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Activator protein-1 (AP-1) is a dimeric transcription factor composed of the Jun, Fos and Atf families of proteins. Batf is expressed in the immune system and participates in AP-1 dimers that modulate gene expression in response to a variety of stimuli. Transgenic (Tg) mice overexpressing human BATF in T cells were generated using the human CD2 promoter (CD2-HA (hemagglutinin antigen) - BATF). By 1 year of age, over 90% of the mice developed a lymphoproliferative disorder (LPD). The enlarged lymph nodes characteristic of this LPD contain a polyclonal accumulation of T cells with a CD4(+) bias, yet efforts to propagate these tumor cells in vitro demonstrate that they do not proliferate as well as wild-type CD4(+) T cells. Instead, the accumulation of these cells is likely due to an apoptotic defect as CD2-HA-BATF Tg T cells challenged by trophic factor withdrawal in vitro resist apoptosis and display a pro-survival pattern of Bcl-2 family protein expression. As elevated levels of Batf expression are a feature of lymphoid tumors in both humans and mice, these observations support the use of CD2-HA-BATF mice as a model for investigating the molecular details of apoptotic dysregulation in LPD.

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The eValuation of IBandronate Efficacy (VIBE) head-to-head database fracture study compared fracture rates between patients treated with monthly ibandronate and weekly oral bisphosphonates (BPs). This large study included women >/=45 years old, newly prescribed monthly oral ibandronate or weekly oral alendronate or risedronate, and without malignancy or Paget's disease of bone. The primary analysis included patients who were adherent to treatment during the first 90 days after the index date. The risks of hip, nonvertebral, vertebral and any clinical fracture were compared using Cox proportional hazards models and adjusted for potential confounding factors. A secondary, "intent-to-treat" analysis included all patients who received at least one BP prescription. Sensitivity analyses based on the primary analysis compared patients receiving ibandronate with patients receiving weekly alendronate or risedronate separately, and explored the effect of excluding patients with potential confounding factors from the analysis. Further sensitivity analyses varied the requirement for adherence during the first 90 days after the index date. The primary analysis population included 7345 monthly ibandronate and 56,837 weekly BP patients. Fracture rates after the 12-month observational period were <2% and fracture risk was not significantly different between patients receiving monthly ibandronate or weekly BPs for hip, nonvertebral or any clinical fracture (adjusted relative risk: hip=1.06, p=0.84; nonvertebral=0.88, p=0.255; any clinical fracture=0.82, p=0.052). Ibandronate patients had a significantly lower risk of vertebral fracture than weekly BP patients (adjusted relative risk 0.36, 95% confidence interval 0.18-0.75, p=0.006). In the secondary, "intent-to-treat" analysis, relative risks of fracture were not significantly different between treatment groups for any fracture type. The results of the sensitivity analyses were generally consistent with the primary analysis. This retrospective cohort study found that patients treated with oral monthly ibandronate or weekly BPs (alendronate and risedronate) had similar, low risks of hip fracture, nonvertebral fracture and any clinical fracture. Ibandronate patients had a significantly lower relative risk of vertebral fracture than weekly BP patients; the clinical implications of these findings require further exploration and validation.

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Staphylococcal scalded skin syndrome is the term used for a spectrum of primarily neonatal blistering skin diseases caused by the exfoliative toxins, ETA and ETB, of Staphylococcus aureus. Despite 25 y of research, the toxins' mechanism of action is still poorly understood, although evidence suggests that they may act as serine proteases. In this study, 0.1 mg purified ETA isolated from a baby with pemphigus neonatorum was incubated with A431 cells (a human squamous cell line) at 37 degrees C for 8, 24 and 48 h and the supernatant tested for protease activity using azocasein as a non-specific substrate. Phosphate-buffered saline was also incubated as negative control. Incubation of ETA with A431 cells for 48 h resulted in a four-fold increase in supernatant azocaseinolytic activity compared with buffer and cells, ETA alone and buffer alone (p < 0.001). Furthermore, this proteolytic activity was inhibited by PMSF (p < 0.001), a specific serine protease inhibitor. These results provide further evidence for the role of the exfoliative toxins as serine proteases. Furthermore, the A431 cell assay provides a simpler, quicker, cheaper and more acceptable alternative to neonatal mouse epidermis to study the mechanism of action of the exfoliative toxins.

