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Biomedical subjects

R A Norman

Publications and source records attributed to R A Norman.

At least 19 recordsLinked to original sources

The effect of seasonal host birth rates on population dynamics: the importance of resonance.

Many of the simple mathematical models currently in use often fail to capture important biological factors. Here we extend current models of insect-pathogen interactions to include seasonality in the birth rate. In particular, we consider the SIR model with self-regulation when applied to specific cases--rabbit haemorrhagic disease and fox rabies. In this paper, we briefly summarize the results of the model with a constant time-independent birth rate, a, which we then replace with the time dependent birth rate a(t), to investigate how this effects the dynamics of the host population. We can split parameter space into an area in which the model without seasonality has no oscillations, in which case a simple averaging rule predicts the behaviour. Alternatively, in the area where oscillations to the equilibrium do occur in the non-seasonal model, disease persistence is more complicated and we get more complex dynamical behaviour in this case. We apply resonance techniques to discover the structure of the subharmonic modes of the SIR model with self-regulation. We then look at whether many biological systems are likely to display these "resonant" dynamics and find that we would expect them to be widespread.

Animals↗

Epidemiological consequences of a pathogen having both virulent and avirulent modes of transmission: the case of rabbit haemorrhagic disease virus.

A number of pathogens cause chronic infection in survivors of acute disease and this is believed to be a common means of persistence, including for highly virulent agents. We present a model in which transmission from chronically infected hosts causes chronic infection in naive individuals, without causing acute disease--indeed 'protecting' against it. Thus the pathogen obtains the benefit of virulence (high transmission rate), but mitigates against the cost (high host mortality). Recent findings suggest that rabbit haemorrhagic disease virus (RHDV), a highly contagious and virulent pathogen, may also utilize this alternative, 'avirulent', mode of transmission. The model may resolve the paradox of how RHDV can be highly prevalent in some populations, in the absence of mortality. Differences in host demography determine whether avirulent transmission prevents large-scale mortality (as in most UK populations) or not. Other pathogens may exhibit similar behaviour and the implications for emerging diseases in general are discussed.

Acute Disease↗

The emergence of rabbit haemorrhagic disease virus: will a non-pathogenic strain protect the UK?

Rabbit haemorrhagic disease virus emerged in China in 1984, and has killed hundreds of millions of wild rabbits in Australia and Europe. In the UK there appears to be an endemic non-pathogenic strain, with high levels of seroprevalence being recorded, in the absence of associated mortality. Using a seasonal, age-structured model we examine the hypothesis that differences in rabbit population demography differentially affect the basic reproductive rates (R(0)) of the pathogenic and non-pathogenic strains, leading to each dominating in some populations and not others. The strain with the higher R(0) excluded the other, with the dynamics depending upon the ratio of the two R(0) values. When the non-pathogenic strain dominated, the pathogenic strain caused only transient mortality, although this could be significant when the two R(0) values were similar. When the pathogenic strain dominated, repeated epidemics led to host eradication. Seroprevalence data suggest that the non-pathogenic strain may be protecting some, but not all UK populations, with half being 'at risk' from invasion by the pathogenic strain and a fifth prone to significant transient mortality. We identify key questions for empirical research to test this prediction.

Animals↗

Steric hindrance regulation of the Pseudomonas aeruginosa amidase operon.

Expression of the amidase operon of Pseudomonas aeruginosa is controlled by AmiC, the ligand sensor and negative regulator, and AmiR the transcription antitermination factor activator. We have titrated out AmiC repression activity in vivo by increased AmiR production in trans and shown AmiC regulation of the antitermination activity of AmiR by a steric hindrance mechanism. In the presence of the co-repressor butyramide we have isolated a stable AmiC.AmiR complex. Addition of the inducing ligand acetamide to the complex trips the molecular switch, causing complex dissociation and release of AmiR. The AmiC.AmiR butyramide complex exhibits acetamide-dependent, sequence-specific RNA binding activity and a K(d) of 1.0 nm has been calculated for the AmiR.RNA interaction. The results show that amidase operon expression is controlled by a novel type of signal transduction system in which activity of a site-specific RNA binding activator is regulated via a sequestration mechanism.

Acetamides↗

Re-assessing the infection strategies of the entomopathogenic nematode Steinernema feltiae (Rhabditidae; Steinernematidae).

