A 12-month randomised pilot trial of the Alzheimer's and music therapy study: a feasibility assessment of music therapy and physical activity in patients with mild-to-moderate Alzheimer's disease.

BACKGROUND: The Alzheimer's and Music Therapy (ALMUTH) study is the first randomised controlled trial (RCT) design with 12 months of active non-pharmacological therapy (NPT) implementing music therapy (MT) and physical activity (PA) for participants with Alzheimer's disease (AD). The aim of the present article is to retrospectively examine the inclusion of mild-to-moderate Alzheimer's Disease patients into the main ALMUTH study protocol and to determine if continued inclusion of AD patients is warranted. METHODS: The randomised pilot trial was conducted as a parallel three-arm RCT, reflecting the experimental design of the ALMUTH study. The trial was conducted in Bergen, Norway, and randomisation (1:1:1) was performed by an external researcher. The study was open label and the experimental design features two active NPTs: MT and PA, and a passive control (no intervention, CON) in Norwegian speaking patients with AD who still live at home and could provide informed consent. Sessions were offered once per week (up to 90 min) up to 40 sessions over 12 months. Baseline and follow-up tests included a full neuropsychological test battery and three magnetic resonance imaging (MRI) measurements (structural, functional, and diffusion weighted imaging). Feasibility outcomes were assessed and were determined as feasible if they met the target criteria. RESULTS: Eighteen participants with a diagnosis of mild-to-moderate AD were screened, randomised, and tested once at baseline and once after 12-months. Participants were divided into three groups: MT (n = 6), PA (n = 6), and CON (n = 6). Results of the study revealed that the ALMUTH protocol in patients with AD was not feasible. The adherence to the study protocol was poor (50% attended sessions), with attrition and retention rates at 50%. The recruitment was costly and there were difficulties acquiring participants who met the inclusion criteria. Issues with study fidelity and problems raised by staff were taken into consideration for the updated study protocol. No adverse events were reported by the patients or their caregivers. CONCLUSIONS: The pilot trial was not deemed feasible in patients with mild-to-moderate AD. To mitigate this, the ALMUTH study has expanded the recruitment criteria to include participants with milder forms of memory impairment (pre-AD) in addition to expanding the neuropsychological test battery. The ALMUTH study is currently ongoing through 2023. TRIAL REGISTRATION: Norsk Forskningsråd (NFR) funded. Regional Committees for Medical and Health Research Ethics (REC-WEST: reference number 2018/206). CLINICALTRIALS: gov: NCT03444181 (registered retrospectively 23 February 2018, https://clinicaltrials.gov/ct2/show/NCT03444181 ).

Author Correction: Inhibition of casein kinase 1δ/εimproves cognitive-affective behavior and reduces amyloid load in the APP-PS1 mouse model of Alzheimer's disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Inhibition of casein kinase 1δ/εimproves cognitive-affective behavior and reduces amyloid load in the APP-PS1 mouse model of Alzheimer's disease.

Circadian rhythm disruption is one of the earliest biomarkers of Alzheimer's disease (AD), and there exists a bidirectional relationship by which dysfunctions in the circadian clock drive AD pathology and AD pathology drives circadian dysfunction. Casein kinase 1 (CK1) isoforms ε and δ, key circadian regulators, are significantly upregulated in AD and may contribute to AD pathogenesis. In the current studies, we have examined how inhibition of CK1ε/δ with PF-670462 (at 10 mg/kg, δ isoform selective, or 30 mg/kg, δ and ε selective) impacts regional Aß and circadian gene expression in 10-13 month old APP-PS1 mice and nontransgenic controls. We have also assessed circadian, cognitive, and affective behavioral correlates of these neural changes. At baseline, APP-PS1 mice showed a short period, as well as impaired cognitive performance in both prefrontal cortex and hippocampus-dependent tasks. Both doses of PF-670462 lengthened the period and improved affect, whereas only the higher dose improved cognition. Further, PF-670462 treatment produced a dose-dependent reduction in amyloid burden - overall Aß signal decreased in all three areas; in the prefrontal cortex and hippocampus, PF-670462 also reduced plaque size. Together, these findings support chronotherapy as a potential tool to improve behavior in AD.

