Biomedical subjects

K Fowler

Publications and source records attributed to K Fowler.

At least 37 records · Page 2Linked to original sources

PubMed1999

Aromatase overexpression and breast hyperplasia, an in vivo model--continued overexpression of aromatase is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate these preneoplastic changes in mammary glands.

To test directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens resulting from the overexpression of aromatase in mammary glands lead to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer. Continued overexpression of aromatase that leads to increased breast-tissue estrogen contributes to a number of epigenetic changes in mammary tissue such as alteration in the regulation of genes involved in apoptosis, activation of genes involved in cell cycle and cell proliferation, and activation of a number of growth factors. Our current studies show aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in female mice without circulating ovarian estrogen. Preneoplastic and neoplastic changes induced in mammary glands as a result of aromatase overexpression can be completely abrogated with the administration of the aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia, we have also seen downregulation of estrogen receptor and a decrease in cell proliferation markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies demonstrate that aromatase overexpression alone, without circulating estrogen, is responsible for the induction of breast hyperplasia and these changes can be abrogated using aromatase inhibitors.

Animals↗

PubMed1998

Intellectual assessment of children with asymptomatic congenital cytomegalovirus infection.

The findings of previous studies examining the neurocognitive development of children with clinically inapparent (asymptomatic) cytomegalovirus (CMV) infection have demonstrated mixed results. These studies have generally depended on small sample sizes (i.e., < 50). We examined the intellectual development of children with asymptomatic congenital CMV infection using a sample larger than previous studies. Two hundred and four cases aged 5 to 200 months were compared with 177 uninfected siblings ranging in age from 6 to 203 months. Parents were administered the Developmental Profile, a measure of developmental achievement. Children who were older than 30 months were administered an objective intelligence measure. Results of this study showed that children with asymptomatic congenital CMV infection do not demonstrate intellectual impairment, and that they perform similarly to uninfected siblings. Parents tended to overestimate their child's level of functioning regardless of whether the child had CMV infection.

Age Factors↗

PubMed1998

The heterocyclic substituted pyridine derivative (+/-)-2-(-3-pyridinyl)-1-azabicyclo[2.2.2]octane (RJR-2429): a selective ligand at nicotinic acetylcholine receptors.

The present report describes in vitro studies demonstrating that the heterocyclic substituted pyridine compound (+/-)-2-(3-pyridinyl)-1-azabicyclo[2.2.2]octane (RJR-2429) is extremely potent in activating human muscle nicotine ACh receptor (nAChR) (EC50 = 59 +/- 17 nM; Emax = 110 +/- 09% vs. nicotine). RJR-2429 is markedly less potent in activating nAChRs in the clonal cell line PC12, with EC50 = 1100 +/- 230 nM and Emax = 85 +/- 20% when compared with nicotine. The activation of a putative alpha 3 beta 4-containing nAChR in PC12 by RJR-2429 reveals a potency intermediate between nicotine and epibatidine (EC50 of 20,000 nM for nicotine and 30 nM for epibatidine). Dose-response curves for agonist-induced ileum contraction indicate that RJR-2429 is equipotent with nicotine, having an EC30 of approximately 2 microM. RJR-2429 binds with high affinity to alpha 4 beta 2 receptor subtype (Ki = 1.0 +/- 0.3 nM), and chronic exposure results in significant up-regulation of the high-affinity [3H]nicotine binding sites. In addition, RJR-2429 does not activate nAChRs present in rat thalamic preparations but is a potent inhibitor of this receptor subtype. It antagonizes nicotine-stimulated ion flux in thalamic synaptosomes with an IC50 of 154 +/- 37 nM. It also is a potent partial agonist at nAChRs mediating dopamine release from rat synaptosomal preparations (EC50 = 2 +/- 1 nM; Emax = 40%; epibatidine and nicotine have EC50 values of 0.4 and 100 nM, respectively). A model for the structure-activity profile of RJR-2429, nicotine and epibatidine was derived by molecular forcefield and quantum mechanics calculations and may provide important clues for the development of ligands selective for nAChR subtypes as probes in the life sciences or as potential therapeutic tools.

