Search PubMed⌕ Search

Biomedical subjects

R P Brown

Publications and source records attributed to R P Brown.

At least 19 recordsLinked to original sources
PubMed2002

The Atlas mountains as a biogeographical divide in North-West Africa: evidence from mtDNA evolution in the Agamid lizard Agama impalearis.

Since the early Miocene there have been several physical events within NW Africa that are likely to have had a major impact on its faunal diversity. Phylogeographical studies will shed new light on the biogeography of the region. We analysed mitochondrial DNA diversity in the agamid lizard Agama impalearis (also called A. bibronii) based on sequences from mitochondrial genes with very different evolutionary rates (16S rRNA and ND2). Well-supported topologies of rooted maximum parsimony trees (with a Laudakia outgroup) and unrooted haplotype networks indicated two major clades with similar branch lengths. These clades have non-overlapping distributions representing respective areas to the North and West and South and East of the Atlas mountain chain and each could be given full species recognition. Nested clade analyses indicate that historical and possible present-day allopatry account for the primary phylogeographic pattern. Further evidence is provided by the estimated timing of cladogenesis, based on calibration of evolutionary rates in the ND2 gene of another continental Agamid. Sequence divergence between clades corresponds to 8.5-9.4mya, coinciding with the main period of orogenic uplift of the Atlas. Additional evidence of cladogenesis by allopatric fragmentation is also detected within the North/West Atlas clade, although contiguous range expansion is the most predominant explanation of more recent phylogeographic effects in this species. Miocene vicariance mediated by the Atlas may provide a general explanation of intra- and interspecific biogeographical patterns in NW African species.

Africa, Northern↗
PubMed2001

A critical review of the scientific literature on potential endocrine-mediated effects in fish and wildlife.

A rigorous approach to evaluating the reliability and relevance of experimental methods and results is critical for making appropriate, scientifically sound decisions. A literature evaluation framework was modified and adapted based on criteria described by Klimisch et al. (H. J. Klimisch, M. Andrae, and U. Tillman, 1997, Reg. Tox. Pharm. 25, 1-5) and requirements of the USEPA High Product Volume Challenge Program. This simple framework was used to evaluate an appropriate selection of peer-reviewed references to assign a Study Reliability "score" to the study design, endpoints, and conclusions compared to established data quality guidelines. Subsequently, the interpretation of the data was evaluated and assigned a Relevance Index based on the overall strength of evidence of endocrine modulation potential, which was evaluated based on the Weybridge (European Commission (1996). European workshop on the impact of endocrine disrupters on human health and wildlife. Report of proceedings from a workshop held in Weybridge, UK, 2-4 December 1996. Report reference EUR 17549, European Commission, DGXII, Brussels, Belgium.) definition. This report describes the evaluation of 50 peer-reviewed primary publications. The vast majority of studies reviewed were published in the period from 1996 to the present and most examined in vivo responses of fish to natural hormones, organochlorines, or alkylphenolic compounds. Of the studies reviewed, approximately 40% received a score of "2-Reliable with Restrictions," while approximately 60% received a score of "3-Not Reliable," where reliability was interpreted to include scientific integrity, technical credibility, endpoint relevance, and regulatory compliance. The most common deficiencies were inadequate methods, lack of suitable controls, exceeding aqueous solubility, inappropriate statistics, and unsupported conclusions. Based on the Relevance Index, few of the studies examined attained the level of quality necessary to identify the study results as providing an acceptable basis for evaluation of endocrine modulation potential directly resulting from identified deficiencies in meeting the established study reliability criteria.

Animals↗
PubMed2001

Phylogeography of Cape Verde Island skinks (Mabuya).