A comparative analysis of heterogeneity in commercially available recombinant factor VIII products.

INTRODUCTION: Advances in analytical technologies enable investigation of possible correlations between molecular structure, aggregation and subvisible particle content. Regulatory agencies place increasing attention on potential risks associated with protein aggregates in the micron range in biological therapeutics. AIM: Assess the heterogeneity, high-molecular-weight protein (HMWP) species, subvisible particle content and posttranslational modifications in six commercially available recombinant FVIII (rFVIII) products. METHODS: Three B-domain-deleted (BDD) or B-domain truncated rFVIII products (turoctocog alfa, simoctocog alfa and moroctocog alfa) and three full-length rFVIII products (octocog alfa FS and two octocog alfa) were analysed. HMWP content, amount of micron range subvisible particles, tyrosine-1680 sulphation and N-glycan analysis were investigated. RESULTS: The B-domain-modified products had more protein size homogeneity vs the full-length products. Size exclusion-high-performance liquid chromatography data indicated no association between B-domain structure and aggregate content or size of the products tested. The rFVIII products showed large variation in subvisible particle concentration, with turoctocog alfa and simoctocog alfa having the lowest numbers (1000-1600 and 1800-2400 particles/100 IU, respectively). Turoctocog alfa and simoctocog alfa displayed the most complete tyrosine sulphation (>99.5%). CONCLUSION: Overall, there was no association between molecular structure (full-length B-domain, BDD or truncated) and subvisible particle or HMWP content. Dissimilarities may be related to production and product handling differences. In this study, turoctocog alfa, such as simoctocog alfa, had one of the lowest levels of subvisible particles and HMWP content, and high protein size homogeneity.

The occurrence of Enterococcus faecium and faecalis Is significantly associated With anastomotic leakage After pancreaticoduodenectomy.

BACKGROUND AND AIMS: Enterococcus has emerged as a virulent species; Enterococcus faecium especially has arisen as a source of nosocomial infections. Furthermore, specific Enterococcus faecalis species are significantly associated with anastomotic leakage in rodent studies. The objective of this study was to investigate whether the occurrence of Enterococci ( E. faecium and E. faecalis) obtained from drain samples was associated with leakage in humans undergoing pancreaticoduodenectomy. MATERIALS AND METHODS: All patients undergoing pancreaticoduodenectomy had a peritoneal drain sample sent for culturing between postoperative days 3 and 10. Postoperative pancreatic fistulas were defined and classified according to the International Study Group of Pancreatic Fistula. Bile leakage was radiologically verified. Postoperative complications were classified according to the Dindo-Clavien classification. RESULTS: A total of 70 patients were eligible and enrolled in this study. Anastomosis leakage was observed in 19 patients; 1 leakage corresponding to the hepaticojejunostomy and 18 pancreatic fistulas were identified. In total, 10 patients (53%) with leakage had Enterococci-positive drain samples versus 12 patients (24%) without leakage [odds ratio (OR) = 5.1, 95% confidence interval (CI) = 1.4-19.4, p = 0.02]. Preoperative biliary drainage with either endoscopic stenting or a percutaneous transhepatic cholangiography catheter was associated with the occurrence of Enterococci in drain samples (OR = 5.67, 95% CI = 1.8-12.9, p = 0.003), but preoperative biliary drainage was not associated with leakage (OR = 0.45, 95% CI = 0.1-1.7, p = 0.23). CONCLUSION: Enterococci in drain sample cultures in patients undergoing pancreaticoduodenectomy occurs significantly more among patients with anastomotic leakage compared to patients without leakage.

A kinase inhibitor screen identifies Mcl-1 and Aurora kinase A as novel treatment targets in antiestrogen-resistant breast cancer cells.

