Disease association of two distinct interleukin-18 promoter polymorphisms in Caucasian rheumatoid arthritis patients.

Interleukin (IL)-18 is an important mediator of innate and adaptive immunity. We searched for an association of IL-18 promoter single-nucleotide polymorphisms (SNP) with rheumatoid arthritis (RA) in Caucasians. The entire study population was composed of two independent cohorts from Germany (n=200) and Scotland (n=410). Presence of IL-18 SNP at positions -607 and -137 was determined by allele-specific PCR in 327 RA patients and 283 healthy donors (HD). Diplotype distributions of both loci were in Hardy-Weinberg equilibrium (HWE) in the German and Scottish HD cohorts. In contrast, locus -607 was in HW disequilibrium in German, and locus -137 in Scottish RA patients. Diplotypic exact chi(2) tests suggested that -607CC was overrepresented in German, and -137CC in Scottish RA patients, but conservative chi(2) trend analyses could not prove any significant disease association of these single loci. SNP -607 and -137 were in strong linkage disequilibrium. The -607C(*)-137C haplotype was more prevalent in German RA (3.2 vs 1.2%) and in Scottish RA patients (4.1 vs 0.9%) than in the respective HD cohorts. These observations suggest that SNP of both positions contribute to the genetic background of RA pathogenesis.

A polymorphism within the interleukin 1 receptor antagonist (IL-1Ra) gene is associated with ankylosing spondylitis.

OBJECTIVE: Genetic factors that predispose individuals to ankylosing spondylitis (AS) are not fully understood, but are unlikely to be restricted to HLA-B27. Proinflammatory cytokines are implicated in the development of sacroiliitis. We have examined the allele frequencies of three polymorphic sites in the interleukin (IL)-1 genes in AS patients to investigate whether genetic regulation of IL-1 production could be implicated in AS pathogenesis. METHODS: DNA from 188 AS patients, 115 healthy controls and 81 HLA-B27-positive healthy controls, all from the West of Scotland, were examined with the polymerase chain reaction in a case-controlled study. Polymorphic sites in genes of the IL-1 family were examined, including the 86-base pair variable number tandem repeat within intron 2 of the IL-1Ra gene, and the restriction fragment length polymorphisms at positions -889 in the IL-1alpha gene and -511 in the IL-1beta gene. RESULTS: No significant differences were seen at the polymorphic alleles in the IL-1alpha and IL-1beta genes, but there was a significant increase in the carriage of allele 2 in the IL-1Ra in the AS patients compared with local controls (16 vs 8%, odds ratio 2.3, 95% confidence interval 1.2-4.4, P=0.01). CONCLUSION: This report of an association with a polymorphic site within the IL-1 locus and AS suggests that genes other than B27 may well be involved in the pathogenesis of AS.

Chest wall tenderness is unhelpful in the diagnosis of recurrent chest pain.

We investigated whether the presence of chest wall tenderness or fibromyalgia helped to distinguish between ischaemic and non-ischaemic chest pain. Seventy-one patients with recurrent chest pain, 36 with normal (group A) and 35 with abnormal coronary angiograms (group B), were assessed by investigator-administered questionnaires, and were examined for chest wall tenderness and fibromyalgia by a single blinded observer. Chest wall tenderness was greater in group A. However, it was much greater in women, who predominated in group A, than in men, who predominated in group B, and this explained the intergroup difference. Seven patients (25%) (six female, one male) in the group A and one patient (3%) (male) in group B (chi(2) p=0.027) fulfilled criteria for fibromyalgia. Patients with recurrent chest pain are more likely to have a ischaemic cause if they are male. Although our study suggests that chest wall tenderness alone in patients with recurrent chest pain has no value in excluding myocardial ischaemia as a cause, the confounding factor of gender prevents our study design from answering this question conclusively. Fibromyalgia is commoner in patients with chest pain and normal coronary angiograms, but may be related to the excess of females in this group. Its presence does not preclude the co-existence of ischaemic heart disease.

Unified wear model for highly crosslinked ultra-high molecular weight polyethylenes (UHMWPE).

Crosslinking has been shown to improve the wear resistance of ultra-high molecular weight polyethylene in both in vitro and clinical in vivo studies. The molecular mechanisms and material properties that are responsible for this marked improvement in wear resistance are still not well understood. In fact, following crosslinking a number of mechanical properties of UHMWPE are decreased including toughness, modulus, ultimate tensile strength, yield strength, and hardness. In general, these changes would be expected to constitute a precursor for lower wear resistance, presenting a paradox in that wear resistance increases with crosslinking. In order to understand better and to analyze this paradoxical behaviour of crosslinked UHMWPE, we investigated the wear behavior of (i) radiation-crosslinked GUR 1050 resin, (ii) peroxide-crosslinked GUR 1050 resin and (iii) peroxide-crosslinked Himont 1900 resin using a bi-directional pin-on-disk (POD) machine. Wear behavior was analyzed as a function of crystallinity, ultimate tensile strength (UTS), yield strength (YS), and molecular weight between crosslinks (Mc). The crosslink density increased with increasing radiation dose level and initial peroxide content. The UTS, YS, and crystallinity decreased with increasing crosslink density. While these variations followed the same trend, the absolute changes as a function of crosslink density were different for the three types of crosslinked UHMWPE studied. There was no unified correlation for the wear behavior of the three types of crosslinked UHMWPE with the crystallinity, UTS and YS. However, the POD wear rate showed the identical linear dependence on Mc with all three types of crosslinked UHMWPEs studied. Therefore, we have strong evidence to propose that Mc or crosslink density is a fundamental material property that governs the lubricated adhesive and abrasive wear mechanisms of crosslinked UHMWPEs, overriding the possible effects of other material properties such as UTS, YS and crystallinity on the wear behavior.

