Biomedical subjects

J Keller

Publications and source records attributed to J Keller.

At least 19 recordsLinked to original sources

PubMed1992

Megestrol acetate in cancer anorexia and weight loss.

High-dose megestrol acetate has been associated with increased appetite and weight. To examine the effects of high-dose megestrol acetate in the treatment of anorexia and weight loss in patients with advanced hormone-insensitive malignant lesions, a randomized double-blind placebo-controlled trial was conducted. Patients receiving megestrol acetate for 1 month reported a significant improvement in appetite and adequacy of food intake compared with those receiving placebo. A three-item scale measuring appetite, adequacy of food intake, and concern about weight revealed a higher improvement with megestrol acetate than with placebo. Patients who worsened while receiving placebo had similar favorable changes after the cross over to megestrol acetate. These data indicate that megestrol acetate may improve appetite and food intake in patients with advanced cancer.

Adult↗

PubMed1992

Effect of local prostaglandin E2 on periosteum and muscle in rabbits.

We assessed the target tissue for the stimulatory effect of prostaglandin E2 (PGE2) on bone formation previously observed during fracture healing. PGE2 was infused into tibial periosteal tissue in the right leg of 7 rabbits and into the anterior tibial muscle in the right leg of 7 other rabbits for 6 weeks. Solvent solution was infused into the left leg. PGE2 infusion at the periosteum caused the formation of primitive woven bone with large amounts of connective tissue; solvent infusion caused small amounts of normal periosteal bone formation. In the neighboring cortical bone, remodeling was increased after PGE2 infusion compared to solvent infusion. In the muscle, PGE2 infusion caused the formation of connective tissue with small amounts of woven bone. Thus, the major effects of PGE2 infusion at the site of the periosteum was the formation of primitive woven bone and in muscles the formation of connective tissue.

Animals↗

PubMed1992

Germinal and somatic activity of the maize element Activator (Ac) in Arabidopsis.

We have investigated the germinal and somatic activity of the maize Activator (Ac) element in Arabidopsis with the objective of developing an efficient transposon-based system for gene isolation in that plant. Transposition activity was assayed with a chimeric marker that consists of the cauliflower mosaic virus 35S promoter and a bacterial streptomycin phosphotransferase gene (SPT). Somatic activity was detected in seedlings germinated on plates containing streptomycin as green-resistant sectors against a background of white-sensitive cells. Germinal excisions resulted in fully green seedlings. The transposition frequency was extremely low when a single copy of the transposon was present, but appeared to increase with an increase in Ac copy number. Plants that were selected as variegated produced an increased number of green progeny. The methylation state of the Ac elements in lines with either low or high levels of excision was assessed by restriction analysis. No difference was found between these lines, indicating that the degree of methylation did not contribute to the level of Ac activity. Germinal excision events were analyzed molecularly and shown to carry reinserted transposons in about 50% of the cases. In several instances, streptomycin-resistant siblings carried the same transposed Ac element, indicating that excision had occurred prior to meiosis in the parent. We discuss parameters that need to be considered to optimize the use of Ac as a transposon tag in Arabidopsis.

DNA↗

PubMed1992

Identification and characterization of novel low-temperature-inducible promoters of Escherichia coli.

Escherichia coli promoters that are more active at low temperature (15 to 20 degrees C) than at 37 degrees C were identified by using the transposon Tn5-lac to generate promoter fusions expressing beta-galactosidase (beta-Gal). Tn5-lac insertions that resulted in low-temperature-regulated beta-Gal expression were isolated by selecting kanamycin-resistant mutants capable of growth on lactose minimal medium at 15 degrees C but which grew poorly at 37 degrees C on this medium. Seven independent mutants were selected for further studies. In one such strain, designated WQ11, a temperature shift from 37 degrees C to either 20 or 15 degrees C resulted in a 15- to 24-fold induction of beta-Gal expression. Extended growth at 20 or 15 degrees C resulted in 36- to 42-fold-higher beta-Gal expression over that of cells grown at 37 degrees C. Treatment of WQ11 with streptomycin, reported to induce a response similar to heat shock, failed to induce beta-Gal expression. In contrast, treatment with either chloramphenicol or tetracycline, which mimics a cold shock response, resulted in a fourfold induction of beta-Gal expression in strain WQ11. Hfr genetic mapping studies complemented by physical mapping indicated that in at least three mutants (WQ3, WQ6, and WQ11), Tn5-lac insertions mapped at unique sites where no known cold shock genes have been reported. The Tn5-lac insertions of these mutants mapped to 81, 12, and 34 min on the E. coli chromosome, respectively. The cold-inducible promoters from two of the mutants (WQ3 and WQ11) were cloned and sequenced, and their temperature regulation was examined. Comparison of the nucleotide sequences of these two promoters with the regulatory elements of other known cold shock genes identified the sequence CCAAT as a putative conserved motif.