The Cape Verde Islands are of volcanic origin with most having appeared between the early Miocene and mid-Pleistocene. They contain six known species of Mabuya skinks. Phylogeographical relationships within and among the relatively widespread taxa M. stangeri, M. spinalis and M. delalandii were inferred, based on approximately 1 kbp of the cytochrome b gene (mitochondrial DNA). Reciprocal monophyly of M. spinalis and M. stangeri was established, which may have arisen from an early Pliocene/late Miocene cladogenetic event. Considerable between-island sequence divergence was detected among M. spinalis, which appears to have colonized the older islands (Sal and Boavista) first. Much lower sequence divergence was found in M. delalandii, indicating a more recent range expansion. Here, evidence points to colonization of the younger islands of Brava and Fogo soon after appearance. There are similarities between some of the described patterns and those seen in lizards from the Canary Islands.

Africa, Western↗
PubMed2000

The illusion of external agency.

People typically underestimate their capacity to generate satisfaction with future outcomes. When people experience such self-generated satisfaction, they may mistakenly conclude that it was caused by an influential, insightful, and benevolent external agent. In three laboratory experiments, participants who were allowed to generate satisfaction with their outcomes were especially likely to conclude that an external agent had subliminally influenced their choice of partners (Study 1), had insight into their musical preferences (Study 2), and had benevolent intentions when giving them a stuffed animal (Study 3). These results suggest that belief in omniscient, omnipotent, and benevolent external agents, such as God, may derive in part from people's failure to recognize that they have generated their own satisfaction.

Adult↗
PubMed2000

Putting the "affirm" into affirmative action: preferential selection and academic performance.

Two studies explored the relation between academic performance and preferential selection. In Study 1, female participants were led to believe that they had been selected to be leaders in a team problem-solving task because of their gender, because of their gender and ability, or at random. Results showed that women who believed they had been selected because of their gender performed significantly worse on a subsequent problem-solving test than women who believed they had been selected at random and women who believed they were selected because of both their gender and their ability. In Study 2, students' suspicion of having benefited from race-based preferences in college admissions was negatively related to their grade point average (GPA). Furthermore, this suspicion partially mediated the GPA gap between academically stigmatized (Black and Latino) and nonstigmatized (Caucasian and Asian) students.

Adult↗
PubMed2000

Mitochondrial DNA evolution and population history of the Tenerife skink Chalcides viridanus.

Recent studies of island lizards have suggested that historical vicariance as a result of volcanism may have played an important role in shaping patterns of within-island genetic diversity. The skink, Chalcides viridanus, shows variation in morphology within the volcanic island of Tenerife. Two mitochondrial DNA (mtDNA) fragments (from the 12S and 16S rRNA regions) were sequenced in individuals from 17 sites to evaluate the relationship between current phylogeography and the geological history of the island. Three main clades were detected. The two most basal clades were restricted to areas representing the ancient precursor islands of Teno and Anaga in the northwest and northeast of Tenerife, respectively. The third clade showed a widespread geographical distribution and provided evidence of a recent rapid expansion after a bottleneck. Within-island cladogenesis appears to have taken place during a recent period of volcanic activity and long after the ancient islands had been united by the eruptions that led to the formation of the Canadas edifice. Evidence of similar biogeographical histories are found in other species in the Canary archipelago, supporting the volcanism scenario as a potentially widespread cause of within-island differentiation in reptiles.

Animals↗
PubMed2000

Mitochondrial DNA control region diversity in the endangered blue chaffinch, Fringilla teydea.

The blue chaffinch (Fringilla teydea) is found only on the two central Canary Islands of Gran Canaria and Tenerife, where it is restricted to pine forest habitat. It is reasonably abundant on the latter island but endangered on the former. Here, sequence variation was studied in a fragment spanning domains I and II of the mitochondrial DNA (mtDNA) control region. Phylogenetic analysis of all haplotypes with a F. coelebs outgroup indicated the two island populations were reciprocally monophyletic, supporting their individual conservation. Unlike in other species, most within-island haplotype diversity was due to mutations in the domain II region. Surprisingly, genetic diversity was greater in the smaller Gran Canarian population. We suggest that this is unlikely to be maintained under current population sizes although it may be mitigated by incorporating genetic information into the captive breeding programme.