Animals↗

PubMed1997

Genetic variation for total fitness in Drosophila melanogaster.

We measured the heterozygous effects on net fitness of a sample of 12 wild-type third chromosomes in D. melanogaster. Effects on fitness were assessed by competing the wild-type chromosomes against balancer chromosomes, to prevent the production of recombinants. The measurements were carried out in the population cage environment in which the life history had been evolving, in an undisturbed population with overlapping generations, and replicated measurements were made on each chromosome to control for confounding effects such as mutation accumulation. We found significant variation among the wild type chromosomes in their additive genetic effect on net fitness. The system provides an opportunity to obtain an accurate estimate of the distribution of heterozygous effects on net fitness, the contribution of different fitness components including male mating success, and the role of intra-chromosomal epistasis in fitness variation.

Animals↗

PubMed1997

Heme oxygenase synthesis is induced in cultured lens epithelium by hyperbaric oxygen or puromycin.

We showed previously that treatment of cultured rabbit lens epithelial cells (LECs) with hyperbaric oxygen (HBO) produced DNA strand-breaks, caused reversible inhibition of protein synthesis and induced the synthesis of a 32 kD protein. In the present work, we employed immunostaining procedures to identify the 32 kD protein as heme oxygenase-1 (HO-1). Increased synthesis of the enzyme was observed as early as 12 hr after HBO-treatment, reached a maximum at 18 hr and was not detectable at 36 hr. Exposure of the cells to hemin also increased the synthesis of HO-1. An HBO-induced inhibition of protein synthesis and the subsequent induction of HO-1 was also observed in the capsule-epithelium of cultured rabbit lenses. For both LECs and the cultured lens, only HO-1 and not heme oxygenase-2 was HBO-inducible. Use of the antioxidant dimethylthiourea with HBO-treated lenses or LECs did not alter the observed effects on protein synthesis or the induction of HO-1. In contrast to results obtained with 50 atm O2, a pressure of 25 atm O2 inhibited protein synthesis only slightly and failed to induce synthesis of the 32 kD protein (although, as shown previously, identical exposure of LECs to 25 atm O2 significantly damaged DNA). Inhibition of protein synthesis in LECs and cultured lenses with the use of puromycin also induced synthesis of HO-1. Both hemin (10 micron), a source of iron, and 50 atm O2 produced a three-fold increase in the concentration of ferritin, a natural iron chelator, in LECs two days after exposure; no effects on ferritin levels were observed after 1 or 3 days. The finding that the increase in ferritin concentration occurred in the cells significantly after hemin- or HBO-induced synthesis of heme oxygenase indicates that chelatable iron rather than the heme molecule itself may have been the primary agent responsible for inducing ferritin synthesis. The data suggest that HBO-induced synthesis of HO-1 in the lens epithelium may be the result of an inhibition of protein synthesis, possibly leading to an accumulation of heme, rather than a direct protective response against oxidative stress.

Animals↗

PubMed1997

AIDS survival progress.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Tolerance induction for islet transplantation.

Type I diabetes is a systemic autoimmune disease. Although transplantation of pancreatic tissues restores glucose homeostasis, grafts are affected by acute and chronic rejection as well as re-occurrence of autoimmune destruction. One newly recognized promising strategy to interrupt these detrimental processes is hematopoietic chimerism induced by bone marrow transplantation (BMT). The application of hematopoietic chimerism has three domains in the treatment of Type I diabetes mellitus: (1) tolerance induction to pancreas or pancreatic islet grafts; (2) prevention of the re-occurrence of autoimmune processes in the graft; (3) prevention of the onset of overt diabetes once the pre-diabetic state is clearly identified. Unfortunately, conventional BMT is associated with significant morbidity and mortality due to graft-versus-host disease (GVHD), failure of engraftment and lethal conditioning. The risk of these complications cannot be justified in the treatment of non-malignant diseases including Type I diabetes. This chapter will outline potential strategies to achieve hematopoietic chimerism without the risk of deadly complications. With these strategies, it may be possible to apply hematopoietic chimerism in the treatment of Type I diabetes, both to induce tolerance to islet allografts as well as to intervene and interrupt the autoimmune process in its early stages.