The -308.1 polymorphism in the promoter region of the tumor necrosis factor gene is associated with ankylosing spondylitis independent of HLA-B27.

OBJECTIVE: To investigate the allele frequencies of 6 polymorphic sites spanning the region of the genome close to the tumor necrosis factor (TNF) gene in a group of HLA-B27 positive patients with ankylosing spondylitis (AS) in the West of Scotland. METHODS: One hundred sixty-seven patients with AS, 93 healthy controls, and 88 HLA-B27 positive healthy controls, all from the West of Scotland, were typed by polymerase chain reaction (PCR) for 3 restriction fragment length polymorphisms (RFLP) and 3 microsatellite polymorphic sites spanning the TNF gene cluster. The distribution of these alleles was correlated with the presence of extraspinal manifestations such as peripheral joint disease and uveitis. RESULTS: The frequency of the Nco-1.2 allele was significantly reduced in patients compared to the genetically unselected control population (p < 0.05), but was no different from the HLA-B27 positive controls. However, the -308.1 allele was significantly increased in the patients compared to the HLA-B27 positive controls (p < 0.03). CONCLUSION: This study confirms the importance of correct matching in genetic analysis in disease association studies, and provides further evidence supporting the involvement of genes other than the MHC class I locus in the pathogenesis and features of AS.

Tumor necrosis factor locus polymorphisms in rheumatoid arthritis.

We examined six polymorphic elements in the tumor necrosis factor (TNF) locus and determined their allelic distribution in 98 Caucasian rheumatoid arthritis patients in comparison with 91 ethnically-matched controls. Polymorphic elements at four biallelic sites were distributed similarly between patients and controls, irrespective of the presence or absence of DR4. Differences were observed between the two groups at the TNFa and TNFe loci, but these were consistent with extended MHC haplotypes known to be present in rheumatoid arthritis patients. Therefore, this study suggests that there is little, if any, independent contribution of the TNF locus to the genetic background for rheumatoid arthritis susceptibility.

Balance, wholeness, and healing in christianity.

The nature of the spiritual journey inevitably leads us to examine our fears, doubts, and conflicts, in life and in our spiritual communities. Psychology and a true spiritual theology acknowledge an unconscious part of ourselves that is the reservoir for suppressed fears, pain, and anger. Unless these conflicted emotions and related experiences or imaginings are sought out and examined, an authentic spiritual search is denied. The result will be a superficial cognitive belief-system, predicated exclusively on shoulds, oughts, and constant accommodation. To make free, intelligent, mature decisions in our search, we need always to ascertain what we want that will bring fulfillment and spiritual and emotional freedom. This can only be done if we truly own the repressed, hidden, negative memories and behavior that often become self-destructive unconscious determinants. The psychological reality is that unless we look at the shadow part of ourselves, the part that is repressed, denied, hidden and which we often find discomforting, it will surface eventually in a more unhealthy, destructive fashion.

Detection of picornavirus genomic and template RNA strands by a novel semi-nested polymerase chain reaction-technique and agarose-gel electrophoresis.

Attempts to evaluate the relative levels of enteroviral genomic and template RNA strands in small biopsy tissue samples from patients have yielded ambiguous data, largely due to the limited amount of RNA available. A novel semi-nested polymerase chain reaction (PCR) technique was developed to enable RNA levels to be examined more accurately. PCR products were visualised by horizontal agarose gel electrophoresis. This technique was demonstrated on linear single-stranded plasmid DNA; viral RNA isolated from a human rhabdomyosarcoma (RD) cell line persistently infected with a mutated coxsackie B5 virus (piRD) and two cell lines, RD and HEp2 cells, acutely infected with a wild-type clinical isolate of coxsackie B5 virus.

Detection of enterovirus-specific RNA in serum: the relationship to chronic fatigue.