Animals↗
PubMed1999

A proposed multigeneration protocol for Japanese medaka (Oryzias latipes) to evaluate effects of endocrine disruptors.

Definitive data on reproductive impairment of chronically exposed populations may be required to assess the appropriateness of the existing test methods for hazard identification and prioritization of endocrine modulators. Multigeneration toxicity testing protocols for wildlife receptors are lacking. To help address this gap we describe a multigeneration fish assay using the freshwater fish, Japanese medake (Oryzias latipes). This test species has been used for the evaluation of carcinogenic, teratogenic and reproductive effects and is sensitive to estrogen exposure producing ovo-testis, altered biochemical parameters and phenotypic characteristics. Due to the short life cycle, a multigeneration test with medaka can be conducted in 1 year. Endpoints evaluated include: survival, growth, sex ratio, fecundity, embryonic lesion occurrence, embryonic stage development, gonadal and hepatic somatic indices, histopathology and biochemical parameters. As new endpoints are developed they can be incorporated into the protocol. Results of a positive control (17 beta-estradiol) study are presented to give an indication of the baseline associated with various test endpoints and to highlight the importance of nutrition in the experimental design. 17 beta-Estradiol treatment induced vitellogenin production in male and female medaka, feminized males, and disrupted egg production. The proposed protocol provides researchers with an effective multigeneration fish test that can be used to examine potential effects of stressors at the population, individual, cellular and subcellular level.

Animals↗
PubMed1998

Phylogeography of skinks (Chalcides) in the Canary Islands inferred from mitochondrial DNA sequences.

Mitochondrial DNA (mtDNA) evolution was investigated in skinks of the genus Chalcides found in the Canary Islands (Ch. sexlineatus, Ch. viridanus and Ch. simonyi), together with some North African congenerics (Ch. polylepis and Ch. mionecton). Several sites were included within islands to cover areas of known within-island geographical variation in morphology. Skinks from the islands of El Hierro and La Gomera appear to be sister taxa. The relationships between this clade and the Tenerife and Gran Canarian skinks were not fully resolved, although the best working hypothesis indicated monophyly with the former, with the latter forming a closely related outgroup. Ch. simonyi from Fuerteventura was more distantly related to the Western Canary Island skinks and did not show close relationships with the North African species Ch. mionecton and Ch. polylepis. Possible colonization sequences for the four most Western Canary Islands were considered. El Hierro appears to have been colonized relatively recently from La Gomera, commensurate with the recent origin of this island, while dispersal between La Gomera and Tenerife and between Gran Canaria and Tenerife or La Gomera appears to have taken place considerably earlier. Substantial within-island haplotype divergence was found in Gran Canaria and Tenerife. This may be a result of recent periods of intense volcanic activity found within these two islands. Lower levels of within-island differentiation are found in La Gomera and El Hierro and may be explained by lower levels of volcanic activity during recent geological history and a more recent colonization, respectively.

Africa, Northern↗
PubMed1997

Subsensitivity of adenylyl cyclase-coupled receptors on mononuclear leukocytes from drug-free inpatients with a major depressive episode.

Previous studies have demonstrated blunted beta-adrenergic responsivity in leukocytes from depressed patients. We sought to determine if this blunted cyclic adenosine monophosphate (AMP) response is specific for beta-adrenergic receptors (homologous), or whether other adenylyl cyclase-coupled receptors are also involved (heterologous), in order to localize this effect at the level of the receptor versus the coupling protein or the transducer, adenylyl cyclase. We studied adenylyl cyclase-mediated responses in peripheral blood mononuclear cells from 95 drug-free patients with a major depressive episode and 69 healthy controls. We found a similar degree of decrease in the peak cyclic AMP response to activation of the beta-adrenergic receptor (28%) and the prostaglandin receptor (34%) in the depressed patients, which indicated heterologous desensitization. Forskolin cyclic AMP responses were not blunted. Blunting of cyclic AMP responses to isoproterenol did not appear to correlate with levels of plasma norepinephrine and epinephrine or hypothalamic-pituitary-adrenocortical function. The absence of a decrease in the peak forskolin-generated cyclic AMP response, which involves direct activation of adenylyl cyclase, suggests an abnormality at the level of the coupling protein in these adenylyl-coupled receptors in depressed patients. Future studies need to determine whether this leukocyte signal transduction defect in depression also involves brain adenylyl cyclase-coupled receptors.

