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Advanced ovarian adenocarcinoma. A prospective clinical trial of melphalan (L-PAM) versus combination chemotherapy.

Eighty patients with advanced ovarian adenocarcinoma were treated in a prospective, randomized trial comparing a four-drug combination--hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil--with the oral alkylating agent, melphalan. Treatment with the four-drug combination was associated with a significantly increased overall response rate (75 vs. 54 per cent) (P less than 0.05), more complete remissions (33 vs. 16 per cent) and longer median survival (29 vs. 17 months) (P less than 0.02) but more severe toxicity than occurred with melphalan. Patients with minimal residual disease had a significantly higher overall response rate than patients with extensive residual disease (84 vs. 53 per cent) (P less than 0.05). Patients with advanced disease who achieved a complete remission documented by peritoneoscopy or laparotomy (or both) have a median survival that will exceed three years. The four-drug regimen is more effective than melphalan in the management of advanced ovarian adenocarcinoma.

Adenocarcinoma↗

Differential prevalence of quality-of-life categories (domains) in Asian women and changes after therapy with three doses of conjugated estrogens/medroxyprogesterone acetate: the Pan-Asia Menopause (PAM) study.

OBJECTIVES: To assess the prevalence of four categories (domains) of menopausal symptoms as markers for quality of life in nine ethnic groups of Asian women. To evaluate changes in quality of life (MENQOL scores) in Asian women following hormone therapy. METHODS: A prospective, randomized, double-blind, multinational clinical trial in 1028 healthy postmenopausal women of nine ethnic groups from 11 Asian countries/regions. Following 2 weeks of baseline observation, the women received one of three conjugated estrogens (CE)/medroxyprogesterone acetate (MPA) doses (in mg) daily for 24 weeks: 0.625/2.5, 0.45/1.5, or 0.3/1.5. At baseline and at the end of weeks 4, 12 and 24 following the start of therapy, the study participants were asked to record, on a menopause-specific quality of life (MENQOL) questionnaire, 29 menopausal symptoms, as experienced during the preceding month. The symptoms were categorized into four domains: vasomotor, psychosocial, physical and sexual. RESULTS: The baseline (pretreatment) symptom scores in each of the four domains varied substantially among the different ethnic groups, ranging from 2.21 to 5.71 in the vasomotor, 2.37-5.96 in the psychosocial, 2.66-5.39 in the physical, and 2.11-6.55 in the sexual domain. Overall, Vietnamese and Pakistani women had the highest baseline scores, i.e. were most afflicted by each set of symptoms in a given domain, and Indonesian, Malay, Taiwanese and Thai women were least afflicted. In the overall population, intervention resulted in statistically significant decreases in the scores of all four domains within 4 weeks of intervention. The beneficial effects were similar in the three dose groups. CONCLUSIONS: The prevalence of four domains of menopausal symptoms, representative of quality of life as recorded on a MENQOL questionnaire, varies considerably among ethnic groups of Asian women. The MENQOL scores in the overall population were significantly lowered in the course of the study, indicating an improvement in quality of life. In the absence of a placebo group, the relative contribution of hormones and placebo in our intervention is unknown.

Adult↗

Augmentation of granulocyte/macrophage colony-stimulating factor expression by ultraviolet irradiation is mediated by interleukin 1 in Pam 212 keratinocytes.

Keratinocytes are a potent source of a variety of cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF). In this study, we have shown that ultraviolet B (UVB) irradiation augments GM-CSF mRNA expression by murine keratinocytes. This is reflected in the increased production of GM-CSF protein by these cells. In the same cell population, exposure to UVB irradiation increases interleukin 1 alpha (IL-1 alpha) mRNA and IL-1 protein as detected by bioactivity. This increase in IL-1 alpha precedes the increase of GM-CSF mRNA. Addition of recombinant IL-1 alpha to the medium increases GM-CSF mRNA expression. Anti-IL-1 alpha antibodies can completely inhibit UV-augmented GM-CSF mRNA expression. These results demonstrate that UVB irradiation-induced augmentation of GM-CSF is mediated by UV-induced IL-1 alpha.

Animals↗

Identification of a plasminogen-binding motif in PAM, a bacterial surface protein.

Surface-associated plasmin(ogen) may contribute to the invasive properties of various cells. Analysis of plasmin(ogen)-binding surface proteins is therefore of interest. The N-terminal variable regions of M-like (ML) proteins from five different group A streptococcal serotypes (33, 41, 52, 53 and 56) exhibiting the plasminogen-binding phenotype were cloned and expressed in Escherichia coli. The recombinant proteins all bound plasminogen with high affinity. The binding involved the kringle domains of plasminogen and was blocked by a lysine analogue, 6-aminohexanoic acid, indicating that lysine residues in the M-like proteins participate in the interaction. Sequence analysis revealed that the proteins contain common 13-16-amino-acid tandem repeats, each with a single central lysine residue. Experiments with fusion proteins and a 30-amino-acid synthetic peptide demonstrated that these repeats harbour the major plasminogen-binding site in the ML53 protein, as well as a binding site for the tissue-type plasminogen activator. Replacement of the lysine in the first repeat with alanine reduced the plasminogen-binding capacity of the ML53 protein by 80%. The results precisely localize the binding domain in a plasminogen surface receptor, thereby providing a unique ligand for the analysis of interactions between kringles and proteins with internal kringle-binding determinants.

Amino Acid Sequence↗

Development of the Patient Activation Measure (PAM): conceptualizing and measuring activation in patients and consumers.

BACKGROUND: Controlling costs and achieving health care quality improvements require the participation of activated and informed consumers and patients. OBJECTIVES: We describe a process for conceptualizing and operationalizing what it means to be "activated" and delineate the process we used to develop a measure for assessing "activation," and the psychometric properties of that measure. METHODS: We used the convergence of the findings from a national expert consensus panel and patient focus groups to define the concept and identify the domains of activation. These domains were operationalized by constructing a large item pool. Items were pilot-tested and initial psychometric analysis performed using Rasch methodology. The third stage refined and extended the measure. The fourth stage used a national probability sample to assess the measure's psychometric performance overall and within different subpopulations. STUDY SAMPLE: Convenience samples of patients with and without chronic illness, and a national probability sample (N=1,515) are included at different stages in the research. CONCLUSIONS: The Patient Activation Measure is a valid, highly reliable, unidimensional, probabilistic Guttman-like scale that reflects a developmental model of activation. Activation appears to involve four stages: (1) believing the patient role is important, (2) having the confidence and knowledge necessary to take action, (3) actually taking action to maintain and improve one's health, and (4) staying the course even under stress. The measure has good psychometric properties indicating that it can be used at the individual patient level to tailor intervention and assess changes.

Adult↗

Interleukin-1 alpha mRNA induced by cycloheximide PMA, and retinoic acid is reduced by dexamethasone in PAM-212 keratinocytes.

Keratinocytes in culture produce detectable amounts of IL-1 alpha mRNA constitutively and can be stimulated to express increased amounts of IL-1 alpha mRNA by cycloheximide, PMA, and retinoic acid. Dexamethasone decreases the amount of IL-1 mRNA induced by these agents, as well as constitutive IL-1 alpha mRNA. RU 486, which interferes with glucocorticosteroid-receptor binding, decreases inhibition of TPA stimulation of IL-1 alpha mRNA by dexamethasone, which suggests that the inhibition by dexamethasone is through a conventional ligand-receptor mechanism.

Animals↗