The serum of 88 chronic fatigue patients was screened for enteroviral specific sequences by polymerase chain reaction (PCR) assay. The PCR method used was "nested" PCR targetting the 5' nontranslated region of the enteroviral genome which yielded a final fragment length of 264 base pairs. Samples were obtained from patients during 1990-1991. In addition, buffy coat specimens and stool specimens were examined in some patients. Samples from two cohorts of comparison individuals were also obtained. The comparison groups were firstly, acutely ill individuals with symptoms consistent with a presumed enteroviral infection (matched by age, sex, and date of receipt of specimen) and secondly, healthy individuals (matched by age and date of receipt of specimen). Enteroviral specific sequences were detected in 36 of 88 serum samples from chronic fatigue patients, 22 of 82 acutely ill individuals, and 3 of 126 healthy individuals. The enteroviral PCR positivity did not correlate with any one particular feature of chronic fatigue nor did it reflect any history of illness at onset of fatigue, duration of fatigue, or age of patient. These results provide new evidence for the presence of enteroviral specific sequences in serum, buffy coat, and stool samples in many patients with chronic fatigue. This may reflect a persistent enterovirus infection in a proportion of chronic fatigue patients.

Studies on enterovirus in patients with chronic fatigue syndrome.

A large study on 121 patients with the chronic fatigue syndrome (CFS) that examined muscle biopsy samples for enterovirus by means of polymerase chain reaction analysis was carried out. The results were compared with those obtained from 101 muscle biopsy specimens from patients with a variety of other neuromuscular disorders (OND), including neurogenic atrophies, dystrophies, and mitochondrial, metabolic, and endocrine myopathies. Thirty-two (26.4%) of the biopsy specimens from the group of patients with CFS were positive, compared with 20 (19.8%) from the group of patients with OND, a difference that was not significant. This finding is in contrast to those of our previous smaller study in which significantly more patients with CFS than control subjects (53% [32 of 60] vs. 15% [6 of 41]) had enterovirus RNA sequences in their muscle. It was concluded that it is unlikely that persistent enterovirus infection plays a pathogenetic role in CFS, although an effect in initiating the disease process cannot be excluded.

Increased transcription of interleukin-6 in the brains of mice with chronic enterovirus infection.

An animal model of chronic enteroviral infection was established by using PCR to detect viral genomes in animal tissues and to compare levels of transcription of a variety of cytokines in the brain. Chronic coxsackie-virus B1 infection was found in both brain and skeletal muscle of mice infected as neonates. The viral infection cleared by 240 days post-infection. Elevated levels of tumour necrosis factor alpha and interleukin-6 (IL-6) would appear to be linked to acute and chronic infection respectively. Levels of IL-6 return to normal upon clearance of the virus.

Extensive porosity at the cement-femoral prosthesis interface: a preliminary study.

This study is the first description of the extensive porosity which is preferentially located at the cement-prosthesis interface of cemented femoral components of total hip replacements. The observation is important because the interfacial porosity may decrease the strength of the cement-femoral prosthesis interface and jeopardize the mechanical integrity of the cement mantle. We examined the cement-metal interfaces from a multiplicity of in vivo and in vitro specimens using both optical and scanning electron microscopy. These samples included several stem designs, implants made from either Co-Cr or Ti alloy, implants made with a variety of surface finishes and both centrifuged and uncentrifuged cement. All in vivo and in vitro samples had marked porosity in the cement focally concentrated at the cement-metal interface. The amount of porosity at the interface greatly exceeded the amount of general porosity found throughout the bulk cement. Centrifuging did not affect the interfacial porosity, and neither did alloy nor surface finish. The presence of these pores may be explained by the rheological characteristics of the cement.

Myth-making, community, and catholic tradition.

Assuming that myths and their stories are among the most prominent vehicles for teaching spiritual values and creating communities of faith, the purpose of this paper is to examine myth relative to its nature, role, and function. The presence of myth in society also allows for the evaluation of those myths that are evil. In addition to that, we have the inappropriateness of certain aspects of myths that need to be identified and removed, lest they contaminate the whole story and its spiritual effect.Each of these issues is addressed, and certain suggestions are made relative to greater community wholeness and spiritual well-being.

Quantification of airborne moulds in the homes of children with and without wheeze.

A population survey of 1000 7 year old children found a significant excess of wheeze among children whose homes were reported to be mouldy (odds ratio 3.70, 95% confidence limits 2.22, 6.15). The airborne mould flora was quantified by repeated volumetric sampling during the winter in three rooms of the homes of 88 children. All of these had previously completed spirometric tests before and after a six minute free running exercise challenge. Total airborne mould counts varied from 0 to 41,000 colony forming units (CFU)/m3, but were generally in the range 50-1500 CFU/m3, much lower than the concentrations found outdoors in summer. The principal types of fungi identified are all known to be common out of doors, and most were found on at least one occasion in most of the homes. Median and geometric mean total mould counts were not related to reports of visible mould in the home, or to a history of wheeze in the index child. The heterogeneous group of non-sporing fungi (mycelia sterilia) were the only airborne fungi present at significantly higher concentrations in the homes of wheezy children (geometric mean 2.1 v 0.7 CFU/m3. A non-significant increase in total mould counts was observed in the homes of children with a 10% or greater decline in FEV1 after exercise (geometric mean 354 v 253 CFU/m3). Questionnaire reports of mould in the home may be a poor indicator of exposure to airborne spores. The total burden of inhaled mould spores from indoor sources is probably not an important determinant of wheeze among children in the general population. Although the association with mycelia sterilia could be a chance finding, these non-sporing isolates may include a potent source of allergen.