Antiestrogen resistance is a major problem in breast cancer treatment. Therefore, the search for new therapeutic targets and biomarkers for antiestrogen resistance is crucial. In this study, we performed a kinase inhibitor screen on antiestrogen responsive MCF-7 cells and a panel of MCF-7-derived tamoxifen- and fulvestrant-resistant cell lines. Our focus was to identify common and distinct molecular mechanisms involved in tamoxifen- and fulvestrant-resistant cell growth. We identified 18 inhibitors, of which the majority was common for both tamoxifen- and fulvestrant-resistant cell lines. Two compounds, WP1130 and JNJ-7706621, exhibiting prominent preferential growth inhibition of antiestrogen-resistant cell lines, were selected for further studies. WP1130, a deubiquitinase inhibitor, induced caspase-mediated cell death in both tamoxifen- and fulvestrant-resistant cell lines by destabilization of the anti-apoptotic protein Mcl-1. Mcl-1 expression was found upregulated in the antiestrogen-resistant cell lines and depletion of Mcl-1 in resistant cells caused decreased viability. JNJ-7706621, a dual Aurora kinase and cyclin-dependent kinase inhibitor, specifically inhibited growth and caused G2 phase cell cycle arrest of the tamoxifen-resistant cell lines. Knockdown studies showed that Aurora kinase A is essential for growth of the tamoxifen-resistant cells and inhibition of Aurora kinase A resensitized tamoxifen-resistant cells to tamoxifen treatment. Preferential growth inhibition by WP1130 and JNJ-7706621 was also found in T47D-derived tamoxifen-resistant cell lines, pointing at Mcl-1 and Aurora kinase A as potential treatment targets. In addition, tumor samples from 244 estrogen receptor-positive breast cancer patients treated with adjuvant tamoxifen showed that higher expression level of Aurora kinase A was significantly associated with shorter disease-free and overall survival, demonstrating the potential of Aurora kinase A as a biomarker for tamoxifen resistance.

[Antibiotic susceptibility of Staphylococcus aureus strains responsible for community-acquired skin infections]. / Sensibilité aux antibiotiques des souches de Staphylococcus aureus responsables d'infections cutanées communautaires.

BACKGROUND: The appearance and worldwide spread of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) skin infections warrant new studies of antibiotic resistance among strains of S. aureus responsible for cutaneous infections seen in general practice. PATIENTS AND METHODS: A prospective, multicentre study was performed from December 2003 to August 2004 in outpatients of both sexes presenting with a common bacterial skin infection presumed due to S. aureus (primary or secondary impetigo, ecthyma, paronychia, folliculitis, furunculosis). The investigators (n=50) were GPs from seven French regions. Clinical data (history, previous hospitalisation, type of infection, site, previous treatment, etc.) were collected using a standard questionnaire. A bacteriological sample was taken in attempt to isolate S. aureus after which antibiograms were prepared and minimal inhibiting concentrations determined (11 antibiotics). RESULTS: Four hundred and eighty patients of mean age 42 years (range: 2-94 years) were included. S. aureus was isolated from cultures in 205 of 477 samples, i.e. in 197 patients (eight had two strains of S. aureus). Patients with S. aureus had a primary skin infection in 104/197 cases (53%) (24 impetigo, 20 paronychia, 45 folliculitis or furunculosis) and a secondary infection in 93/197 cases (47%), with 4.9% patients being hospitalized within the preceding six months (median: 10 days). Percentages of resistant S. aureus strains were as follows: penicillin: 86%, erythromycin: 32%, ciprofloxacin: 9.3%, tetracycline: 5.8%, oxacillin: 5.8% (representing MRSA strains), fusidic acid: 4.4%, clindamycin: 3.4%, mupirocin: 1% and gentamicin: 0.5%. All S. aureus strains were sensitive to vancomycin and rifampicin. Except for one strain also resistant to tetracycline and fusidic acid, all MRSA strains were also resistant to ciprofloxacin. DISCUSSION: Multiresistant bacterial strains could become a concern in the community in France in the near future. In our study, only 14/197 (6.8%) S. aureus strains were sensitive to all tested antibiotics, whereas 21/197 (10.7%) were resistant to at least three of them. Compared to a French study performed in private practice in 2000, the level of MRSA is growing only slowly (5.8% versus 3.9%), whereas the percentage of strains of Peni-R/Oxa-S S. aureus are stable (80.5%). CONCLUSION: Common bacterial infections of the skin due to MRSA or to multiresistant S. aureus are not rare in France and have tended to increase slowly in recent years.

