Investigation of Caucasian rheumatoid arthritis susceptibility loci in African patients with the same disease

Introduction

The largest genetic risk to develop rheumatoid arthritis (RA) arises from a group of alleles of the HLA DRB1 locus ('shared epitope', SE). Over 30 non-HLA single nucleotide polymorphisms (SNPs) predisposing to disease have been identified in Caucasians, but they have never been investigated in West/Central Africa. We previously reported a lower prevalence of the SE in RA patients in Cameroon compared to European patients and aimed in the present study to investigate the contribution of Caucasian non-HLA RA SNPs to disease susceptibility in Black Africans.

Methods

RA cases and controls from Cameroon were genotyped for Caucasian RA susceptibility SNPs using Sequenom MassArray technology. Genotype data were also available for 5024 UK cases and 4281 UK controls and for 119 Yoruba individuals in Ibadan, Nigeria (YRI, HapMap). A Caucasian aggregate genetic-risk score (GRS) was calculated as the sum of the weighted risk-allele counts.

Results

After genotyping quality control procedures were performed, data on 28 Caucasian non-HLA susceptibility SNPs were available in 43 Cameroonian RA cases and 44 controls. The minor allele frequencies (MAF) were tightly correlated between Cameroonian controls and YRI individuals (correlation coefficient 93.8%, p = 1.7E-13), and they were pooled together. There was no correlation between MAF of UK and African controls; 13 markers differed by more than 20%. The MAF for markers at PTPN22, IL2RA, FCGR2A and IL2/IL21 was below 2% in Africans. The GRS showed a strong association with RA in the UK. However, the GRS did not predict RA in Africans (OR = 0.71, 95% CI 0.29 - 1.74, p = 0.456). Random sampling from the UK cohort showed that this difference in association is unlikely to be explained by small sample size or chance, but is statistically significant with p<0.001.

Conclusions

The MAFs of non-HLA Caucasian RA susceptibility SNPs are different between Caucasians and Africans, and several polymorphisms are barely detectable in West/Central Africa. The genetic risk of developing RA conferred by a set of 28 Caucasian susceptibility SNPs is significantly different between the UK and Africa with p<0.001. Taken together, these observations strengthen the hypothesis that the genetic architecture of RA susceptibility is different in different ethnic backgrounds.     

Using historical ecology to understand patterns of biodiversity in fragmented agricultural landscapes

Aim To enhance current attempts to understand biodiversity patterns by using an historical ecology approach to highlight the over‐riding influence of land‐use history in creating past, current and future patterns of biodiversity in fragmented agricultural landscapes. Methods We develop an integrative conceptual framework for understanding spatial and temporal variations in landscape patterns in fragmented agricultural landscapes by presenting five postulates (hypotheses) which highlight the important role of historical, anthropogenic disturbance regimes. We then illustrate each of these postulates with examples drawn from fragmented woodlands in agricultural areas of south‐eastern Australia, and discuss these findings in an international context. Location examples are drawn from agricultural areas in south‐eastern Australia. Results We conclude that there is limited potential to refine our understanding of patterns of biodiversity in human‐modified landscapes based on traditional concepts of island biogeography, or simple assumptions of ongoing destruction and degradation. Instead, we propose that in agricultural landscapes that were largely cleared over a century ago: (1) present‐day remnant vegetation patterns are not accidental, but are logically arrayed due to historic land‐use decisions, (2) historic anthropogenic disturbances have a major influence on current ecosystem conditions and diversity patterns, and (3) the condition of remnant ecosystems is not necessarily deteriorating rapidly. Main conclusions An historical ecology approach can enhance our understanding of why different species and ecosystem states occur where they do, and can explain internal variations in ecological conditions within remnant ecosystems, too often casually attributed to the ‘mess of history’. This framework emphasizes temporal changes (both past and future) in biotic patterns and processes in fragmented agricultural landscapes. Integration of spatially and temporally explicit historical land‐use information into ecological studies can prove extremely useful to test hypotheses of the effects of changes in landscape processes, and to enhance future research, restoration and conservation management activities.     

