Generally, misinformation was more likely to be associated with a know judgment than with a remember judgment after a short retention interval. This outcome suggests that, in many cases, misleading information is judged as having a different subjective quality than memory for actual events. However, over a relatively long retention interval, misinformation that simply added new information about the event was more often judged as remembered.

Adult↗
PubMed1999

In vitro modulation of cyst formation by a novel tyrosine kinase inhibitor.

BACKGROUND: Recessively transmitted polycystic kidney disease (PKD) in many murine models is characterized by the initial formation of proximal tubular cysts (stage 1), followed by growth and enlargement of renal collecting tubule (CT) cysts (stage 2). Previous studies have reported that stage 1 cyst formation and growth could be manipulated in vitro by using embryonic kidney explants and newborn explant microslices in organ culture. METHODS: Microslices of postnatal kidneys cultured on Transwell tissue culture inserts allow experimental manipulation of stage 2 CT cyst development and growth. This system was used to test a potential therapeutic compound for treatment of PKD. This compound, EKI-785, modulates altered epidermal growth factor receptor (EGFR) expression in CT cysts by inhibition of EGFR autophosphorylation. RESULTS: These studies demonstrate that: (a) minor modifications of the previously described organ culture system permit successful culture of more mature renal tissue, and (b) cystic explants treated with EGF and EKI-785 demonstrated a marked reduction in CT cystic lesions compared with cystic explants treated with EGF alone. CONCLUSIONS: This study suggests that pharmacological strategies can be used to decrease EGFR tyrosine kinase activity and CT cyst formation and enlargement in murine PKD.

Animals↗
PubMed1999

Shoulder impingement syndrome in relation to shoulder intensive work.

OBJECTIVES: To analyse the risk of shoulder impingement syndrome relative to shoulder intensive work. METHODS: A cross sectional study of a historical cohort of 1591 workers employed between 1986 and 1993 at a slaughterhouse or a chemical factory. Workers not doing tasks in slaughtering or meat processing constituted the reference group. Intensity of shoulder work in meat processing tasks was assessed by video based observations. Information on shoulder disorders was collected by questionnaire and by physical examinations. Impingement syndrome was diagnosed when shoulder symptoms had been present for at least 3 months during the past year and there were signs of subacromial impingement in the corresponding shoulder at physical examination. Shoulder function was assessed at the same occasion with the Constant scoring technique. Prevalence of shoulder impingement syndrome was analysed according to job title and cumulative exposure. RESULTS: Prevalence ratio for shoulder impingement syndrome was 5.27 (95% confidence interval (95% CI), 2.09 to 12.26) among currently working and 7.90 (95% CI, 2.94 to 21.18) among former slaughterhouse workers. Transformed model based prevalence ratios according to years in slaughterhouse work showed an overall association between cumulative exposure and risk for shoulder impingement syndrome. CONCLUSIONS: This study supports the hypothesis that shoulder intensive work is a risk factor for impingement syndrome of the shoulder. Despite the historical cohort design healthy worker selection may have influenced the exposure-response relation found.

Abattoirs↗
PubMed1998

Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program. SHEP Cooperative Research Group.

BACKGROUND: Previous studies often of short duration have raised concerns that antihypertensive therapy with diuretics and beta-blockers adversely alters levels of other cardiovascular disease risk factors. METHODS: The Systolic Hypertension in the Elderly Program was a community-based, multicenter, randomized, double-blind, placebo-controlled clinical trial of treatment of isolated systolic hypertension in men and women aged 60 years and older. This retrospective analysis evaluated development of diabetes mellitus in all 4736 participants in the Systolic Hypertension in the Elderly Program, including changes in serum chemistry test results in a subgroup for 3 years. Patients were randomized to receive placebo or treatment with active drugs, with the dose increased in stepwise fashion if blood pressure control goals were not attained: step 1, 12.5 mg of chlorthalidone or 25.0 mg of chlorthalidone; and step 2, the addition of 25 mg of atenolol or 50 mg of atenolol or reserpine or matching placebo. RESULTS: After 3 years, the active treatment group had a 13/4 mm Hg greater reduction in systolic and diastolic blood pressure than the placebo group (both groups, P<.001). New cases of diabetes were reported by 8.6% of the participants in the active treatment group and 7.5% of the participants in the placebo group (P=.25). Small effects of active treatment compared with placebo were observed with fasting levels of glucose (+0.20 mmol/L [+3.6 mg/dL]; P<.01), total cholesterol (+0.09 mmol/L [+3.5 mg/dL]; P<.01), high-density lipoprotein cholesterol (-0.02 mmol/L [-0.77 mg/dL]; P<.01) and creatinine (+2.8 micromol/L [+0.03 mg/dL]; P<.001). Larger effects were seen with fasting levels of triglycerides (+0.9 mmol/L [+17 mg/dL]; P<.001), uric acid (+35 micromol/L [+.06 mg/dL]; P<.001), and potassium (-0.3 mmol/L; P<.001). No evidence was found for a subgroup at higher risk of risk factor changes with active treatment. CONCLUSIONS: Antihypertensive therapy with low-dose chlorthalidone (supplemented if necessary) for isolated systolic hypertension lowers blood pressure and its cardiovascular disease complications and has relatively mild effects on other cardiovascular disease risk factor levels.

