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Biomedical subjects

R Brenner

Publications and source records attributed to R Brenner.

At least 55 records · Page 3Linked to original sources
PubMed1998

Bioassay-directed fractionation and chemical identification of mutagens in bioremediated soils.

Soil from a Superfund site (Reilly Tar Site, St. Louis Park, Minnesota) contaminated with polycyclic aromatic hydrocarbons (PAHs) from creosote was treated with several bioremediation technologies including bioslurry (BS), biopile (BP), compost (CMP), and land treatment (LT). These treatment technologies are being evaluated in pilot scale laboratory systems by the U.S. Environmental Protection Agency's National Risk Management Research Laboratory in Cincinnati, Ohio. To evaluate the genotoxicity and identify the mutagens in the soil before and after the various treatments, fractionated extracts of five soils were bioassayed for mutagenic activity with a microsuspension modification of the Salmonella histidine reversion assay. Soils were extracted by sonication using dichloromethane (DCM). The five extracts were fractionated in triplicate (two for bioassay and one for chemical analysis) by reverse-phase high-performance liquid chromatography (HPLC) using hexane/DCM/methanol, and the fraction for bioassay were solvent-exchanged into dimethyl sulfoxide by nitrogen evaporation. Forty HPLC fractions for each sample were bioassayed in strain YG1041 with and without exogenous liver metabolic activation. As shown in a companion paper, the mutagenicity of two treatments (BS and BP) was significantly greater than the mutagenicity of the untreated soil. Mutagenic fractions (> 500 revertants) were analyzed by gas chromatography/mass spectrometry (GC/MS). PAH analysis of the soils indicated that all treatments were effective in reducing the total PAH concentration (48-74%). Qualitative GC/MS analysis of the mutagenic fractions from the BS and BP treatments indicated that they contained azaarenes, which are mutagens. The CMP and LT processes were the most effective and least toxic bioremediation procedures based on mutagenic potency and chemical analysis. This research demonstrated that the combination of bioassays and chemical analysis provided a more accurate determination of toxicity in these complex environmental mixtures.

Biological Assay↗
PubMed1998

An approach to switching patients from baclofen to tizanidine.

With the introduction of the antispasticity agent, tizanidine hydrochloride (Zanaflex), physicians have requested information about the optimal way to switch appropriate patients from baclofen to tizanidine. A group of neurologists and rehabilitation specialists with a particular interest in spasticity was therefore asked to draw up a suitable approach to changing treatment.

Baclofen↗
PubMed1997

Novel embryonic regulation of Ca(2+)-activated K+ channel expression in Drosophila.

The slowpoke gene of Drosophila melanogaster encodes a Ca(2+)-activated K+ channel that is expressed in neurons, muscles, tracheal cells and the middle midgut. The entire transcriptional control region of slowpoke is contained in 11 kb of genomic DNA. Previous work has identified four different tissue-specific promoters (Promoters C1, C1b, C1c and C2) and sequences that regulate their activity. Here we describe and contrast the regulation of neuronal and muscle expression during embryogenesis with its regulation during larval and adult stages. Embryonic regulation is fundamentally different. The embryo uses Promoter C1 and a previously undescribed promoter, called Promoter Ce, to drive neuronal expression. The expression patterns of these promoters are distinct. Muscle expression arises from Promoter C2 as in other developmental stages. A downstream intronic region has been shown to contain control elements that modulate promoter activity differently in embryos, larvae and adults. Embryonic CNS expression is not dependent on the intron, however; its deletion has substantial effects on neuronal expression in larvae and adults. In embryonic muscle, removal of the intron eliminates muscle expression even though this deletion does not reduce larval muscle expression.

Animals↗
PubMed1997

Calcium-activated potassium channel gene expression in the midgut of Drosophila.

The slowpoke gene of Drosophila encodes a pore-forming subunit of a BK-type Ca(2+)-activated K+ channel. The gene is expressed in neurons, muscles, tracheal cells and in the midgut. The P1 transgene gene contains the entire slowpoke transcriptional control region and drives the expression of a reporter protein comprised of slowpoke amino terminal sequences fused to beta-galactosidase. Here we show that midgut expression is limited to the copper cell and iron cell regions. The copper cell region is composed of two cell types, the copper cells and the interstitial cells. The P1 transgene is expressed in the interstitial cells but not the copper cells. Furthermore, we show that the reporter protein is apically localized in the interstitial cells. In these cells, the slowpoke Ca(2+)-activated K+ channel is thought to participate in the transport of ions between the hemolymph and the lumen of the gut. Subcellularly localized BK channels may be involved in the secretion of acid into the gut lumen. An analogous role for basolaterally localized BK channels has been proposed in the acid-secreting intercalating cells of the human kidney.