Previous studies have indicated that between 60 and 80% of a population of entomopathogenic nematodes do not infect their insect hosts at any one period in time. Two hypotheses explain this behaviour: the first that there is a subpopulation of non-infectious nematodes and the second that the non-infectious group is created by inhibitory cues derived from infected insects. Through an experimental approach with the Galleria mellonella-Steinernema feltiae system we show that both mechanisms operate together. When conditions for infection were optimized, the sum of individual infection behaviours was similar to the number infecting as a population, implying observed infection rates are driven by intrinsic mechanisms. In addition, there was evidence that an infected host released a chemical cue into the environment which inhibited subsequent levels of infection. This degree of inhibition was independent of the number of infecting nematodes. Both these mechanisms are dynamic, so the observed proportion of infectious nematodes depended heavily on the time of exposure. The implications of these findings for both the design of laboratory trials and the use of entomopathogenic nematodes in biological control are discussed.

Animals↗

EPIFIL: the development of an age-structured model for describing the transmission dynamics and control of lymphatic filariasis.

Mathematical models of transmission dynamics of infectious diseases provide a useful tool for investigating the impact of community based control measures. Previously, we used a dynamic (constant force-of-infection) model for lymphatic filariasis to describe observed patterns of infection and disease in endemic communities. In this paper, we expand the model to examine the effects of control options against filariasis by incorporating the impact of age structure of the human community and by addressing explicitly the dynamics of parasite transmission from and to the vector population. This model is tested using data for Wuchereria bancrofti transmitted by Culex quinquefasciatus in Pondicherry, South India. The results show that chemotherapy has a larger short-term impact than vector control but that the effects of vector control can last beyond the treatment period. In addition we compare rates of recrudescence for drugs with different macrofilaricidal effects.

Adolescent↗

An unusual case.

Explore the source record for details and available documents.

Adult↗

Geriatric dermatology in chronic care and rehabilitation.

The skin care of disabled elders living in nursing homes and adult congregate, subacute, and home health settings requires special effort and consideration. Practitioners who regularly assist elders in these situations may be unfamiliar with dermatology problems related to chronic disability. As the U.S. population ages, skin care in the elderly and disabled will continue to be a challenge. However, if the diseases and problems can be addressed in a knowledgeable and problem-oriented manner, treatment can be maximized.

Aged↗

Crystal structure and induction mechanism of AmiC-AmiR: a ligand-regulated transcription antitermination complex.

Inducible expression of the aliphatic amidase operon in Pseudomonas aeruginosa is controlled by an antitermination mechanism which allows production of the full-length transcript only in the presence of small-molecule inducers, such as acetamide. Ligand-regulated antitermination is provided by AmiC, the ligand-sensitive negative regulator, and AmiR, the RNA-binding positive regulator. Under non-inducing or repressing growth conditions, AmiC and AmiR form a complex in which the activity of AmiR is silenced. The crystal structure of the AmiC-AmiR complex identifies AmiR as a new and highly unusual member of the response-regulator family of bacterial signal transduction proteins, regulated by sequestration rather than phosphorylation. Comparison with the structure of free AmiC reveals the subtle mechanism of ligand-induced release of AmiR.

Amino Acid Sequence↗

Absence of genetic variation in some obesity candidate genes (GLP1R, ASIP, MC4R, MC5R) among Pima indians.

OBJECTIVE: To examine the obesity candidate genes glucagon-like-peptide receptor (GLP1R), agouti signaling protein (ASIP) and the melanocortin receptors 4 and 5 (MC4R and MC5R) for DNA polymorphisms in their coding regions. SUBJECTS: Unrelated, non-diabetic Pima Indians (8 to 12 from each extreme of body fat). MEASUREMENTS: DNA sequencing within the coding regions of each gene. RESULT: Only one variant was detected, a silent substitution in exon 6 of GLP1R. CONCLUSION: The exclusion of any common amino-acid polymorphisms (allele frequency > or = 0.20). implies that structural variants of these genes do not contribute to variation in the high level of obesity observed among the Pima Indians.

Agouti Signaling Protein↗

Autosomal genomic scan for loci linked to obesity and energy metabolism in Pima Indians.

An autosomal genomic scan to search for linkage to obesity and energy metabolism was completed in Pima Indians, a population prone to obesity. Obesity was assessed by percent body fat (by hydrodensitometry) and fat distribution (the ratio of waist circumference to thigh circumference). Energy metabolism was measured in a respiratory chamber as 24-h metabolic rate, sleeping metabolic rate, and 24-h respiratory quotient (24RQ), an indicator of the ratio of carbohydrate oxidation to fat oxidation. Five hundred sixteen microsatellite markers with a median spacing of 6.4 cM were analyzed, in 362 siblings who had measurements of body composition and in 220 siblings who had measurements of energy metabolism. These comprised 451 sib pairs in 127 nuclear families, for linkage analysis to obesity, and 236 sib pairs in 82 nuclear families, for linkage analysis to energy metabolism. Pointwise and multipoint methods for regression of sib-pair differences in identity by descent, as well as a sibling-based variance-components method, were used to detect linkage. LOD scores >=2 were found at 11q21-q22, for percent body fat (LOD=2.1; P=.001), at 11q23-q24, for 24-h energy expenditure (LOD=2.0; P=.001), and at 1p31-p21 (LOD=2.0) and 20q11.2 (LOD=3.0; P=.0001), for 24RQ, by pointwise and multipoint analyses. With the variance-components method, the highest LOD score (LOD=2.3 P=.0006) was found at 18q21, for percent body fat, and at 1p31-p21 (LOD=2.8; P=.0003), for 24RQ. Possible candidate genes include LEPR (leptin receptor), at 1p31, and ASIP (agouti-signaling protein), at 20q11.2.