Epidemiological differences between the UK and Ireland versus France in Staphylococcus aureus isolates resistant to fusidic acid from community-acquired skin and soft tissue infections.

OBJECTIVES: To characterize the epidemiology of Staphylococcus aureus isolates resistant to fusidic acid isolated from patients with skin and soft tissue infections (SSTIs) in France, the UK and Ireland. METHODS: One hundred and thirty-six S. aureus isolates with an MIC of fusidic acid above 1 mg/L were isolated during the EPISA study from patients more than 2 years old attending their general practitioners for SSTIs. All isolates were related to clonal complex by a combination of PFGE, spa typing and multilocus sequence typing. The presence of toxin genes and of the fusB determinant was monitored to characterize each represented clonal complex. RESULTS: Eight different clonal complexes were identified. CC121 constituted the majority of the isolates from Ireland and the UK but was not represented in France. Among the other clonal complexes, CC8 and CC5 were the most common in the three countries, although the number of French isolates was limited. CC121 was the only clonal complex significantly associated with a skin infection, namely impetigo (P < 0.05). Toxin genes were present in CC121 and CC80. The fusB determinant was also detected in the same clonal complexes. Enterotoxins were found in four clonal complexes (CC1, CC5, CC8 and CC22). CONCLUSIONS: The impetigo clone (CC121: ST123) was present in the majority of S. aureus isolates from the UK and Ireland but was not detected in France. This strain was associated with impetigo, exfoliative toxins and the fusB determinant. No other clonal complex appeared to be dominant in other types of skin infections.

The EPISA study: antimicrobial susceptibility of Staphylococcus aureus causing primary or secondary skin and soft tissue infections in the community in France, the UK and Ireland.

OBJECTIVES: To provide information on the susceptibility of Staphylococcus aureus causing skin and soft tissue infections (SSTIs) in France, Ireland and the UK. PATIENTS AND METHODS: One thousand three hundred and ninety patients attending their general practitioners for skin infections were recruited. Susceptibility to 11 antimicrobials using CLSI (formerly NCCLS) broth microdilution was determined for 646 S. aureus isolates detected in the evaluable patient population. RESULTS: Susceptibility results were similar in the UK and Ireland, but differed in France. The largest difference between countries was observed for erythromycin and fusidic acid. In France, 67.8% of isolates were susceptible to erythromycin when compared with 88.6% in Ireland and 92.8% in the UK. However, 93.7% of French isolates were susceptible to fusidic acid, compared with 68.6% in Ireland and 75.6% in the UK. A diagnosis of impetigo was associated with reduced fusidic acid susceptibility. CONCLUSIONS: Differences in the prevalence of certain diagnoses, particularly impetigo, rather than differences in antibiotic consumption may explain some of the observed differences in susceptibility seen between these countries.

Characterization of the epidemic European fusidic acid-resistant impetigo clone of Staphylococcus aureus.

Resistance to the antibiotic fusidic acid in European strains of Staphylococcus aureus causing impetigo has increased in recent years. This increase appears to have resulted from clonal expansion of a strain we have designated the epidemic European fusidic acid-resistant impetigo clone (EEFIC), which carries the fusidic acid resistance determinant fusB on its chromosome. To understand better the properties of the EEFIC responsible for its success, we have performed detailed phenotypic and genotypic characterization of this clone. Molecular typing revealed the EEFIC to be ST123, spa type t171, and agr type IV and therefore unrelated to earlier prevalent fusB(+) strains found in the United Kingdom. EEFIC strains exhibited resistance to fusidic acid, penicillin, and, in some cases, erythromycin, which are all used in the treatment of impetigo. PCR analysis of the EEFIC and complete DNA sequencing of the 39.3 Kb plasmid it harbors identified genes encoding several toxins previously implicated in impetigo (exfoliative toxins A and B and EDIN-C). The location of fusB was mapped on the chromosome and found to be associated with a novel 16.6-kb genomic island integrated downstream of groEL. Although this element is related to classical staphylococcal pathogenicity islands, it does not encode any known virulence factors and consequently has been designated SaRI(fusB) (for "S. aureus resistance island carrying fusB").