Adenylyl Cyclases↗
PubMed1997

Health risk assessment practices in the U.S. Food and Drug Administration.

The U.S. Food and Drug Administration (FDA) regulates a wide variety of consumer products. Safety issues involve chemical and microbial contaminants in food, biologies, and medical devices; side effects from prescription and nonprescription drugs; residues of animal drugs in food; and radiation from electronic devices. Because of this wide diversity, the legal standards, rules, and policies governing the regulation of these products differ considerably. Hence, risk assessment and risk management practices within the FDA are of necessity quite diverse. This paper presents a summary of risk assessment practices at each of the product centers of the FDA (Center for Food Safety and Applied Nutrition, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Center for Devices and Radiological Health, and Center for Veterinary Medicine) and of the development of risk assessment procedures at the National Center for Toxicological Research.

Animals↗
PubMed1996

Inhibition of TEM-2 beta-lactamase from Escherichia coli by clavulanic acid: observation of intermediates by electrospray ionization mass spectrometry.

Clavulanic acid, the therapeutically important inhibitor of beta-lactamases containing a nucleophilic serine residue at their active sites, inhibits Escherichia coli TEM-2 beta-lactamase via a complex mechanism. Electrospray ionization mass spectrometry (ESIMS) studies revealed that a minimum of four different modified proteins are formed upon incubation of clavulanate with the TEM-2 enzyme. These exhibit mass increments relative to the unmodified TEM-2 beta-lactamase of 52, 70, 88, and 155 Da. Time course studies implied that no long-lived forms of clavulanate-inhibited TEM-2 beta-lactamase retain the carbons of the oxazolidine ring of clavulanate. The absence of a 199 Da increment to unmodified TEM-2 suggests rapid decarboxylation of clavulanate upon binding to the enzyme. Proteolytic digestions of purified forms of clavulanate inhibited TEM-2 beta-lactamase followed by analyses using high-performance liquid chromatography coupled to ESIMS (HPLC-ESIMS) and chemical sequencing were used to provide positional information on the modifications to the enzyme. Increments of 70 and 80 Da increments were shown to be located in a peptide containing Ser-70. A further 70 Da mass increment, assigned as a beta-linked acrylate, was localized to a peptide containing Ser-130. A mechanistic scheme for the reaction of clavulanate with TEM-2 beta-lactamase is proposed in which acylation at Ser-70 and subsequent decarboxylation is followed either by cross-linking with Ser-130 to form a vinyl ether or by reformation of unmodified enzyme via a Ser-70 linked (hydrated) aldehyde. Purified cross-linked vinyl ether was observed to slowly convert under acidic conditions to a Ser-70 linked (hydrated) aldehyde with concomitant conversion of Ser-130 to a dehydroalanyl residue.

Clavulanic Acid↗
PubMed1996

A parallelogram approach for safety evaluation of ingested acetaldehyde.

Route-specific carcinogenicity data are often lacking for compounds of regulatory importance. Acetaldehyde (AA), for example, a natural constituent in foods, is a rodent carcinogen via the inhalation route, but oral carcinogenicity data are not available. In the absence of such data, a parallelogram approach can be used to estimate the oral carcinogenic potency of this chemical. The relative potency of AA to the structurally related compound formaldehyde (FA) in the nose and the relative potency of FA in the nose and stomach serve as the basis for estimating the potency of AA in the stomach. On a dosimetric basis, inhaled AA is 14- to 35-fold less potent than FA in producing nasal DNA-protein crosslinks (DPX), subchronic tissue injury, and tumors. Ingested AA is also considerably ( approximately 5-fold) less potent than FA in producing gastric injury and DPX. Compared to the nose, the stomach is 10- to 60-fold less sensitive to both AA- and FA-induced DPX and subchronic tissue injury. The parallelogram approach will not supplant long-term oral carcinogenicity studies with AA; however, the consistent pattern of decreased sensitivity of acetaldehyde compared to formaldehyde, lower sensitivity of the stomach to the nose, and the lack of gastric tumorigenicity of orally ingested formaldehyde strongly suggests that ingested acetaldehyde is not likely to be carcinogenic. Successful estimation of the carcinogenic potency of ingested glutaraldehyde, for which chronic oral and inhalation data are available, provides further support that the parallelogram approach can provide a reasonable estimate of the carcinogenic potency of closely related aldehydes, such as AA.