Aged↗
PubMed1998

Occurrence of carpal tunnel syndrome among slaughterhouse workers.

OBJECTIVES: The aim of this study was to examine the risk of carpal tunnel syndrome (CTS) among workers with daily occupational exposure to high-force and high-velocity manual work. METHODS: The study was carried out retrospectively among a cohort of 1591 workers employed at a slaughterhouse or at a chemical factory; 1141 persons (71.7%) participated. Workers not doing tasks in slaughtering or meat processing constituted the reference group. Exposure assessments were made for 46 different tasks in slaughtering and meat processing from video-based observations at the workplace. CTS was diagnosed if there were current symptoms typical of CTS in combination with positive neurophysiological signs of CTS or if the subject had previously been operated on for CTS. RESULTS: Altogether 1.6% of the reference group, 5.1% of the nondeboning slaughterhouse workers [prevalence ratio (PR) 3.23, 95% confidence interval (95% CI) 1.3-7.99] and 7.8% of the deboning slaughterhouse workers (PR 4.91, 95% CI 2.03-11.81) had CTS. Increased risk estimates persisted after adjustment for other potential risk factors by logistic regression. The prevalence of CTS in the dominant hand was equally increased in both groups of slaughterhouse workers (but only statistically significant for the workers in deboning tasks), while the prevalence of CTS in the nondominant hand was significantly increased only among the slaughterhouse workers in deboning tasks. CONCLUSIONS: This study supports the hypothesis that daily high-velocity and high-force manual work is a risk factor for CTS.

Abattoirs↗
PubMed1997

Immunosensitization of prostate carcinoma cell lines for lymphocytes (CTL, TIL, LAK)-mediated apoptosis via the Fas-Fas-ligand pathway of cytotoxicity.

Several reports suggest that immunotherapy mediated by cytotoxic lymphocytes is beneficial in the destruction of drug-resistant tumor cells. Cytotoxic T lymphocytes kill target cells by two main mechanisms, namely by the perforin pathway and by the Fas-ligand (Fas-L) pathway. The role of the Fas-L pathway in tumor cell killing is not clear because many Fas(+)-expressing tumor cells are resistant to the Fas-L agonist cytotoxic anti-Fas antibody. The human prostate tumor cell lines (PC-3, DU145, and LnCAP) express Fas on the cell surface but are resistant to killing by anti-Fas antibody. This study examined the sensitivity of prostate tumor cells to Fas-L-mediated cytotoxicity and sensitization of the tumor cells by drugs to Fas-L-mediated killing. All three prostate tumor cell lines are resistant to Fas-L killing as determined by the use of the murine CTL hybridoma PMMI that kills only through the Fas-L pathway. However, the addition of subtoxic concentrations of CDDP or VP-16 significantly sensitized the PC-3 and DU145, but not LnCAP, tumor cells to Fas-L killing and apoptosis by PMMI. The sensitization of tumor cells by drugs was inhibited by neutralizing anti-Fas antibody. These findings demonstrate that immunoresistant Fas(+)-expressing DU145 and PC-3 prostate tumor cells can be sensitized by drugs to Fas-L killing. We then examined the role of Fas-L killing by TIL and LAK cells. All three prostate tumor cell lines were sensitive to killing by TIL and LAK and cell killing was primarily mediated through the Ca(2+)-dependent perforin pathway because it was blocked by the addition of EGTA/MgCl2. Sensitization by CDDP or VP-16 did not significantly augment killing of untreated tumor cells by TIL or LAK cells. However, in the presence of EGTA/MgCl2, the addition of CDDP or VP-16 significantly augmented killing of PC-3 and DU145, but not LnCAP, by TIL and LAK, and killing was blocked by neutralizing anti-Fas antibody. These findings demonstrate that both TIL and LAK exhibit a Fas-L-mediated killing pathway that is revealed once the perforin pathway is blocked by the Ca2+ chelator EGTA/MgCl2. Altogether, these findings show that drug-resistant, Fas(+)-expressing PC-3 and DU145 prostate tumor cells can be sensitized by CDDP and VP-16 to killing by Fas-L-bearing CTL, TIL, and LAK cells. Sensitization of tumor cells by drugs may augment the efficacy of immunotherapy in the eradication of tumor cells that are resistant to Fas-L-mediated killing.

Animals↗
PubMed1997

Nucleic acid immunization of chimpanzees as a prophylactic/immunotherapeutic vaccination model for HIV-1: prelude to a clinical trial.

Vaccine development strategies have often utilized recombinant envelope glycoproteins which usually generate strong humoral immune responses but which do not generate strong cytotoxic T lymphocytes (CTL). A recent novel experimental vaccination approach involves the technology known as nucleic acid immunization in which DNA plasmids expressing a gene of interest is injected intramuscularly in experimental animals. These expressed proteins then are presented to the immune system with the subsequent development of strong antibody and cellular (particularly CTL) immune responses. These types of immune responses have been elicited in rodents as well as nonhuman primates including chimpanzees. Results from studies on nucleic acid immunization of HIV-1 infected chimpanzees with envelope glycoprotein expressing constructs indicated that this method was able to decrease substantially HIV-1 viral load in these chimpanzees. These data are useful for the development and implementation of human phase I clinical trials with HIV constructs expressing various genes from the HIV-1 genome.

AIDS Vaccines↗