Genetic basis of resistance to fusidic acid in staphylococci.

Resistance to fusidic acid in Staphylococcus aureus often results from acquisition of the fusB determinant or from mutations in the gene (fusA) that encodes the drug target (elongation factor G). We now report further studies on the genetic basis of resistance to this antibiotic in the staphylococci. Two staphylococcal genes that encode proteins exhibiting ca. 45% identity with FusB conferred resistance to fusidic acid in S. aureus. One of these genes (designated fusC) was subsequently detected in all fusidic acid-resistant clinical strains of S. aureus tested that did not carry fusB or mutations in fusA, and in strains of S. intermedius. The other gene (designated fusD) is carried by S. saprophyticus, explaining the inherent resistance of this species to fusidic acid. Fusidic acid-resistant strains of S. lugdunensis harbored fusB. Thus, resistance to fusidic acid in clinical isolates of S. aureus and other staphylococcal species frequently results from expression of FusB-type proteins.

Person-task-context: a model for designing curriculum and in-training assessment in postgraduate education.

Structured curricula for senior house officers have often been lacking. The aim of this study was to trial a person-task-context model in designing a curriculum and in-training assessment (ITA) programme for SHOs in internal medicine. A working group designed the programme based on triangulation of information from interviews with trainees and programme directors, analysis of patient case mix and national quality assurance data. The interview data showed that the main difference currently between trainee levels was in expected degree of responsibility for patient management rather than in actual tasks. Key learning needs were how to take a structured approach to the tasks and get an overview of situations. SHOs expressed a need for explicit learning goals and standards of performance. SHOs requested formal teaching in non-medical aspects of competence such as communication, interpersonal skills and professionalism. This article points out how consideration of the type of trainees involved, the tasks they must do and learn, and the context in which they work are important in designing postgraduate curricula. The person-task-context model can be used to tailor curricula and ITA that support learning and may be especially beneficial in promoting learning in non-dominant areas of a specialty.

Educational impact of in-training assessment (ITA) in postgraduate medical education: a qualitative study of an ITA programme in actual practice.

OBJECTIVES: To investigate the experiences and opinions of programme directors, clinical supervisors and trainees on an in-training assessment (ITA) programme on a broad spectrum of competence for first year training in anaesthesiology. How does the programme work in practice and what are the benefits and barriers? What are the users' experiences and thoughts about its effect on training, teaching and learning? What are their attitudes towards this concept of assessment? METHODS: Semistructured interviews were conducted with programme directors, supervisors and trainees from 3 departments. Interviews were audiotaped and transcribed. The content of the interviews was analysed in a consensus process among the authors. RESULTS: The programme was of benefit in making goals and objectives clear, in structuring training, teaching and learning, and in monitoring progress and managing problem trainees. There was a generally positive attitude towards assessment. Trainees especially appreciated the coupling of theory with practice and, in general, the programme inspired an academic dialogue. Issues of uncertainty regarding standards of performance and conflict with service declined over time and experience with the programme, and departments tended to resolve practical problems through structured planning. DISCUSSION: Three interrelated factors appeared to influence the perceived value of assessment in postgraduate education: (1) the link between patient safety and individual practice when assessment is used as a licence to practise without supervision rather than as an end-of-training examination; (2) its benefits to educators and learners as an educational process rather than as merely a method of documenting competence, and (3) the attitude and rigour of assessment practice.

Gender differences in asthma prevalence may depend on how asthma is defined.