Animals↗
PubMed1997

Increased turnover of small proteoglycans synthesized by human osteoblasts during cultivation with ascorbate and beta-glycerophosphate.

The small proteoglycan decorin had been localized previously at the d-band in the gap zone of collagen fibrils in nonmineralizing tissues. In bone matrix this zone is proteoglycan free and is at least in some species the place where mineralization along collagen fibrils starts. To study the metabolism of the small proteoglycans decorin and biglycan under mineralizing conditions, osteoblasts from human nasal bone were cultured for several weeks in the presence or absence of beta-glycerophosphate and ascorbate. An immediate consequence of the treatment was a reduced expression of decorin, as judged by immune precipitation, whereas the biosynthesis of biglycan was not affected. Pulse-chase experiments were performed with osteoblasts embedded in floating type I collagen gels. In the presence of beta-glycerophosphate and ascorbate, a more rapid turnover of both proteoglycans was noted; the one of biglycan reached statistical significance. Indirect evidence for an enhanced rate of proteoglycan endocytosis was obtained. This effect was not seen in cultured skin fibroblasts. Thus, osteoblasts respond rapidly to mineralizing conditions with alterations of small proteoglycan biosynthesis and turnover.

Adolescent↗
PubMed1996

Developmental- and eye-specific transcriptional control elements in an intronic region of a Ca(2+)-activated K+ channel gene.

The range of electrical properties that a neuron or muscle cell can manifest is determined by which ion channel genes it expresses and in what amounts. The Drosophila slowpoke Ca(2+)-activated K+ channel gene has four distinct promoters. Here we assess the role that a downstream intronic region, called the C2/C3 region, plays in modulating Promoter C1 and Promoter C2 activity. Promoter C1 and Promoter C2 appear to be responsible for all neuronal and muscle expression, respectively. Transgenic flies were used to determine the expression pattern from each promoter in the presence and absence of the C2/C3 region. Deletion of this region silences Promoter C1 in adult but not larval CNS and causes a substantial reduction in Promoter C2 activity in adult but not larval muscle. The C2/C3 region also activates Promoter C1 in the animal's eye. By placing the C2/C3 region adjacent to a basal HSP70 promoter we have demonstrated that it contains elements that can specifically activate a heterologous promoter in the eye and in adult but not larval muscle. These results demonstrate that the C2/C3 region has a important role in regulating slowpoke developmental expression in the CNS and musculature and in regulating eye expression.

Animals↗
PubMed1996

Tissue-specific expression of a Ca(2+)-activated K+ channel is controlled by multiple upstream regulatory elements.

The electrical properties of a cell are produced by the complement of ion channels that it expresses. To understand how ion-channel gene expression is regulated, we are studying the tissue-specific regulation of the slowpoke (slo) Ca(2+)-activated K+ channel gene. This gene is expressed in the central and peripheral nervous system, in midgut and tracheal cells, and in the musculature of Drosophila melanogaster. The entire transcriptional control region has been cloned previously and shown to reproduce the tissue and developmental expression pattern of the endogenous gene. Here we demonstrate that s/o has at least four promoters distributed over approximately 4.5 kb of DNA. Promoter C1 and C1c display a TATA box-like sequence at the appropriate distance from the transcription start site. Promoters C1b and C2, however, are TATA-less promoters. C1, C1b, and C1c transcripts differ in their leader sequence but share a common translation start site. C2 transcripts incorporate a new translation start site that appends 17 amino acids to the N terminus of the encoded protein. Deletion analysis was used to identify sequences important for tissue-specific expression. We used a transgenic in vivo expression system in which all tissues and developmental stages can be assayed easily. Six nested deletions were transformed into Drosophila, and the expression pattern was determined using a lacZ reporter in both dissected tissues and sectioned animals. We have identified different sequences required for expression in the CNS, midgut, tracheal cells, and muscle.

Amino Acid Sequence↗
PubMed1996

Evaluating new vaccines for developing countries. Efficacy or effectiveness?

