Linkage analysis of SLE susceptibility: confirmation of SLER1 at 5p15.3

We detected a novel susceptibility gene, SLER1, for systemic lupus erythematosus (SLE) at 5p15.3.(1) This finding was based on a selected subgroup of SLE families, where two or more family members have had alleged rheumatoid arthritis (SLE-RA). The main objective of this study was to replicate the linkage at 5p15.3 based on an independent data set of 88 SLE-RA families. Heterogeneity in the genetic model led us to use a nonparametric allele-sharing method. Since our a priori hypothesis of linkage at 5p15.3 was fixed, we genotyped six markers at the linked region. Our new results replicate the initial linkage at 5p15.3 (Zlr=2.58, P<0.005, LOD=1.45). Moreover, evidence of linkage was sustained when analysis was restricted to the subset of SLE families who had 3 or more individuals with alleged RA (Zlr=3.32, P=0.008, LOD=2.40) The results of our previous findings, together with these new results, confirm the SLER1 linkage at 5p15.3. Our results also demonstrate the utility of clinically defined subgroup analysis for detecting susceptibility loci for complex genetic diseases, such as SLE.     

The Lapidus Arthrodesis: Examining the Effect of the Metatarsal Base Transfixion Screw

The modified Lapidus bunionectomy is a useful and highly powerful procedure for correcting hallux abducto valgus. Traditionally reserved for “severe” deformities, this procedure has seen a recent resurgence in the podiatric community for its unique ability to achieve tri-planar correction of this challenging deformity. Although this procedure has been extensively studied in both biomechanical labs and the clinical arenas, no clear consensus has been achieved regarding optimal fixation for this thought-provoking procedure. The current study examined the differences in strength between commercially available 5-hole locking plates with interfragmentary compression vs a crossed-screw with a third “transfixation” screw construct in a controlled setting. Ten fresh-frozen cadaveric match pair limbs (20 total limbs) were used to complete this study. Ten limbs were randomly assigned to a 3-screw construct. The other 10 contralateral limbs were assigned to a commercially available 5-hole locking plate (5 stainless steel and 5 titanium alloy) with an interfragmentary lag screw construct. The first rays were then isolated and potted into a 4-point bending device. The specimens were loaded to failure in a servohydraulic load frame at a controlled rate. Failure was defined as catastrophic or 3 mm of plantar gapping at the arthrodesis site. The mean maximal load to failure was 310.9 ± 109.4 N for the 3-screw construct. The mean maximal load to failure for the locking plate constructs was 264.1 ± 100.9 N. This difference was not statistically significant (p = .328). These results suggest that a 3-screw construct for Lapidus arthrodesis is as strong as commercially available locking plate constructs.     

Flow microcalorimetric assay of antibiotics--II. Neomycin sulphate and its combinations with polymyxin B sulphate and zinc bacitracin on interaction with Bacillus pumilus (NCTC 8241)

A flow microcalorimetric assay for Neomycin has been developed which is monitored through interaction of the antibiotic with Bacillus pumilus as the test organism. The assay has better reproducibility (relative standard deviation 2.3%) and is more sensitive than conventional microbiological bioassay (0.5-2 micrograms ml-1). The effects of combinations with zinc bacitracin, with polymyxin B sulphate, and with both zinc bacitracin and polymyxin B sulphate (both in equimolar proportions), and in those proportions present in the commercial preparation TrisepR (ICI, Macclesfield, UK) have also been investigated. Synergy was observed for the combinations of Neomycin with the other two antibiotics in binary mixtures at the relative proportions found in TrisepR. The addition of all three antibiotics at the levels used in TrisepR did not show synergy. However, addition of all three antibiotics at equimolar concentrations did show synergy. It is suggested that microcalorimetry may be useful in in vitro experiments for exploring the relative proportions required for maximal effect in antibiotic combinations.     