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The exfoliative (epidermolytic) toxins of Staphylococcus aureus are the causative agents of the staphylococcal scalded-skin syndrome (SSSS), a blistering skin disorder that predominantly affects children. Clinical features of SSSS vary along a spectrum, ranging from a few localized blisters to generalized exfoliation covering almost the entire body. The toxins act specifically at the zona granulosa of the epidermis to produce the characteristic exfoliation, although the mechanism by which this is achieved is still poorly understood. Despite the availability of antibiotics, SSSS carries a significant mortality rate, particularly among neonates with secondary complications of epidermal loss and among adults with underlying diseases. The aim of this article is to provide a comprehensive review of the literature spanning more than a century and to cover all aspects of the disease. The epidemiology, clinical features, potential complications, risk factors, susceptibility, diagnosis, differential diagnoses, investigations currently available, treatment options, and preventive measures are all discussed in detail. Recent crystallographic data on the toxins has provided us with a clearer and more defined approach to studying the disease. Understanding their mode of action has important implications in future treatment and prevention of SSSS and other diseases, and knowledge of their specific site of action may provide a useful tool for physiologists, dermatologists, and pharmacologists.

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Alfredo's story is part of a larger phenomenological study of nursing, self care, and HIV disease that incorporated the anthropological tradition of reconstructing a life-story in the person's own words. This exemplar emphasizes Alfredo's shifts perspective organized around three turnings, or shifts in perspective, which are illustrated with narrative text and discussed. The three turnings include becoming HIV-infected, becoming a positive force, and reclaiming self. Implications for nursing include the importance of story telling in life history, the value of knowing the patient as a person, the positive impact of negative events, and the educational impact of a paradigm case.

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Four copies of the insertion sequence IS257 are found in the mec region of the chromosome of the Australian methicillin resistant Staphylococcus aureus (MRSA) strain ANS46, two flanking a merAmerB sequence (encoding resistance to mercurial compounds), the other two flanking an integrated copy of the plasmid pT181 (tetracycline resistance). The termini of the integrated copy of the plasmid pT181 carry a direct repeat of 8 bp of plasmid sequence, but otherwise there are no similarities in the 8 bp sequences flanking the four copies of IS257 in this strain. Integrated copies of pT181 in strains R35 (a New Jersey MRSA) and GH32 (MRSA of Greek origin) have the same terminal repeat as in ANS46, suggesting either a specific site of insertion of IS257 into the free plasmid before integration into the chromosome, or a common evolutionary lineage for these geographically diverse isolates. A different 8 bp terminal repeat of plasmid sequence is found in the chromosomally integrated copy of pUB110 (flanked by a pair of IS257s) in R155, another New Jersey MRSA. This 8 bp repeat differs from that reported previously for pUB110/IS257 inserted into the plasmid pSK41, indicating insertion of IS257 into different sites of pUB110 before integration into the chromosome or into pSK41. In the plasmid pSK1, the two outer copies of IS257 of the three associated with Tn4003 (trimethoprim resistance) are also flanked by 8 bp repeats.(ABSTRACT TRUNCATED AT 250 WORDS)

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Phenotypic loss of protein A production was tested in six methicillin-resistant (McR) Staphylococcus aureus (MRSA) isolates and their isogenic methicillin-sensitive (McS) variants by a radiolabelled IgG-binding assay with washed cells and by Western blotting of supernates prepared from lysed washed cells. Genomic DNA was probed for homology with the protein A gene (spa) in EcoRI digests and for homology to the methicillin resistance gene (mec) in HindIII digests. The McS variants had lost homology with mec. An isogenic pair of McR and McS strains, and derivatives of S. aureus 8325-4 with site-specific mutations of the accessory gene regulator locus (agr) and spa, were tested for adherence to human peritoneal mesothelial cells in monolayer culture. The isogenic pair were also tested for adherence to HEp-2 and Vero cell monolayers in assays with 3H thymidine-labelled bacteria. McR isolates produced protein A which was absent from three strains that had become McS. This correlated with deletion of the spa locus. Spa homology, but reduced production of protein A, was retained in one McS strain which also showed reduced adherence to HEp-2, Vero and mesothelial cells (p < 0.05) compared with the parent McR strain. A spa mutation in strain 8325-4 did not significantly affect adherence to mesothelial cells but mutation in agr increased adherence significantly in both Spa+ and Spa- strains.

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Strains of Staphylococcus aureus, isolated from the effluent of patients with peritonitis on CAPD (continuous ambulatory peritoneal dialysis), adhered well to both cultured human mesothelial cells and to fibronectin, but not to laminin or gelatin. Mesothelial cells grown in medium M199 exhibited more surface fibronectin compared to cells grown in MEM-Dval and demonstrated higher levels of S. aureus adherence. Soluble fibronectin concentrations up to 10 micrograms/ml increased the adherence of S. aureus to cultured mesothelial cells. The dose-response curve was consistent with the binding of fibronectin to a saturable receptor of apparent dissociation constant (KD) = 1.7 x 10(-10) M. This corresponds closely to the KD (2 x 10(-10) M) of the staphylococcal fibronectin-binding protein. S. aureus adherence was increased following the preincubation of mesothelial cell monolayers with interleukin-1 and was maximal after 6 h preincubation. Treating mesothelial cells with interferon-gamma for 48-72 h reduced the adherence of S. aureus.