Acetaldehyde↗
PubMed1996

Use of the vial equilibration technique for determination of metabolic rate constants for dichloromethane.

Metabolism of methylene chloride, or dichloromethane (DCM), plays a key role in determining the kinetics and carcinogenicity of the halocarbon. The objectives of this study were: to evaluate and optimize the vial equilibration technique, originally described by Sato and Nakajima (1979a), in order to characterize the hepatic metabolism of DCM by Sprague-Dawley rats; to employ different hepatic microsomal preparations to examine buffer effects on DCM metabolism; and to assess the relative importance and metabolic constants of the mixed-function oxidase (MFO) and glutathione (GSH) S-transferase (GST) metabolic pathways. A crude liver homogenate (20% W/V) was prepared from perfused livers of male Sprague-Dawley (S-D) rats (275-325 g). A 30% glycerol buffer was found to significantly inhibit DCM metabolism, while 0.25 M sucrose buffer containing 10 mM EDTA and 1.15% KCl did not. DCM was incubated with the liver 10,000 g supernatant or microsomes and cofactors in sealed headspace vials. Disappearance of DCM, as a measure of the chemical's metabolism, was monitored by headspace gas chromatography. Different trials were conducted to elucidate time-, enzyme-, and substrate-activity relationships. The scaled-up K(m) and Vmax values for the microsomal fraction were quite similar to optimized in vivo values reported by other investigators. In the current study, DCM appeared to be metabolized preferentially by cytochrome P450 IIE1, since substrates (e.g., pyrazole, ethanol, and glycerol) for this isozyme completely inhibited DCM metabolism. Thus, glycerol should not be used as a P450 stabilizer for preparation or storage of microsomes. Phorone pretreatment caused marked hepatic GSH depletion, but had little effect on the overall rate of DCM metabolism. Quantitatively, the GST pathway in the cytosol played a very minor role in DCM metabolism. It was not possible to accurately calculate metabolic constants for this pathway in S-D rats. The vial equilibration technique, as described here, is a relatively simple and reliable method, which should be broadly applicable for measuring the microsomal metabolism of DCM and other VOCs.

Animals↗
PubMed1996

Improved sternal fixation in the transsternal bilateral thoracotomy incision.

The success of bilateral sequential single-lung transplantation has led to the rebirth of the transsternal bilateral thoracotomy incision. Despite the multiple advantages of this incision over a median sternotomy for this operation, one distinct disadvantage is the high prevalence of sternal disruption at the transverse sternotomy site, which is traditionally closed with sternal wires. This disruption rate is between 20% and 40% in most institutions and can lead to significant pain and deformity in addition to slowing the postoperative recovery and increasing the risk of sternal infection. To overcome this problem we have designed and manufactured a device that provides a sound method of fixating the sternum. The device is composed of two plates, one anterior and one posterior to the sternum, that are fixed to each other and to the sternum by means of screws into internally threaded posts positioned in predrilled holes through the bone on either side of the sternotomy. All components of the device are made from titanium and a range of post lengths are available to accommodate variability in sternal thickness. The structure of the device is demonstrated. The device has now been inserted into a total of 20 patients after bilateral lung transplantation and the preliminary results suggest this is a superior technique for closure of a transverse sternotomy and support continued and routine use.

Bone Wires↗