Chromosome Mapping↗

Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima indians.

The UCP2-UCP3 gene cluster maps to chromosome 11q13 in humans, and polymorphisms in these genes may contribute to obesity through effects on energy metabolism. DNA sequencing of UCP2 and UCP3 revealed three polymorphisms informative for association studies: an Ala-->Val substitution in exon 4 of UCP2, a 45 bp insertion/deletion in the 3'-untranslated region of exon 8 of UCP2 and a C-->T silent polymorphism in exon 3 of UCP3. Initially, 82 young (mean age = 30 +/- 7 years), unrelated, full-blooded, non-diabetic Pima Indians were typed for these polymorphisms by direct sequencing. The three sites were in linkage disequilibrium ( P < 0.00001). The UCP2 variants were associated with metabolic rate during sleep (exon 4, P = 0.007; exon 8, P = 0.016) and over 24 h (exon 8, P = 0.038). Heterozygotes for UCP2 variants had higher metabolic rates than homozygotes. The UCP3 variant was not significantly associated with metabolic rate or obesity. In a further 790 full-blooded Pima Indians, there was no significant association between the insertion/deletion polymorphism and body mass index (BMI). However, when only individuals >45 years of age were considered, heterozygotes (subjects with the highest sleeping metabolic rate) had the lowest BMI (P = 0.04). The location of the insertion/deletion polymorphism suggested a role in mRNA stability; however, it appeared to have no effect on skeletal muscle UCP2 mRNA levels in a subset of 23 randomly chosen Pima Indians. In conclusion, these results suggest a contribution from UCP2 (or UCP3) to variation in metabolic rate in young Pima Indians which may contribute to overall body fat content later in life.

Adolescent↗

A common variant in PPP1R3 associated with insulin resistance and type 2 diabetes.

Selected candidate genes have been analyzed in the Pima Indians of Arizona based on evidence that insulin resistance and type 2 diabetes have significant genetic determinants. An amino acid substitution at codon 905 of the glycogen-targeting subunit of type 1 protein phosphatase that regulates skeletal muscle glycogenesis was recently reported to be associated with changes in insulin action in Danish subjects. In addition to the variant at 905, we report here a novel substitution at codon 883 and common variant of an "ATTTA" element in the 3'-untranslated region (UTR) of the corresponding gene (PPP1R3). The 3'-UTR variant resembled the mRNA-destabilizing AT(AU)-rich elements (AREs) and resulted in a 10-fold difference in reporter mRNA half-life, was correlated with PPP1R3 transcript and protein concentrations in vivo, and was associated with insulin resistance and type 2 diabetes in the Pimas. The variant is more common in Pimas (0.56) than in Caucasians (0.40). Because of its apparent effect on expression of PPP1R3, it may, in part, contribute to the higher prevalence of type 2 diabetes in this Native American population.

Adult↗

Epifil: a dynamic model of infection and disease in lymphatic filariasis.

The lack of a quantitative framework that describes the dynamic relationships between infection and morbidity has constrained efforts aimed at the community-level control of lymphatic filariasis. In this paper, we describe the development and validation of EPIFIL, a dynamic model of filariasis infection intensity and chronic disease. Infection dynamics are modeled using the well established immigration-death formulation, incorporating the acquisition of immunity to infective larvae over time. The dynamics of disease (lymphodema and hydrocele) are modeled as a catalytic function of a variety of factors, including worm load and the impact of immunopathological responses. The model was parameterized using age-stratified data collected from a Bancroftian filariasis endemic area in Pondicherry in southern India. The fitted parameters suggest that a relatively simple model including only acquired immunity to infection and irreversible progression to disease can satisfactorily explain the observed infection and disease patterns. Disease progression is assumed to be a consequence of worm induced damage and to occur at a high rate for hydrocele and a low rate for lymphodema. This suggests that immunopathology involvement may not be a necessary component of observed age-disease profiles. These findings support a central role for worm burden in the initiation and progression of chronic filarial disease.