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Susceptibility to six metal ions--cadmium (Cd), mercury (Hg), arsenate (Asa), arsenite (Asi), antimony (Sb) and zinc (Zn)--was tested in 23 independent isolates of methicillin-resistant Staphylococcus aureus (MRSA) obtained from Guy's Hospital (GH) during 1984-1986, which included 10 isolates of the UK epidemic EMRSA-1 strain. Strains were also tested for resistance to antibiotics and the nucleic-acid-binding compounds propamidine isethionate and ethidium bromide. A further 19 methicillin-resistant isolates, including 10 EMRSA-1 were obtained from other sources. Ten methicillin-sensitive, antibiotic sensitive isolates were from Guy's Hospital. Resistance to Hg was associated with methicillin resistance in 19 of the 20 EMRSA-1 isolates, all of which were resistant to Cd. Resistance to Cd and Hg was found in 13 out of 22 other MRSA isolates. Hg resistance was not present in the methicillin-sensitive isolates which were often (13 out of 19) moderately resistant to Cd. Multiple resistance to metal ions, including resistance to Hg, Asa, Asi and Sb, was uncommon. Resistance to Cd (MIC greater than 32 mg/L or 8-16 mg/L) was associated with increased resistance to Zn. In 11 of the consecutive MRSA isolates from Guy's Hospital seven distinct strains were recognised by phage type. Methicillin resistance in these strains varied from 16 to 1024 mg/L at 30 degrees C with a 2-8-fold lower minimum inhibitory concentration at 37 degrees C indicating some degree of heterogeneity. Representatives of the EMRSA-1 strain had the higher levels of resistance. Loss of methicillin resistance occurred in 0.2-5.0% of colonies tested after storage at room temperature in 10 of these isolates.(ABSTRACT TRUNCATED AT 250 WORDS)

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Adherence of four strains of Staphylococcus aureus to eukaryotic cell monolayers was assayed with [3H]-thymidine labelled bacterial cells and the results were analysed by non-parametric statistical tests. Adherence to primary (human mesothelial) and semi-continuous (human embryonic lung) cell monolayers was significantly better than to continuous cell lines (HEp2, HeLa and Vero). HEp2 cell monolayers provided the most reliable assay substrate of the continuous cell lines tested. Variation occurred between bacterial culture batches but the assay measured significant differences between adhesion levels of the strains and distinguished between high level (RN92, 8325-4) and low level (Wood46, ISP458) adhering strains. Adherence to different batches of cell monolayers also varied but relative adherence values for strains were similar and the ranking of strains according to adhesion values was unchanged. Potential adhesion mediators have been monitored for their effect on adhesion of a highly adherent strain (RN92) to HEp2 monolayers. Fibronectin, protein A and anti-protein A did not significantly affect adhesion. Lipoteichoic acid caused a significant inhibition of adhesion. With critical statistical analysis to accommodate inherent variations, this assay provides a useful model to study factors involved in adherence of Staph. aureus to eukaryotic cells.

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During the summer of 1987, an epidemic of pemphigus neonatorum took place at Guy's Hospital. It involved more than 80 neonates in the maternity unit. Swabs from the umbilical stumps of the babies and from the noses of several attending midwives yielded Staphylococcus aureus of phage-type Group II 3A/3C. Despite an extensive disinfection policy, which included identification and treatment of carriers, the outbreak persisted for 3 months. Final resolution came only after detailed epidemiological research revealed those midwives most likely to be involved. After these had been singled out for further treatment, the outbreak ended. The epidemic strains were later subjected to reverse phage-typing, plasmid profiling and in vivo testing for production of epidermolytic toxin in order to confirm true carriers and cases. Retrospective analysis identified those persons most likely to have been responsible for propagation of the epidemic strain. The exact course of the outbreak was then clarified.

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Over a three-year period, 217 episodes of bacterial peritonitis occurred in 183 patient years. Thirty-seven episodes were due to Staphylococcus aureus and 19 (51%) of these required removal of the catheter to eradicate infection. This compared with catheter loss in 4/63 (6.3%) coagulase negative staphylococci infections (p less than 0.001); 7/67 (9.5%) culture negative peritonitis (p less than 0.001); and 10/30 (33.3%) episodes due to gram-negative organisms (p less than 0.05). Over half (51.3%) the episodes due to S. aureus were associated with exit-site infections, and this rose to 100% (10/10) with recurrent peritonitis (p less than 0.01). A prospective analysis of nasal carriage and exit-site infections due to S. aureus was carried out in 87 patients. Exit-site infections were present in 21 (24%), almost entirely due to different strains as judged by sensitivity patterns and phage typing. Nasal carriage, defined as two positive swabs within the study period, was present in 20 (23%) patients. Fourteen (70%) of these had exit-site infections due to the same strain as that isolated from the nose, whereas no patient grew different strains from either site. Nasal carriage increased the risk of infection sixfold (p less than 0.001).