Development of a neuronal pressure sensor

Neuronal sensory systems are capable of performing very complex signal processing functions. Reconstruction of such sensory systems in vitro should enable whole-cell biological sensors to be generated that possess inherent signal processing capabilities. In this paper, the results of preliminary investigations to produce a mechanosensory neuronal network are presented. An in vitro network of rat dorsal root ganglion neurons has been produced on a microelectrode plate revealing an interesting rhythmical pattern of spontaneous discharges. This periodic activity has been shown to be disrupted following the application of a static pressure to the cell culture. These results indicate that neuronal networks represent a practical system that may be used for the development of intelligent, whole-cell, biological sensors.     

How do slow‐growing,fire‐sensitive conifers survive in flammable eucalypt woodlands?

Question: To what extent do low flammability fuel traits enhance the survival and persistence of fire‐sensitive (slowing‐growing, non‐serotinous, non‐resprouting) dominant trees in highly flammable landscapes, under varying fire‐weather conditions? Location: Mixed forests co‐dominated by flammable Eucalyptus species and fire‐sensitive Callitris glaucophylla in Pilliga State Forest, southeast Australia. Methods: The influence of vegetation composition (relative abundance of Callitris and flammable Eucalyptus) on fire intensity and survival of fire‐sensitive Callitris was assessed across gradients of Callitris abundance in mixed Eucalyptus–Callitris forests that burned under low‐moderate and extreme fire‐weather conditions. Results: In areas that burned under low‐moderate fire‐weather conditions, as Callitris abundance increased, fire intensity declined and Callitris survival increased (46%). By comparison, in extreme fire‐weather conditions, lower fire intensity at higher levels of Callitris abundance, was not sufficient to increase Callitris survival (4%). Callitris survival was also positively related to trunk diameter. Ground fuel type, but not biomass, varied with vegetation composition. Conclusions: These results demonstrate that flammable feedbacks, mediated by low flammability fuel traits of dominant trees, can provide an important mechanism for enhancing the survival and persistence of slow‐growing, non‐serotinous, non‐resprouting, fire‐killed trees in highly flammable landscapes. By modifying vegetation and fuel structure, patches of fire‐sensitive Callitris reduce fire intensity, and thereby reduce Callitris mortality, enhancing population persistence. However, this feedback loop is insufficient to ensure Callitris survival under extreme fire‐weather conditions, when fire intensity is greater. After burning, stands remain vulnerable to future fires, until trees grow large enough to modify fuel levels and reduce stand flammability.     

Terminal care: present services and future priorities.

Since 1975 hospices and other specialist services for terminal cancer have expanded rapidly. In December 1980 this survey found 72 such services in Britain providing 58 inpatient units, 32 home care teams, and eight hospital support teams. Many were outside the NHS. Inpatient units provided 1297 beds (modal size 21-25 beds) and dealt with under 7% of deaths from cancer. Home care teams provided 76.5 full-time equivalent nurses (modal size two nurses). Regional variations were considerable: from 10.9 beds/million population in Trent to 48.5 beds/million in South-west Thames; no home care nurses in Mersey and Wales, and 5.1 nurses/million in Wessex. Of 58 more services being planned, the 17 starting in 1981 will not substantially alter these regional imbalances. Respondents'' opinions suggest a target of 40-50 inpatient unit beds/million population. This might be reduced if hospitals were better equipped to deal with these patients. Suggested priorities are to redress regional inequalities, develop home care and hospital support teams rather than inpatient units, and improve teaching and training. Co-ordination of plans between the NHS and the voluntary sector is needed.     