Anti-Bacterial Agents↗

PubMed1992

Phenotypes of murine leukemia virus-induced tumors: influence of 3' viral coding sequences.

Murine leukemia viruses (MuLVs) induce leukemias and lymphomas in mice. We have used fluorescence-activated cell sorter analysis to determine the hematopoietic phenotypes of tumor cells induced by a number of MuLVs. Tumor cells induced by ecotropic Moloney, amphotropic 4070A, and 10A1 MuLVs and by two chimeric MuLVs, Mo(4070A) and Mo(10A1), were examined with antibodies to 13 lineage-specific cell surface markers found on myeloid cell, T-cell, and B-cell lineages. The chimeric Mo(4070A) and Mo(10A1) MuLVs, consisting of Moloney MuLV with the carboxy half of the Pol region and nearly all of the Env region of 4070A and 10A1, respectively, were constructed to examine the possible influence of these sequences on Moloney MuLV-induced tumor cell phenotypes. In some instances, these phenotypic analyses were supplemented by Southern blot analysis for lymphoid cell-specific genomic DNA rearrangements at the immunoglobulin heavy-chain, the T-cell receptor gamma, and the T-cell receptor beta loci. The results of our analysis showed that Moloney MuLV, 4070A, Mo(4070A), and Mo(10A1) induced mostly T-cell tumors. Moloney MuLV and Mo(4070A) induced a wide variety of T-cell phenotypes, ranging from immature to mature phenotypes, while 4070A induced mostly prothymocyte and double-negative (CD4- CD8-) T-cell tumors. The tumor phenotypes obtained with 10A1 and Mo(10A1) were each less variable than those obtained with the other MuLVs tested. 10A1 uniformly induced a tumor consisting of lineage marker-negative cells that lack lymphoid cell-specific DNA rearrangements and histologically appear to be early undifferentiated erythroid cell-like precursors. The Mo(10A1) chimera consistently induced an intermediate T-cell tumor. The chimeric constructions demonstrated that while 4070A 3' pol and env sequences apparently did not influence the observed tumor cell phenotypes, the 10A1 half of pol and env had a strong effect on the phenotypes induced by Mo(10A1) that resulted in a phenotypic consistency not seen with other viruses. This result implicates 10A1 env in an active role in the tumorigenic process.

Animals↗

PubMed1992

Controlled trial of respiratory muscle training in chronic airflow limitation.

BACKGROUND: Whether respiratory muscle training is of benefit to patients with chronic airflow limitation is controversial. The objective of the study was to determine the effect of resistance breathing training on physiological and functional measures in patients with chronic airflow obstruction. METHODS: The design was a randomised, double blind, controlled trial with a six month follow up. Eighty two patients with a forced expiratory volume in one second (FEV1) of less than 70% predicted, and an FEV1/vital capacity ratio of less than 0.7, were randomised to receive training for 10 minutes five times daily with progressively larger resistances through a resistive breathing device (PFLEX) as tolerated or to a sham device which gave minimal resistance. The main outcome measures, respiratory muscle strength and endurance, a progressive exercise test, a six minute walk test and physical and emotional function (chronic respiratory questionnaire) were assessed at monthly intervals. Patients in both groups were also randomised to wear or not wear nose clips during their training. RESULTS: No significant differences were observed between treatment and control groups, with or without nose clips, for any of the outcomes. Confidence intervals on the difference between treatments were narrow, excluding clinically important difference in any major outcome. CONCLUSION: This training regimen fails to strengthen respiratory muscles or improve exercise or functional capacity in patients with chronic airflow limitation.