Despite the profusion of promising new vaccines against illnesses prevalent in developing countries, uncertainties about the balance between costs and benefits of new vaccines have retarded their use in public health practice. Conventional prelicensure trials of vaccine protection exacerbate these uncertainties by focusing on measurement of vaccine efficacy--the performance of a vaccine under idealized conditions. Vaccine effectiveness trials provide a more pragmatic perspective by addressing the performance of a vaccine under the ordinary conditions of a public health program, by capturing direct as well as indirect effects of vaccination, and by comprehensively addressing outcomes of public health concern. The use of effectiveness trials should enable more rational triaging of new vaccines for developing countries and may accelerate the introduction of new vaccines into public health practice by resolving speculative debates about practical costs and benefits.

Case-Control Studies↗
PubMed1995

Agonadism in two sisters with XY gonosomal constitution, mental retardation, short stature, severely retarded bone age, and multiple extragenital malformations: a new autosomal recessive syndrome.

We report on 12- and 14-year old sisters with a 46, XY chromosome constitution, normal female external genitalia, and absence of gonadal tissue. Except for omphalocele, right renal agenesis and malrotation of the colon in the elder sister, the internal organs were normal. Both were mentally retarded, of short stature, and had extremely retarded bone age. In addition, they had an almost identical pattern of minor anomalies: peculiar face, hypodontia, short neck, inverted nipples, thoracolumbar scoliosis, "dysplastic" hips, partial clino-/syndactyly of toes. The occurrence of a basically similar set of malformations in two sisters and the first cousin consanguinity of the parents suggests autosomal recessive inheritance. The conserved region of the SRY gene ([high mobility group] HMG box) was sequenced in the elder sib and was normal. No consistent malformations are observed at present in agonadal patients. This supports the idea that several autosomal genes have the potential of influencing the sequence of events of sex determination.

Abnormalities, Multiple↗
PubMed1995

Efficacy of risperidone treatment for psychoses associated with schizophrenia, schizoaffective disorder, bipolar disorder, or senile dementia in 11 geriatric patients: a case series.

BACKGROUND: Clinical trials of risperidone, a recently approved novel antipsychotic, included elderly healthy patients, but more data are needed on the effects of risperidone in this population, especially those with comorbid medical illnesses. METHOD: Risperidone was used to treat 11 elderly hospitalized patients between 61 and 79 years of age who manifested signs of psychoses related to schizophrenia, schizoaffective disorder, bipolar disorder, or senile dementia. All patients had been treated previously with classic antipsychotics. Response was assessed by clinical observation of the patients' behavior. RESULTS: Eight patients responded to treatment, 1 did not respond, and 2 had treatment discontinued because of hypotension or dizziness. Positive and negative symptoms decreased markedly in 7 of the responding patients. Four patients had preexisting extrapyramidal symptoms (EPS) and symptoms of tardive dyskinesia that also decreased in response to risperidone treatment. In addition, 4 patients were able to discontinue anti-parkinsonian medications, and 2 were able to discontinue antihypertensive medications. Side effects related to blockade of dopamine, histamine, and serotonin were negligible. No adverse consequences occurred when electroconvulsive therapy, carbamazepine, or lithium was given concurrently. CONCLUSION: The reduction of both positive and negative symptoms of schizophrenia and the lack of significant EPS, tardive dyskinesia, sedation, and anticholinergic side effects indicate that risperidone is a safe and effective medication for the elderly.

Aged↗
PubMed1995

Tissue-specific expression of a Drosophila calcium-activated potassium channel.

The Drosophila slowpoke (slo) gene encodes a subunit of a CAK channel homologous to the vertebrate BK channel. We have examined slo expression throughout development. It is expressed in muscle cells, neurons of the CNS and PNS, mushroom bodies, a limited number of cells in embryonic and larval midgut and in epithelial-derived tracheal cells. The promoter has been cloned and shown to direct expression in the same pattern as the endogenous gene in both neural and epithelial-derived cells. During pupariation and embryogenesis, slo is expressed in muscles many hours prior to the appearance of functional channels.

Animals↗
PubMed1993

Osteogenesis imperfecta and hyperplastic callus formation: light- and electron-microscopic findings.

In rare cases of osteogenesis imperfecta, an "overshoot" growth of new bone may occur, which, clinically gives the impression of a tumour. This condition is known as hyperplastic callus formation. Morphology showed an excessive mixed desmal-chondral osteoneogenesis. Atypical collagen fibrils in non-callus tissue represent an indicator for this callus formation in individual patients.

Bony Callus↗