Animals↗

PubMed1996

Mechanism for cotolerance in nonlethally conditioned mixed chimeras: negative selection of the Vbeta T-cell receptor repertoire by both host and donor bone marrow-derived cells.

Bone marrow (BM) chimeras prepared by complete recipient ablation (A-->B) exhibit donor-specific tolerance, yet survival is often limited by graft-versus-host disease (GVHD). Negative selection of potentially donor-reactive T cells, as assessed by relative T-cell receptor (TCR)-Vbeta expression, is dependent on donor BM-derived deleting ligands. Mixed chimerism and tolerance for both donor and host antigens can be achieved using partial recipient myeloablation with 500 cGy total-body irradiation (TBI) before transplantation followed by cyclophosphamide (CyP) on day +2. To examine the influence of residual host elements on negative selection, the peripheral TCR-Vbeta repertoire was analyzed in partially ablated C57BL/10SnJ (B10) recipients reconstituted with BM from major histocompatibility complex (MHC)-disparate B10.BR/SgSnJ or MHC, Hh-1 and Mls-disparate BALB/cByJ donors, which delete Vbeta5+ and 11+ or Vbeta3+, 5+, and 11+ TCR subsets, respectively. As in myeloblated recipients, donor-reactive subfamilies were deleted in B10.BR-->B10 and BALB/c-->B10 chimeras, suggesting that donor I-E and minor lymphocyte-stimulating (Mls) antigens contribute to the deleting ligands in the nonmyeloablated host. In striking contrast to completely ablated B10-->B10.BR chimeras, partially ablated recipients showed intramedullary I-E expression in the thymus and deleted host-reactive Vbeta5+ and Vbeta11+ subfamilies. These data demonstrate that efficient clonal deletion occurs after partial myeloablation and that both donor and host ligands contribute to TCR repertoire selection.

Animals↗

PubMed1995

Thermal evolution of growth efficiency in Drosophila melanogaster.

Drosophila melanogaster shows geographic clines in body size, with genetically larger flies being found further from the equator and at higher altitudes. In the laboratory, evolution at lower temperatures results in genetically larger flies, and development at low temperature increases adult body size. This study demonstrates that when newly hatched larvae from laboratory temperature selection lines were raised on fixed amounts of food (yeast) at the same temperature, larvae from the lines with the cold evolutionary history required less food to produce a given size of adult. Larvae from both high- and low-temperature selection lines required more food, however, to make a given size of adult when grown in the cold than when grown in the hot. The opposite associations between growth efficiency and adult body size seen with evolution or development at low temperature are puzzling, and suggest that different mechanisms may underlie the size changes. Since environmental and evolutionary effects of temperature on body size seem to be widespread among ectotherms, some basic aspects of thermal physiology must be involved.

Analysis of Variance↗

PubMed1995

Mechanisms of up-regulation of neuronal nicotinic acetylcholine receptors in clonal cell lines and primary cultures of fetal rat brain.

There is a consensus that high-affinity [3H]-L-nicotine binding sites in the mammalian brain, which are thought to represent a predominant form of central nervous system nicotinic acetylcholine receptor (nAChR) composed of alpha 4 and beta 2 subunits, are increased in number after chronic nicotine exposure. However, mechanisms responsible for this effect have not yet been elucidated. To evaluate this issue, we have used, as models, primary cell cultures of fetal rat brain cortex, in which high-affinity [3H]-L-nicotine binding sites are naturally expressed, and clonal cell cultures of fibroblasts stably transfected to express nAChR composed of transgenic chick alpha 4 and beta 2 subunits under control of dexamethasone-inducible promoters. Chronic nicotine exposure induced an approximately 2.5-fold increase in high-affinity [3H]-L-nicotine binding sites in M10 cells maintained in the presence of dexamethasone or in primary fetal rat brain cortical cultures. Up-regulation of [3H]-L-nicotine binding sites was evident for M10 cells treated at nicotine concentrations as low as 10 nM (EC50 and EC100 values were 100 nM and 10 microM, respectively). Scatchard analyses of [3H]-L-nicotine binding data in M10 cells indicated a change in Bmax with no significant change in affinity for radioligand (KD = 2.5 +/- 0.5 nM in control cells vs. 2.0 +/- 0.4 nM in nicotine-treated cells). Northern blot analyses indicated that nicotine treatment alone had no direct effect on the promoter driving transgenic nAChR subunit gene transcription in M10 cells and that steady state levels of fetal rat brain cortical cell or M10 cell nAChR alpha 4 or beta 2 mRNAs were unaffected under conditions of chronic nicotine treatment that produced up-regulation of high-affinity [3H]-L-nicotine binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Fluctuating asymmetry does not increase with moderate inbreeding in Drosophila melanogaster.