Aged↗

PubMed1992

Are race and sex differences in lung function explained by frame size? The CARDIA Study.

Using the CARDIA cohort of 20- to 32-yr-old black and white men and women, FVC and FEV1 were standardized for standing height, sitting height, leg height, elbow breadth, and biacromial diameter in such a way that the standardized lung function showed minimal statistical dependence on these measures of frame size. Race and sex differences in lung function have been reported even after adjustment for height; however, these differences might depend on aspects of frame size other than height. We found that within this age group height2 provided robust standardization for FVC and FEV1 for all race and sex strata of the population. Height explained approximately 40% of the variance of FVC and FEV1 in whites, 30% in black women, and 20% in black men. In black men only, standardization for the combination of sitting height, leg height, elbow breadth, and biacromial diameter improved explained variance to nearly 40% for FVC and nearly 30% for FEV1. After standardization for height, FVC and FEV1 were found to be 14 to 19% higher in whites than in blacks, and in men than in women. Standardization of FVC and FEV1 for sitting height, leg height, elbow breadth, and biacromial diameter combined reduced these differences to 13-16%. Thus, race and sex differences in lung function exist even after detailed adjustment for frame size.

Adult↗

PubMed1992

Abnormalities of cutaneous microcirculation in atopic eczematics.

There are signs of abnormal microcirculation in atopics, yet reliable methods for its non-invasive measurement are scarce so far. Since the phenomenon of dermographism (D) elicited by blunt stroking of the skin reflects the functional response of cutaneous vessels to pressure, we studied the haemodynamics of D using laser-Doppler microfluxometry (LDF) and infrared thermography (IR-TH) in patients with atopic eczema (n = 23) and in healthy controls (n = 21) under standardized investigative conditions. Only in-patients not treated with corticoids were selected. LDF values showed a marked reduction in the intensity of hyperaemia in the patients as compared with the controls, according to the visual degree of the dermographic blanching effect (white, delayed white, indifferent; pink). A reduction of the radiating skin temperature vis-à-vis the controls was measured by IR-TH. These results yield evidence that dermographic pallor of atopic skin depends on the strength of local vasoconstriction, possibly including altered blood flow in cutaneous shunt vessels.

Adolescent↗

PubMed1991

Effects of recombinant transforming growth factor-beta 1 on hematologic recovery after treatment of mice with 5-fluorouracil.

Transforming growth factor beta 1 (TGF-beta 1) has been shown to inhibit bone marrow colony formation after in vitro treatment as well as after in vivo administration to normal mice. These data suggest that TGF-beta might either protect, or further depress, progenitor cell levels in mice exposed to a cell cycle-active drug such as 5-fluorouracil (5FU). rTGF-beta 1 was administered repeatedly by either the i.v. or i.p. routes to mice during the hyperproliferative state of the bone marrow that occurs 7 to 9 days after the i.v. administration of 150 mg/kg 5FU. The formation of both multilineage and the more differentiated (CFU-c) colonies was inhibited by 20 to 40%/culture, and 66 to 93%/mouse. When multiple doses of rTGF-beta 1 were administered systemically immediately before the injection of 5FU, the resulting rebound in the number of CFU-c and multilineage colonies containing granulocyte, erythroid, megakaryocyte, and macrophage lineage colonies per culture was markedly inhibited by 30 to 77%, whereas the total number of CFU per mouse was inhibited up to 93%. This effect was maximal when rTGF-beta 1 was administered at daily doses of greater than or equal to 5 micrograms/mouse for at least 3 days. This inhibition of the recovery of the bone marrow from 5FU treatment induced by rTGF-beta 1 was a delayed transient response because by day 16 the progenitor cell numbers and bone marrow cellularity were identical to the 5FU-treated marrow controls.