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Over a period of 2 months, 12 babies born in the maternity unit at Guy's Hospital developed staphylococcal scalded skin syndrome in two distinct outbreaks. Staphylococci isolated from the babies, together with those from the mothers and attending medical staff were phage-typed. All isolates from the babies were of type 3A/3C. During the first outbreak only one carrier of the epidemic strain (a paediatrician) was found but a further 12 persons were identified as possible carriers during the second outbreak. In order to confirm the link between outbreaks, all phage group II isolates were subjected to reverse phage-typing, testing for metal-ion resistance, plasmid profiling and in-vivo testing for production of epidermolytic toxin. It was shown that the same epidemic strain of toxin-producing Staphylococcus aureus was responsible for both outbreaks. The affected neonates responded rapidly to a short course of intravenous flucloxacillin. The outbreak ceased after appropriate treatment of all carriers and the implementation of an extensive disinfection policy within the maternity unit.

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Methicillin resistance (Mecr) was transduced into a methicillin-susceptible variant of the Mecr donor Staphylococcus epidermidis BS10. UV irradiation of phage stimulated Mecr transduction frequency. If loss of Cd and Hg ion resistance occurred in this recipient, or if the three markers Mecr, Cdr, and Hgr were co-eliminated from the donor, neither strain acted as a recipient for Mecr.

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Strains of propionibacteria resistant to clindamycin or clindamycin and erythromycin were isolated from four patients with acne, three of whom were receiving clindamycin. Four strains of P. acnes and one of P. granulosum with moderate levels of tetracycline resistance were isolated from 25 patients with acne being treated with tetracycline. A similar increase in tetracycline resistance was achieved by training sensitive strains in vitro. P. acnes was sensitive to sulphonamide and trimethoprim but some strains of P. granulosum were resistant to sulphonamide. Similar reports of clindamycin and erythromycin resistance from the USA suggest resistance may be increasing in isolates from patients with acne.

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The thyroids of forty patients were imaged using 2 mCi(74 MBq) 99mTc pertechnetate (99mTcO4) followed within one week by 2 mCi (74 MBq) 123I Iodide. The images obtained were evaluated by eight observers for 6 morphological criteria and assigned to 6 diagnostic categories with a confidence grading on a seven level scale (grade 1 being that for maximum confidence). Images were obtained with 123I for the same counts and the same times as those with 99mTcO4 and compared using an index in which the number of diagnostic categories and the mean confidence grading within each category were taken into account. The mean index obtained for 99mTcO4 images (9.2) was significantly greater (P less than 0.05, thus representing a lower observer confidence and less interobserver diagnostic agreement) than the mean indices for 123I equal count images (5.6) and 123I equal time images (6.8). The diagnoses made on the basis of 123I images were more frequently concordant with the final diagnosis after six months follow up (75% for equal counts and 77% for equal time) than those with 99mTcO4(63%). The radioisotope of iodine most suited to modern nuclear medicine instrumentation and with the most favourable radiation dosimetry is 123I which is recommended for those areas of thyroid imaging where iodine is superior.

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138 different coliform isolates from patients with UTI in 2 General Practices in Stockport, England, showed an incidence of drug resistance of 36%: 47% of these strains transferred resistance to E. coli K12. Multiple resistance, i.e. resistance to more than 2 drugs occurred in more than a quarter of resistant isolates and sulphonamide resistance was most common. More than twice as many strains in this series (1973--74) were sulphonamide resistant compared with a previous survey (1968--70). MIC values of R+ resistant isolates were much higher with sulphonamide resistant strains than the probable urine levels during therapy, but the situation with ampicillin and tetracycline levels was variable.

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Transduction of resistance from a multiply antibiotic-resistant strain of Staphylococcus epidermidis sub-group II was studied using the typing phage 108. The effect of increasing doses of ultraviolet radiation on the transducing phage was used to indicate the chromosomal or plasmid nature of the genes. Tetracycline and chloramphenicol resistance behaved as plasmid genes and streptomycin resistance as a chromosomal marker. It was also possible to transduce penicillin resistance (Pc) due to penicillinase production (bla+) using a low level of benzylpenicillin (0.03 microgram ml-1) for recovery. Approximately 10(-5) transductant colonies per phage input were obtained and ultraviolet kinetics indicated that Pc was plasmid carried. Pc transductants fell into two categories. In one group PC was stable as in the donor strain and transductants had the same phage sensitivity as the recipient. In the other, Pc was unstable at 37 degrees C and the instability was enhanced by growth at approximately 43.5 degrees C; these transductants also gained genes for restriction and modification of certain phages. Transductants that subsequently lost bla+ also lost the restriction and modification characters.

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