Fluctuating asymmetry, the unsigned difference between character values on the left and right sides of an individual, is often thought to be highly correlated with the heterozygosity of individuals or populations. A large sample of Drosophila melanogaster individuals with an inbreeding coefficient of F = 0.25 was derived from a laboratory population and compared to a sample of outbred individuals for the fluctuating asymmetry of sternopleural bristle number. Inbred flies were not more asymmetric than outbred flies. There was no evidence for heritability of fluctuating asymmetry, as measured by variance among full-sib lines. Fluctuating asymmetry may not be a reliable measure of the degree of inbreeding at the relatively low levels found in most animal populations and should be used with caution in the management of endangered species.

Animals↗

PubMed1994

Gene-environment interaction for body size and larval density in Drosophila melanogaster: an investigation of effects on development time, thorax length and adult sex ratio.

We measured the effect of larval density on thorax length, development time, sex ratio and a measure of total fitness, using strains of Drosophila melanogaster artificially selected for increased thorax length, control lines otherwise cultured in an identical way, and the base stock from which the lines had been derived. We used the addition experimental design (Mather & Caligari, 1981). No genotype-environment interaction was observed when comparing the reduction in thorax length of 'large' and 'control' lines with increasing larval density for any culture series, i.e. rank ordering of genotypes and additive genetic variances remained the same in all the environments tested. In contrast, the reduction in thorax length for the base stock as density increased was proportionally smaller than that of the 'large' and 'control' lines. Development time increased more rapidly with larval density in the 'large' lines than in the 'controls' or base stock. Sex ratio was unaffected by larval density but thorax length and the development time of females were more affected than those of males by increasing larval density. The estimate of total fitness showed clear evidence of gene-environment interaction for the effect of body size on fitness, with genetically large individuals at an increasing disadvantage with increasing larval density.

Animals↗

PubMed1994

The value of ultrasound in the child with an acute urinary tract infection.

OBJECTIVE: To assess the value of an ultrasound examination in children with a proven urinary tract infection. PATIENTS AND METHODS: The results of renal ultrasound and 99mTc-dimercapto-succinic acid (DMSA) studies were compared in 112 children with a first documented symptomatic Escherichia coli urinary tract infection. RESULTS: Ultrasound was particularly effective in detecting the presence of obstruction, renal swelling and parenchymal change consistent with acute pyelonephritis. However, ultrasound failed to detect half of the kidneys with photon deficient areas on 99mTc DMSA scan and was unreliable in detecting the presence of scarring. CONCLUSION: An ultrasound examination alone should not be relied on in the child with an acute urinary tract infection.

Adolescent↗

PubMed1993

Congenital cytomegalovirus infection and neonatal auditory screening.

Auditory screening of newborn infants has been recommended on the basis of the presence of risk criteria, including congenital infection. We assessed the ability of risk criteria-based neonatal auditory brain stem response to identify infants with hearing loss resulting from congenital cytomegalovirus (CMV) infection. Data from 6 1/2 years of risk criteria-based neonatal auditory screening were compared with the results of screening of all newborn infants for congenital CMV infection. Infants with congenital CMV infection received follow-up hearing evaluations. Congenital CMV infection was found in 167 (1.3%) of 12,371 infants; 134 had follow-up hearing evaluations, and 14 (10.4%) had confirmed sensorineural hearing loss. The rate of sensorineural hearing loss resulting from congenital CMV infection was 14 per 12,371 infants, of 1.1 per 1000 live births; the rate of bilateral loss > or = 50 dB was 0.6 per 1000. Although 2036 infants received auditory screening because of risk criteria, only 34 (20%) of 167 infants with congenital CMV infection were included. Only 2 (14%) of 14 children with sensorineural hearing loss caused by CMV were identified by risk criteria-based screening. We conclude that congenital CMV infection is an important cause of hearing impairment. Neonatal auditory screening based on the presence of risk criteria will fail to identify the majority of cases of sensorineural hearing loss caused by congenital CMV infection.