Animals↗

PubMed1991

Differential expression of transforming growth factor-beta 1 (TGF-beta 1) receptors in murine myeloid cell lines transformed with oncogenes. Correlation with differential growth inhibition by TGF-beta 1.

Transforming growth factor-beta 1 (TGF-beta 1) is a pleiotropic polypeptide hormone known to play an important role as a modulator of hematopoietic processes in human and murine cells. One of the characteristics of TGF-beta 1 is the ability to inhibit the growth of several cell types, including cells of the myeloid lineage. To study the mechanism by which TGF-beta 1 inhibits the growth of myeloid cells, we have used three murine myeloid cell lines, the parental interleukin-3-dependent 32D-123 cell line and two retrovirally infected interleukin-3-independent cell lines (32D-abl, 32D-src), all of which are growth inhibited by TGF-beta 1. Each of these oncogene-transfected cells expresses a greater number of TGF-beta 1 receptors than the parental cell line and responds to TGF-beta 1 with increased sensitivity; 32D and 32D-src cells are 2- and 58-fold more sensitive to TGF-beta 1 inhibition than the parental cell line (ED50 = 35 pM). Both 32D-abl- and 32D-src-transformed cell lines expressed higher levels of the 65- and 85-kDa TGF-beta 1 receptor species than did the parental cells. We observed a correlation between the greater sensitivity of 32D-src cells to TGF-beta 1 and the more rapid down-modulation and reappearance of cell surface TGF-beta 1 receptors on 32D-src cells. Thus, the level of TGF-beta 1 receptor expression and rate of reexpression both have a crucial regulatory effect on the functional activity of the TGF-beta 1 ligand.

Animals↗

PubMed1991

Mechanism of bronchodilator effect in chronic airflow limitation.

OBJECTIVE: To examine the mechanisms through which two bronchodilators (theophylline and salbutamol) influence dyspnea during daily activities. METHODS: Twenty-four patients with chronic airflow limitation participated in a multiple crossover, randomized, placebo-controlled trial. The effect of theophylline and salbutamol, alone or combined, on pulmonary function and dyspnea during daily activities was examined. Correlations of changes in forced expiratory volume in 1 second (FEV1) and maximum expiratory pressures (MIPs) (independent variables) and changes in dyspnea score during daily activities (dependent variable) were also examined. RESULTS: The two drugs proved to be beneficial the effects in general were additive rather than synergistic. The drugs improved the FEV1; theophylline significantly improved the MIPs. The correlation between the changes in FEV1 and those in dyspnea score, after adjustment for the changes in MIPs, was 0.55 (p less than 0.001). The correlation between the changes in MIPs and those in dyspnea score, after adjustment for the changes in FEV1, was 0.39 (p less than 0.001). CONCLUSIONS: Changes in airway calibre and in respiratory muscle strength play an independent and important role in dyspnea during daily activities in patients with chronic airflow limitation. Changes in airway calibre may be of greater importance.

Activities of Daily Living↗

PubMed1991

Early hemodynamic response to tibial osteotomy in rabbits: influence of indomethacin and prostaglandin E2.

The hemodynamic role of prostaglandins in the inflammatory phase of bone healing was studied on day 4 after creation of a nailed midtibial osteotomy in 40 rabbits, divided into groups of 10, treated with either indomethacin (oral dosage 10 mg/kg), subcutaneous (s.c.) prostaglandin E2 (PGE2) (dosage 1 mg/kg), or PGE2 infusion into the abdominal aorta (rate 20 ng/kg/min) for a 20-min period immediately before the animals were killed. The last group served as controls. Regional blood flow was measured by means of radioactive microspheres, and plasma volume was assessed by distribution of circulating [125I]fibrinogen. Neither indomethacin nor s.c. PGE2 treatment had any hemodynamic effects in the osteotomy area. PGE2 infusion caused increased blood flow in bone, bone marrow, and muscle of the lower limbs except in the osteotomy area. Thus, the influence of prostaglandins and indomethacin on bone healing of a rabbit midtibial osteotomy does not appear to be a direct vascular effect in the early healing phase.