Adolescent↗

Genomewide search for genes influencing percent body fat in Pima Indians: suggestive linkage at chromosome 11q21-q22. Pima Diabetes Gene Group.

On the basis of accumulating evidence that obesity has a substantial genetic component, a genomewide search for linkages of DNA markers to percent body fat is ongoing in Pima Indians, a population with a very high prevalence of obesity. An initial screen of the genome (>600 markers in 874 individuals) has been completed using highly polymorphic markers (mean heterozygosity = .67). Reported here are the sib-pair linkage results for percent body fat (277 siblings), the best available indicator of overall obesity. Single-marker linkages to percent body fat were evaluated by sib-pair analysis for quantitative traits. From these analyses, the best evidence of genes influencing body fat came from markers at chromosome 11q21-q22 and 3p24.2-p22 (P = .001; LOD = 2.0). Regions flanking these markers were further investigated by multipoint linkage. The evidence for linkage at 11q21-q22 increased to P = .0002 (LOD = 2.8), peaking between markers D11S2000 and D11S2366. Evidence for linkage at 3p24.2-p22 did not change. No association was detected for any marker in the region. Although several genes are known in the 11q21-q22 region, none have been implicated as candidate genes for obesity.

Adipose Tissue↗

Expression of the genes encoding myelin basic protein and proteolipid protein in human malignant gliomas.

Pathological differentiation of oligodendroglioma and mixed oligoastrocytoma from astrocytoma is difficult, relying on morphological characteristics due to the lack of reliable immunohistochemical stains. Oligodendrocytes, the presumed cell of origin of oligodendrogliomas, highly express the genes encoding myelin basic protein (MBP) and proteolipid protein (PLP). We analyzed the expression of these genes to determine whether they might be useful molecular markers of oligodendrocytic tumors. MBP and PLP were highly expressed in all oligodendrogliomas and minimally expressed in glioblastomas multiforme. MBP was highly expressed in mixed oligoastrocytomas, whereas PLP expression was minimal. The association between tumor classification and expression of the MBP and PLP genes was statistically significant. Expression of these genes may serve as a useful molecular marker for some subtypes of human gliomas.

Adult↗

Transcription antitermination regulation of the Pseudomonas aeruginosa amidase operon.

In vivo titration experiments have demonstrated a direct interaction between the Pseudomonas aeruginosa transcription antiterminator, AmiR, and the mRNA leader sequence of the amidase operon. A region of 39 nucleotides has been identified which is sufficient to partially titrate out the AmiR available for antitermination. Site-directed mutagenesis has shown that the leader open reading frame has no role in the antitermination reaction, and has identified two critical elements at the 5' and 3' ends of the proposed AmiR binding site which are independently essential for antitermination. A T7 promoter/RNA polymerase-driven system shows AmiR-mediated antitermination, demonstrating a lack of promoter/polymerase specificity. Using the operon negative regulator, AmiC, immobilized on a solid support and gel filtration chromatography, an AmiC-AmiR complex has been identified and isolated. Complex stability and molecular weight assayed by gel filtration alter depending on the type of amide bound to AmiC. AmiC-AmiR-anti-inducer is a stable dimer-dimer complex and the addition of the inducer, acetamide, causes a conformational change which alters the complex stability and either this new configuration or dissociated AmiR interacts with the leader mRNA to cause antitermination.

Amidohydrolases↗

The evolutionary history of the amylase multigene family in Drosophila pseudoobscura.

In Drosophila pseudoobscura, the amylase (Amy) multigene family is contained within a series of inversions, or gene arrangements, on the third chromosome. The Standard (ST), Santa Cruz (SC), and Tree Line (TL) inversions are central to the phylogeny of arrangements, and have clusters of other arrangements derived from them. The gene arrangements belonging to each of these three clusters have a characteristic number of Amy genes, ranging from three in ST to two in SC to one in TL. This distribution pattern can reflect a history of either duplications or deletions, although the data available in the past did not permit a decision between these alternatives. We provide unambiguous evidence that three Amy genes were present before the divergence of the ST, SC, and TL arrangements. Thus, the current status of the Amy multigene family is the result of deletions in the TL and SC arrangements, which created three new pseudogenes: TL Amy2-psi, TL Amy3-psi, and SC Amy3-psi. Analysis of pseudogene sequences revealed that, in the SC and ST arrangements, pseudogene evolution has been retarded, most likely due to the homogenization effect of gene conversion. Finally, by determining the original copy number, we have reconstructed the evolutionary history of the Amy multigene family and linked it with the evolution of the central gene arrangements.

Animals↗