BACKGROUND: Asthma may be defined either as wheeze within the previous 12 months (current wheeze) doctor-diagnosed asthma (DDA), or current wheeze plus confirmed airway hyperresponsiveness (AHR). AIMS: We wanted to estimate asthma prevalence in randomly selected adolescents based on different criteria for asthma diagnosis, study gender differences in reported asthma-like symptoms vs DDA, and relate our findings to measurements of AHR, levels of exhaled nitric oxide (ENO) and total IgE. METHODS: As part of the health survey of North-Trøndelag (HUNT), 8571 adolescents aged 13-19 years were investigated with an interview on allergic and respiratory symptoms (phase I study). Of these, 401 subjects who reported wheeze within the previous 12 months (current wheeze) and 213 non-symptomatic controls were randomly selected and investigated with allergy screening, methacholine bronchoprovocation test and measurements of ENO (phase II study). RESULTS: In the phase I study prevalence of current wheeze was 26% (30% in girls and 23% in boys, P < 0.01). Prevalence of DDA was 10.8% (10.5% in girls and 11% in boys). Among subjects with current wheeze, the likelihood of having DDA was reduced in girls compared to boys, odds ratio (95% CI) 0.82 (0.68-0.98) which was partly explained by a longer history of wheeze among boys. In the phase II study, although more girls than boys with current wheeze had AHR (62% versus 50%, P < 0.02) more boys than girls reported DDA (44% vs. 32%, P < 0.02). Of the objective parameters, increased levels of ENO most strongly increased the risk of having DDA. CONCLUSIONS: When asthma is defined as DDA, there is a risk of underestimating the prevalence of asthma, especially among girls.

Major venom allergen of yellow jackets, Ves v 5: structural characterization of a pathogenesis-related protein superfamily.

Ves v 5 is one of three major allergens found in yellow-jacket venom: phospholipase A(1) (Ves v 1), hyaluronidase (Ves v 2), and antigen 5 (Ves v 5). Ves v 5 is related by high amino acid sequence identity to pathogenesis-related proteins including proteins from mammals, reptiles, insects, fungi, and plants. The crystal structure of Ves v 5 has been solved and refined to a resolution of 1.9 A. The majority of residues conserved between the pathogenesis-related proteins can be rationalized in terms of hydrogen bonding patterns and hydrophobic interactions defining an alpha-beta-alpha sandwich core structure. A small number of consensus residues are solvent exposed (including two adjacent histidines) and located in an elongated cavity that forms a putative active site. The site has no structural resemblance to previously characterized enzymes. Homologous antigen 5's from a large number of different yellow jackets, hornets, and paper wasps are known and patients show varying extents of cross-reactivity to the related antigen 5's. The structure of Ves v 5 allows a detailed analysis of the epitopes that may participate in antigenic cross-reactivity, findings that are useful for the development of a vaccine for treatment of insect allergy.

Shedding light on disulfide bond formation: engineering a redox switch in green fluorescent protein.

To visualize the formation of disulfide bonds in living cells, a pair of redox-active cysteines was introduced into the yellow fluorescent variant of green fluorescent protein. Formation of a disulfide bond between the two cysteines was fully reversible and resulted in a >2-fold decrease in the intrinsic fluorescence. Inter conversion between the two redox states could thus be followed in vitro as well as in vivo by non-invasive fluorimetric measurements. The 1.5 A crystal structure of the oxidized protein revealed a disulfide bond-induced distortion of the beta-barrel, as well as a structural reorganization of residues in the immediate chromophore environment. By combining this information with spectroscopic data, we propose a detailed mechanism accounting for the observed redox state-dependent fluorescence. The redox potential of the cysteine couple was found to be within the physiological range for redox-active cysteines. In the cytoplasm of Escherichia coli, the protein was a sensitive probe for the redox changes that occur upon disruption of the thioredoxin reductive pathway.

Differential activity and structure of highly similar peroxidases. Spectroscopic, crystallographic, and enzymatic analyses of lignifying Arabidopsis thaliana peroxidase A2 and horseradish peroxidase A2.