Animals↗

PubMed1991

Interpreting changes in quality-of-life score in N of 1 randomized trials.

To provide additional evidence regarding the plausible range of the differences in health-related quality of life (HRQL) questionnaire scores within which the minimal important difference (MID) falls, we reviewed the results of 32 randomized controlled trials in individual subjects (N of 1 RCTs) with chronic diseases. These trials had been conducted to establish whether a patient was obtaining more good than harm from a medication. Each N of 1 RCT included a series of pairs of treatment periods, one period on active drug, and one on placebo or alternative drug. We examined the relationship between small (MID), medium, and large differences between periods within pairs, as indicated by Global Ratings and differences between these same periods according to HRQL questionnaires. The results showed a mean difference of 0.29 points per question in HRQL questionnaire scores corresponded to the MID. Differences of approximately 0.66 points per question corresponded to a moderate difference as ranked by the Global Rating; difference of about 1.09 points per question represented marked difference.

Drug Therapy↗

PubMed1991

Measuring functional status in chronic lung disease: conclusions from a randomized control trial.

The optimal method of assessing the effect of treatment on the day-to-day function of patients with chronic airflow limitation has not yet been established. Therefore, we examined the performance of the 6-min walk test, a rating of dyspnea following the walk test, and three different questionnaires measuring dyspnea in daily activities, in a controlled trial of inhaled salbutamol and oral theophylline in 24 patients with primary fixed chronic airflow limitation. Clinically important and statistically significant effects of salbutamol and theophylline on dyspnea during the day-to-day activities were detected by each measure, but the Chronic Respiratory Questionnaire (CRQ) was more powerful than the other questionnaires, either the Oxygen Cost Diagram or the Medical Research Council Dyspnea Questionnaire as modified by the Rand Corporation. Changes in the CRQ dyspnea score showed a higher correlation with changes in spirometry, walk test score, dyspnea following the walk test, and global ratings of dyspnea than did the other two measures. We conclude that the CRQ is a responsive, valid measure of functional status for clinical trials in chronic lung disease.

Aged↗

PubMed1991

Clinical usefulness of amitriptyline in fibromyalgia: the results of 23 N-of-1 randomized controlled trials.

Twenty-three double blind, randomized, multiple crossover trials (N-of-1 RCT) of amitriptyline were conducted in patients with fibromyalgia. The benefit of amitriptyline was assessed using a symptom questionnaire and count of tender points. To assess the usefulness of the method, the proportion of trials that provided a definite answer was examined. Completing the trial resulted in reaching a high degree of confidence in the final management decision in 74% of trials. In 35% of trials, results led to discontinuation of the drug which otherwise would have been continued indefinitely. The drug benefit, if present, was evident within first 2 weeks of therapy. We concluded that these results support the feasibility and usefulness of N-of-1 RCT in rheumatology practice.

Adult↗

PubMed1990

Chemoprotective effects of recombinant human IL-1 alpha in cyclophosphamide-treated normal and tumor-bearing mice. Protection from acute toxicity, hematologic effects, development of late mortality, and enhanced therapeutic efficacy.