Cytomegalovirus Infections↗

PubMed1993

Healthcare foodservice report 1993. Getting ready for reform. Interview by Mitchell Schechter.

Hospital foodservice directors & dietitians are facing the greatest challenge of their careers -- to prepare, along with their institutions, for the most thoroughgoing reform of America's healthcare system ever proposed. Healthcare institutions across the country are seeking the means to offer enhanced patient services & gain competitive advantages by forming new alliances, new patient-centered care systems & cost-reduction programs. To aid in these efforts, their foodservices are developing comprehensive cross-training schemes, inter-departmental teams with other service groups & new ways to cut operating subsidies. Here's how five hospital foodservice departments are using cost controls, revenue building, quality management processes & enhanced efficiencies to help their institutions prepare for the changes ahead.

Cost Control↗

PubMed1992

On the use of tester stocks to predict the competitive ability of genotypes.

It has been recently claimed that the outcome of competition between two phenotypically indistinguishable strains cannot be predicted from comparisons of their respective performances against a mutant tester stock. Our aim in the present paper is to disprove this claim and to show the potential pitfalls of deriving conclusions from a statistical analysis of experimental designs commonly employed for the study of competitive interactions in genetically homogeneous and heterogeneous mixtures. Using our own data, we conclude that evaluating the competitive interactions of phenotypically indistinguishable wild-type strains by competing them against mutant marked stocks still remains a valuable method.

Analysis of Variance↗

PubMed1992

Patient-interactive, computer-controlled neurological stimulation system: clinical efficacy in spinal cord stimulator adjustment.

Over the past 20 years, continuing technical advances have rendered spinal cord stimulation an easily implemented low-morbidity technique for the management of chronic intractable pain in properly selected patients. Percutaneous methods for the insertion of arrays of multiple epidural electrodes, which are driven by noninvasively programmable "multichannel" implanted devices, have been among the most important of these technical improvements. The same implanted electronics may be used with peripheral nerve or intracerebral electrodes. If the capabilities of this new hardware are to be used to full advantage, a major investment of time and effort is required to adjust the system postoperatively for optimum effect. Ideally, these adjustments should be based upon psychophysical data, obtained in a manner that minimizes influences such as potential operator bias or stimulus presentation-order effects. These requirements have been met by the development of a computerized system designed for direct patient interaction and for greater ease of operation than the standard external devices used with these implants. The system has been tested clinically in 25 patients with spinal cord stimulation for pain. It rapidly tests the available electrode combinations and stimulus pulse parameters at a rate comparable to or greater than that of a skilled human operator using the standard device. It records detailed graphic data and patient analog ratings at varying thresholds and implements "pain drawing" methods with novel input and analytical techniques. This patient-interactive computerized system has proved to be safe and effective clinically. The time required by the average patient working with this system to adjust the stimulator is comparable to or less than the time required by the same patient working with a physician's assistant. Psychophysical data collected by the system may be correlated with clinical observations. Ongoing development will permit delivery of novel pulse sequences and protocols to assess the mechanisms by which stimulation affords relief from pain.

Electric Stimulation Therapy↗

PubMed1990

Unusual X chromosome inactivation in a mentally retarded girl with an interstitial deletion Xq27: implications for the fragile X syndrome.

A de novo interstitial deletion (X)(q27.1q27.3), between the loci DXS 105 and F8, has been found in a mentally retarded female. The deleted X chromosome is preferentially early replicating in fibroblasts, B cells and T cells, suggesting that the missing region plays a role in inactivation of the X chromosome. None of the available DNA probes except DXS 98 maps to the deleted region of about 10,000 kb. The locus FRAXA is either included in the deletion, or located close to the distal break point.

Blotting, Southern↗