Flow microcalorimetric assay of antibiotics--I. Polymyxin B sulphate and its combinations with neomycin sulphate and zinc bacitracin on interaction with Bordetella bronchiseptica (NCTC 8344)

A flow microcalorimetric assay for polymyxin B sulphate has been developed which has a better reproducibility (relative standard deviation less than 3%) and sensitivity (0.35 micrograms ml-1) than conventional microbiological assays, and requires an assay time of ca. 4.5 h. The combinations with zinc bacitracin, with neomycin sulphate, and with both zinc bacitracin and neomycin sulphate indicate antagonism between these antibiotics upon interaction with Bordetella bronchiseptica (NCTC 8344). The combinations of all three antibiotics assayed were: (1) equimolar proportions; and (2) those proportions present in the commercial preparation TrisepR (ICI, Macclesfield, UK).     

Genetic variants of G4 globulin. A unique relationship to other classes of G globulin

Two types of γG4 proteins, termed 4a and 4b, were characterized through antigenic studies of myeloma proteins. Both were recognized by specific antigens on the Fc fragment which were shared with other γG classes. The distinctive antigen of the common 4a type was shared with all γG1 and γG3 proteins but missing in those of the γG2 class; that for the rarer 4b type was selectively found in proteins of the γG2 class. Analyses on γG4 fractions isolated from normal sera showed that either the 4a or the 4b or a mixture of the two types was present in each serum. Evidence was obtained that these differences were on a genetic basis and that allelic genes linked to those of the Gm system were involved. Such a reciprocal occurrence in other classes of γG globulin of the antigenic markers distinguishing genetic variants has not been observed previously. A number of questions regarding the evolutionary development of the genes responsible are discussed. The possibility is raised that those for the γG4 class arose relatively early and preceded the development of those for the other γG classes.     

The serpin-enzyme complex (SEC) receptor mediates the neutrophil chemotactic effect of alpha-1 antitrypsin-elastase complexes and amyloid-beta peptide.

The serpin-enzyme complex (SEC) receptor mediates catabolism of alpha 1-antitrypsin (alpha 1-AT)-elastase complexes and increases in synthesis of alpha 1-AT in cell culture. The SEC receptor recognizes a pentapeptide domain on alpha 1-AT-elastase complexes (alpha 1-AT 370-374), and the same domain in several other serpins, amyloid-beta peptide, substance P, and other tachykinins. Thus, it has also been implicated in the biological properties of these ligands, including the neurotoxic effect of amyloid-beta peptide. In this study, we examined the possibility that the SEC receptor mediates the previously described neutrophil chemotactic activity of alpha 1-AT-elastase complexes, and whether the other ligands for the SEC receptor have neutrophil chemotactic activity. The results show that 125I-peptide 105Y (based on alpha 1-AT 359-374) binds specifically and saturably to human neutrophils, and the characteristics of this binding are almost identical to that of monocytes and hepatoma-derived hepatocytes. Peptide 105Y and amyloid-beta peptide mediate chemotaxis for neutrophils with maximal stimulation at 1-10 nM. Mutant or deleted forms of peptide 105Y, which do not bind to the SEC receptor, have no effect. The neutrophil chemotactic effect of alpha 1-AT-elastase complexes is blocked by antiserum to peptide 105Y and by antiserum to the SEC receptor, but not by control antiserum. Preincubation of neutrophils with peptide 105Y or substance P completely blocks the chemotactic activity of amyloid-beta peptide, but not that of FMLP. These results, therefore, indicate that the SEC receptor can be modulated by homologous desensitization and raise the possibility that pharmacological manipulation of this receptor will modify the local tissue response to inflammation/injury and the neuropathologic reaction of Alzheimer's disease.     

Breast screening clinic versus health education session as outlets for education in breast self-examination.

A population based programme to educate women in breast self-examination (BSE) was organised as part of the UK Trial of Early Detection of Breast Cancer. Women who responded to an invitation to a meeting were educated in groups and were not routinely screened. Open access clinics offered x ray and clinical examination to all women in the study age group of 45 to 64. Women who presented for screening without prior BSE education were taught individually by clinic staff. Women taught by the two methods were surveyed by post and their BSE practice since education was compared. It was hypothesised that the women taught in clinics, who had been reassured of their breast normality, would practice BSE more regularly and correctly. Results did not confirm this hypothesis. Lower standards of practise and a higher level of anxiety at the time of survey were found in the group who presented at a free access clinic and had received individual teaching at the time of screening.