Factors controlling upper Jurassic ammonite assemblages in north-central Mexico

Lower Kimmeridgian to Lower Tithonian (Upper Jurassic) sections studied at Sierra de Palotes (Durango) and Sierra de Catorce (San Luis Potosí), Mexico, show low-energy deposits in which the composition of fossil macroinvertebrate assemblages, including megabenthos, reflects biostratinomic control. Monotonous siltstones provide continuous records of ammonite assemblages and reflect dominant deposition of shells in living areas; meanwhile, discontinues records were forced by episodic post-mortem transportation of shells, which was especially accentuated under storm influence. Rhythmic marly-silty limestones and marls illustrate a fossil record probably determined by minor transgressive-regressive pulses. The major changes in lithofacies are reflected by condensed silty and phosphatic mudstones deposited during significant floodings affecting areas under dominant terrigenous sedimentation. These changes determined more or less significant variations in the composition of fossil assemblages according to their relation to changing ecological conditions. However, shifting ecospaces exhibit no direct relationship to changes in lithofacies. Post-mortem transportation, operating in relation to both marine floodings and changes in the pattern of upper-water currents, was the main biostratinomic factor affecting the areal distribution of ammonite populations. Shell transportation and sedimentation rate controlled preservation and ultimately influenced diversity in recorded ammonite assemblages. The post-mortem behaviour (interpreted from shell structure and preservation), and therefore distribution, of ammonite shells points to shallow-water environments during the Kimmeridgian - Early Tithonian in areas (such as SE Durango and San Luís Potosí) close to the changing boundary between dominant carbonate and terrigenous sedimentation. No reworking affecting ammonite biostratigraphy has been identified in the sections studied.     

Properties of α-bungarotoxin binding sites in foetal human brain

Maximum levels of binding of α-bungarotoxin to foetal human brain membranes were found to remain essentially constant at 30–50 fmol/mg protein (1.1–1.5 pmol/g wet weight in whole brain) between gestational ages of 10 and 24 weeks. Equilibrium binding of α-bungarotoxin to both membranes and to detergent extracts showed saturable specific binding to a single class of sites with K_d (app) values of 3.5 × 10^?9 M and 2.4 × 10^?9 M respectively. Association rate constants, determined from time courses of binding of α-bungarotoxin to membranes and detergent extracts, were 2.3 × 10⁵ M^?1 sec^?1 and 2.6 × 10⁵ M^?1 sec^?1 respectively. Dissociation of α-bungarotoxin from both membrane and detergent extracts showed a rapid initial rate with $\text{T}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ approx 15 min which, in the case of the detergent extract, was followed by a slower dissociation accounting for the remaining 20% of the bound ligand. Competition studies with a number of cholinergic ligands indicated that the α-bungarotoxin-binding sites in foetal brain display a predominantly nicotinic profile.     

Day-night periodicity of exudation in detopped tobacco

Exudate was collected periodically from the root systems of detopped tobacco plants. Volume, cations, and ⁴²K or ⁸⁶Rb transfer were measured. According to measurements of K by ⁴²K and by the flame photometer, when concentrations of KCl and KNO₃ were lower than 10⁻² m, the K in the exudate came mostly from a pool in the plant rather than from the external solution. With higher external KNO₃ solutions, within a few hours nearly all of the K in the exudate came directly from the external solutions. Studies with ⁸⁶Rb lead to the same conclusion. In contrast the maximum proportion of K in the exudate that came from KCl in the external solution was reached usually in many hours after detopping and amounted to from 50 to 75%. The higher the external concentration the faster it was reached. These data for KCl are indicative of the ⁴²K passing through a K pool in the root cells. K and Rb from high concentrations of KNO₃ and RbNO₃, however, may not pass through such a pool. The addition of 10⁻² m KNO₃ into the external solution during exudation essentially eliminated the effect of periodicity at least for a period of time and under the conditions of the experiments. Hydrochloric acid, mercuric chloride, anaerobiosis, and 2,4-dinitrophenol had the same effect and each resulted in a massive final exudation that usually persisted for 1 to 3 days before stopping. These results all lead to a hypothesis that periodicity is regulated at the tonoplast.