Search PubMed⌕ Search

Biomedical subjects

J Keller

Publications and source records attributed to J Keller.

At least 181 records · Page 10Linked to original sources
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↗
PubMed1990

N of 1 randomized trials for investigating new drugs.

Presently, in the process of new drug development, large sample parallel group randomized trials are often begun without the detailed knowledge of optimal dose, most responsive patient group, and optimal outcomes which would be desirable. We propose that randomized trials in individual subjects (N of 1 RCTs) could be used to elucidate these issues at an early stage of drug development. In appropriate conditions N of 1 RCTs can be used to define the rapidity with which a drug begins and ceases its clinical action, the likely range of the optimal drug dose, and the optimal outcomes on which subsequent trials should focus. N of 1 RCTs can also generate initial estimates of the proportion of patients who respond to a new agent and for determining sample size, inclusion criteria, and dosage regimen(s) for subsequent parallel group trials. We provide an example of 14 N of 1 RCTs of amitriptyline in fibrositis that illustrate the ways in which N of 1 RCTs can elucidate these issues. The multiple uses of N of 1 RCTs suggest that the method has immense potential for use in the early phases of drug development programs.

Amitriptyline↗
PubMed1990

Indomethacin and bone trauma. Effects on remodeling of rabbit bone.

The influence of indomethacin on remodeling activity in normal trabecular and cortical bone and its influence on cortical bone close to a midtibial drill hole, 2 mm in diameter were histomorphometrically evaluated. Eight rabbits were treated with indomethacin (12.5 mg/kg/day), and another 8 rabbits served as controls. After 3 days, the mean plasma indomethacin level was 542 ng/mL, resulting in an almost complete inhibition of prostaglandin synthesis as reflected by the serum levels. In the control rabbits the remodeling activity after 6 weeks was increased 1 mm away from the drill hole but not at 3 and 8 mm. In conclusion, indomethacin had no effect on the activated remodeling process in cortical bone neighboring a small drill hole or on remodeling in nontraumatized cortical and cancellous bone. This suggests that the inhibitory effect of indomethacin on the remodeling process following local trauma to bone depends on the extent of the trauma.

Animals↗
PubMed1990

[Risk factors for acute infantile diarrhea in a rural community in Chiapas, Mexico. A strategy for intervention].

A community-based, case-control study was conducted during the summer peak season for diarrhea in the highlands of Chiapas, Mexico, to identify risk and protective factors associated with acute diarrhea in children less than 6 years of age. To estimate the diarrheal morbidity rate, the community was divided into 13 sectors, each of about 20 households. A resident (volunteer mother) made daily visits to every household in her sector to identify new cases of diarrhea. During 3 weeks of surveillance, 63 children with diarrhea and 48 control children were identified. The diarrheal attack rate during this period for children less than 6 years of age was 30%. Analysis of 29 neighborhood-matched case-control pairs showed that children with diarrhea were more likely than their controls to have had a mother with diarrhea in the 2 weeks preceding the onset of the child's diarrhea (P less than 0.05; relative risk = 10). The association of childhood diarrhea with maternal diarrhea may serve as a focus for more detailed studies as well as an intervention that may be appropriate and effective for this community.

Adult↗
PubMed1990

Risk factors for acute childhood diarrhea in the highlands of Chiapas, Mexico: a strategy for intervention.

A case-control study was conducted in the highlands of Chiapas, Mexico, to identify factors associated with acute diarrhea in children less than six years old. The study found that the diarrhea attack rate among the children surveyed during three weeks in the month of August (the peak diarrhea season) was approximately 30%, and that children whose mothers had diarrhea were especially likely to contract the illness themselves. The methods employed could prove relevant to studies in other areas, and the results obtained could provide the basis for more detailed study of the area involved--and for preventive action.

Case-Control Studies↗
PubMed1989

[The thermoregulatory effectiveness of calcitonin in progressive scleroderma].

During a 10-day hospitalization, 21 patients suffering from systemic sclerosis (SS) with Raynaud's phenomenon were treated intermittently with intravenous infusions of calcitonin for 5 hours daily. Telethermographically, we measured a significantly shortened rewarming period of the patients' hand after standardized cooling. Up to now, as many as 47 patients with SS have been treated in the same way during 152 10-day cycles of calcitonin infusion. Only 7 patients interrupted the calcitonin therapy because of transient headache or nausea. Allergic reactions have not been observed, so far.

Adult↗