In this study, recombinant human IL-1 alpha (rhIL-1 alpha) was used to protect normal and tumor-bearing BALB/c mice from the acute toxicity caused by lethal doses of cyclophosphamide (Cy) and 5-fluorouracil. Pretreatment of mice for 7 days with 10,000 U/day of rhIL-1 alpha protected 70 to 100% of mice from the acute death induced by lethal doses of both Cy (380 mg/kg) and 5-fluorouracil (250 mg/kg). In contrast, post-treatment of mice with single or multiple doses of rhIL-1 alpha was not chemoprotective. Pretreatment of mice with rhIL-1 alpha increased the acute LD90 of Cy from 380 mg/kg to greater than 500 mg/kg in normal mice, an LD90 dose-modifying effect of at least 1.25, was accompanied by a more rapid recovery from neutropenia and a less severe reduction in the number of bone marrow single lineage monocyte, myeloid, or myelomonocytic colonies. Some of the mice (10 to 50%) that were successfully protected by pretreatment with rhIL-1 alpha died after day 50. These mice consistently presented with extensive pulmonary inflammation and fibrosis at death. Mice bearing murine renal cancer (Renca) were also protected from the acute toxic effects of Cy (450 mg/kg) by pretreatment with rhIL-1 alpha. Renca-bearing mice pretreated with rhIL-1 alpha and either sublethal (300 mg/kg) or lethal (450 mg/kg) doses of Cy exhibited enhanced survival times over those of untreated Renca-bearing mice. Interestingly, the cause of death in Renca-bearing mice that ultimately failed treatment with rhIL-1 alpha plus 300 mg/kg Cy was recurrent tumor, whereas most mice treated with rhIL-1 alpha plus 450 mg/kg Cy had no detectable tumor, although several died from late pulmonary inflammation and fibrosis. Thus, the dose escalation of Cy in rhIL-1 alpha-pretreated mice results in greater antitumor effects of Cy. However, the dose escalation of some cytotoxic agents allowed by the use of myelostimulatory agents can result in late fatal complications not detected in acute toxicity testing.

Animals↗

PubMed1990

Effects of mutations altering SOS regulation on a nalidixic acid-inducible system for the production of heterologous proteins in Escherichia coli.

The major leftward early promoter of phage lambda pL, has frequently been used to drive expression of heterologous genes in Escherichia coli. pL is typically maintained fully repressed by the lambda cl protein. When induction of heterologous protein synthesis is desired, one of several potential mechanisms of destroying cl function is employed and the expression of the foreign gene commences. One method of derepressing pL involves exposing cells to nalidixic acid, which results in the "activation" of RecA protein and the subsequent RecA-mediated proteolytic cleavage of cl. Activated RecA also mediates the cleavage of the E. coli LexA protein, resulting in induction of the SOS regulon (at least 15 E. coli genes, including recA). We have examined the effect of two chromosomal mutations on the productivity of nalidixic acid inductions. One of the tested mutations (recA o) increased the intracellular concentration of RecA prior to induction; the other (lexAind-) resulted in a mutated lexA protein insensitive to RecA-mediated cleavage. These mutations were introduced into a strain carrying a cl+ defective lysogen. Synthesis of two heterologous proteins, human alpha 1-antitrypsin and a fusion protein partially derived from the Plasmodium falciparum circumsporozoite surface antigen, was examined in the wild-type and mutant strains. The maximum alpha-1 antitrypsin concentration achieved was improved by 50% when the recA o strain was used rather than the wild-type; however, only smaller changes (20% or less) in the maximum concentration of the malaria fusion protein were observed. Use of the lexAind- strain resulted in a decrease in the maximum concentration attained for both heterologous products.

Animals↗

PubMed1990

Maternal serum alpha-fetoprotein levels in pregnancies complicated by diabetes: implications for screening programs.

Maternal serum alpha-fetoprotein may be reduced in diabetic pregnancies, but the association with elevated glycosylated hemoglobin has been controversial. We tested the hypothesis that reductions in maternal serum alpha-fetoprotein may reflect the same phenomena that can also impair normal rates of embryo growth in the presence of poorly compensated maternal diabetes. If so, associations would be expected among maternal serum alpha-fetoprotein, embryo rates of growth, and levels of glycosylated hemoglobin reflective of regulation of maternal diabetes during the period of organogenesis. We found maternal serum alpha-fetoprotein levels in 93 pregnant patients with diabetes to be negatively associated with the earliest (4 to 12 weeks) glycosylated hemoglobin determinations. At glycosylated hemoglobin values greater than 9.6% (which approximates the upper quartile), all maternal serum alpha-fetoprotein values fell below the median for patients without diabetes (below 0.8 multiple of the median after weight adjustment). Moreover, there was a trend for pregnancies with lower maternal serum alpha-fetoprotein levels and higher glycosylated hemoglobin values to also demonstrate early fetal growth delay as measured by ultrasonography.

Embryo, Mammalian↗