Anionic Arabidopsis thaliana peroxidase ATP A2 was expressed in Escherichia coli and used as a model for the 95% identical commercially available horseradish peroxidase HRP A2. The crystal structure of ATP A2 at 1.45 A resolution at 100 K showed a water molecule only 2.1 A from heme iron [Ostergaard, L., et al. (2000) Plant Mol. Biol. 44, 231-243], whereas spectroscopic studies of HRP A2 in solution at room temperature [Feis, A., et al. (1998) J. Raman Spectrosc. 29, 933-938] showed five-coordinated heme iron, which is common in peroxidases. Presented here, the X-ray crystallographic, single-crystal, and solution resonance Raman studies at room temperature confirmed that the sixth coordination position of heme iron of ATP A2 is essentially vacant. Furthermore, electronic absorption and resonance Raman spectroscopy showed that the heme environments of recombinant ATP A2 and glycosylated plant HRP A2 are indistinguishable at neutral and alkaline pH, from room temperature to 12 K, and are highly flexible compared with other plant peroxidases. Ostergaard et al. (2000) also demonstrated that ATP A2 expression and lignin formation coincide in Arabidopsis tissues, and docking of lignin precursors into the substrate binding site of ATP A2 predicted that coniferyl and p-coumaryl alcohols were good substrates. In contrast, the additional methoxy group of the sinapyl moiety gave rise to steric hindrance, not only in A2 type peroxidases but also in all peroxidases. We confirm these predictions for ATP A2, HRP A2, and HRP C. The specific activity of ATP A2 was lower than that of HRP A2 (pH 4-8), although a steady-state study at pH 5 demonstrated very little difference in their rate constants for reaction with H2O2 (k1 = 1.0 microM(-1) x s(-1). The oxidation of coniferyl alcohol, ferulic, p-coumaric, and sinapic acids by HRP A2, and ATP A2, however, gave modest but significantly different k3 rate constants of 8.7 +/- 0.3, 4.0 +/- 0.2, 0.70 +/- 0.03, and 0.04 +/- 0.2 microM(-1) x s(-1) for HRP A2, respectively, and 4.6 +/- 0.2, 2.3 +/- 0.1, 0.25 +/- 0.01, and 0.01 +/- 0.004 microM(-1) x s(-1) for ATP A2, respectively. The structural origin of the differential reactivity is discussed in relation to glycosylation and amino acid substitutions. The results are of general importance to the use of homologous models and structure determination at low temperatures.

Synthesis and conformational analysis of fusidic acid side chain derivatives in relation to antibacterial activity.

Novel fusidic acid type antibiotics having flexible side chains are described. Saturation of the double bond between C-17 and C-20 of fusidic acid produces four stereoisomers differing in the configuration at C-17 and C-20. The structure-activity relationship of the stereoisomers was studied using computer-assisted analyses of low-energy conformations and crystallographic data. Only one of the four stereoisomers showed potent antibiotic activity comparable with that of fusidic acid, whereas the other three stereoisomers retained little or no activity. The orientation of the side chain is crucial, and there is only a limited space for bioactive side chain conformations. This investigation demonstrates the essential role of the side chain conformations in relation to antibacterial activity and contradicts earlier assumptions that the Delta17(20) bond is an essential feature in the molecule.

[Takayasu's arteritis]. / Takayasus arteritt.

BACKGROUND: Takayasu's arteritis is a chronic, idiopathic, inflammatory disease that affects aorta and its main branches. The disease is rare; its etiology is unknown and shows race differences. The inflammation of the arteries may lead to stenosis, occlusions, dilatations or aneurysms. The clinical picture and angiographic findings are not previously reported in a Norwegian cohort. MATERIAL AND METHODS: We report a retrospective, hospital-based study describing the clinical picture, diagnostic findings, treatment and prognosis in a cohort of six patients in Central Norway with Takayasu's arteritis. The data was extracted through chart review. RESULTS: In the period 1988-2000, six patients with Takayasu's arteritis, five women and one man, were identified. All the patients were of Norwegian origin. Median age at diagnosis was 39 years, range 24-63 years, and median time from first symptoms to definite diagnosis was six months, range 1-36 months. The estimated minimum annual incidence was 0.8 per million. All patients had elevated erythrocyte sedimentation rate; five out of six patients had unilateral or bilateral subclavian stenosis; one patient had a thoracoabdominal aneurysm. All patients were treated with prednisolone. There were no deaths in the observation period of median 7.5 years, range 0-26 years. INTERPRETATION: Takayasu's arteritis is a rare disease in our region, with lower incidence than reported in the literature. The prognosis is excellent, but the morbidity was substantial. The clinical findings are similar to those reported in other studies. The location and appearance of the angiographic findings were characteristic for the disease.