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Nitisinone has been approved for treatment of alkaptonuria (AKU). Non-invasive biomarkers of joint tissue remodelling could aid in understanding the molecular changes in AKU pathogenesis and how these can be affected by treatment. Serological and urinary biomarkers of type I collagen and II collagen in AKU were investigated in patients enrolled in the randomized SONIA 2 (NCT01916382) clinical study at baseline and yearly until the end of the study (Year 4). The trajectories of the biomarkers over time were observed. After treatment with nitisinone, the biomarkers of type I collagen remodelling increased at Year 1 (19% and 40% increase in CTX-I and PRO-C1, respectively), which was potentially reflected in the higher degree of mobility seen following treatment. The biomarkers of type II collagen remodelling decreased over time in the nitisinone group: C2M showed a 9.7% decline at Year 1, and levels then remained stable over the following visits; CTX-II showed a 26% decline at Year 3 and 4 in the nitisinone-treated patients. Nitisinone treatment induced changes in biomarkers of bone and cartilage remodelling. These biomarkers can aid patient management and deepen our knowledge of the molecular mechanisms of this rare disease.

In an open‐label, controlled study of nitisinone in alkaptonuria (SONIA 2), patients were advised to lower dietary protein intake to reduce serum tyrosine (s‐Tyr) levels and the risk of keratopathy. A body weight increase was observed in the nitisinone‐treated patients but not in the control group. To investigate the effectiveness and consequence of protein restriction in patients with alkaptonuria, a post‐hoc analysis of SONIA 2 was performed. One hundred and thirty‐eight patients were randomised (nitisinone: n = 69, controls: n = 69). Comparison of baseline and Month 12 data on 24‐h urinary excretion of HGA (u‐HGA24) and urea (u‐urea24, used as an approximate protein intake measure), tyrosine and body weight were performed using paired t tests. Comparisons of data between groups were made using 2‐sample t tests. We found that u‐urea24 decreased more in nitisinone‐treated than controls. The study centre with lowest average s‐Tyr and u‐urea24 (nitisinone arm) at Month 12 also had lowest keratopathy incidence (3.1%), while the centre with highest values showed the highest (14.6%). S‐Tyr was generally high in those with keratopathy, but those without keratopathy had similar elevated values. A similar pattern across centres was seen for body weight changes, with a statistically significant weight increase in nitisinone‐treated patients at centres with lower u‐urea24 values. Therefore, in nitisinone‐treated patients, protein restriction led to increased body weight but may also have lowered the risk of developing keratopathies. If introduced, a protein‐restricted diet should be supervised by a dietician and, when appropriate, include amino acid supplements deficient in tyrosine and phenylalanine, to avoid malnutrition and undesired weight increase.

ObjectivesOchronotic spondyloarthropathy represents one of the main clinical manifestations of alkaptonuria (AKU); however, prospective data and description of the effect of nitisinone treatment are lacking.MethodsPatients with AKU aged 25 years or older were randomly assigned to receive either oral nitisinone 10 mg/day (N=69) or no treatment (N=69). Spine radiographs were recorded yearly at baseline, 12, 24, 36 and 48 months, and the images were scored for the presence of intervertebral space narrowing, soft tissue calcifications, vacuum phenomena, osteophytes/hyperostosis and spinal fusion in the cervical, thoracic and lumbosacral segment at each of the time points.ResultsAt baseline, narrowing of the intervertebral spaces, the presence of osteophytes/hyperostosis and calcifications were the three most frequent radiographic features in AKU. The rate of progression of the five main features during the 4 years, ranked from the highest to lowest was as follows: intervertebral spaces narrowing, calcifications, vacuum phenomena, osteophytes/hyperostosis and fusions. The rate of progression did not differ between the treated and untreated groups in any of the five radiographic parameters except for a slower rate of progression (sum of all five features) in the treatment group compared with the control group (0.45 (1.11) nitisinone vs 0.74 (1.11) controls, p=0.049) in the thoracic segment.ConclusionThe present study shows a relatively slow but significant worsening of radiographic features in patients with AKU over 4 years. Our results demonstrate a modest beneficial effect of 10 mg/day of nitisinone on the slowly progressing spondylosis in AKU during the relatively limited follow-up time.Trial registration numberNCT01916382.

Objectives We have assessed the effect of elevated concentrations of hydroxyphenylpyruvic acid (HPPA), hydroxyphenyllactic acid (HPLA) and tyrosine, on a range of chemistry tests in serum and urine to explore the potential for chemical interference on routine laboratory analyses in patients with alkaptonuria (AKU) treated with nitisinone and similarly implications for patients with hereditary tyrosinemia type 1 (HT-1). Materials and methods HPPA, HPLA and tyrosine were added separately to pooled serum from subjects without AKU in a range of assays with Roche Modular chemistries. Effects on urine were assessed by changes in urine strip chemistries after mixing a positive control urine with various amounts of the test compounds and reading on a Siemens urine strip meter. Results No significant effect (p > 0.1) was observed up to 225 μmol/L of HPPA and HPLA, and up to 5000 μmol/L tyrosine, on any of the serum-based assays including those with peroxidase-coupled reaction systems of enzymatic creatinine, urate, total cholesterol, HDL cholesterol and triglyceride. Both the monohydroxy HPPA, and the dihydroxy homogentisic acid (HGA), at increased urine concentrations typical of nitisinone-treated AKU and non-treated AKU respectively, did however show marked negative interference in strip assays for glucose and leucocytes; i.e. those with peroxide-linked endpoints. The effect of increased HPLA was less marked. Conclusions In patients with AKU or on nitisinone treatment and HT-1 patients on nitisinone, urine strip chemistry testing should be used sparingly, if at all, to avoid false negative reporting. It is recommended that urine assays should be organised with a suitable specialist laboratory.

Alkaptonuria (AKU) is a rare metabolic disorder caused by a deficient enzyme in the tyrosine degradation pathway, homogentisate 1,2-dioxygenase (HGD). In 172 AKU patients from 39 countries, we identified 28 novel variants of the HGD gene, which include three larger genomic deletions within this gene discovered via self-designed multiplex ligation-dependent probe amplification (MLPA) probes. In addition, using a reporter minigene assay, we provide evidence that three of eight tested variants potentially affecting splicing cause exon skipping or cryptic splice-site activation. Extensive bioinformatics analysis of novel missense variants, and of the entire HGD monomer, confirmed mCSM as an effective computational tool for evaluating possible enzyme inactivation mechanisms. For the first time for AKU, a genotype–phenotype correlation study was performed for the three most frequent HGD variants identified in the Suitability Of Nitisinone in Alkaptonuria 2 (SONIA2) study. We found a small but statistically significant difference in urinary homogentisic acid (HGA) excretion, corrected for dietary protein intake, between variants leading to 1% or >30% residual HGD activity. There was, interestingly, no difference in serum levels or absolute urinary excretion of HGA, or clinical symptoms, indicating that protein intake is more important than differences in HGD variants for the amounts of HGA that accumulate in the body of AKU patients.

Background Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit. Methods SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA24) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA24 measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382). Findings Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA24 at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p

The clinical effects of alkaptonuria (AKU) are delayed and ageing influences disease progression. Morbidity of AKU is secondary to high circulating homogentisic acid (HGA) and ochronosis. It is not known whether HGA is produced by or processed in the kidney in AKU. Data from AKU patients from four studies were merged to form a single AKU group. A control group of non-AKU subjects was generated by merging data from two non-AKU studies. Data were used to derive renal clearance and fractional excretion (FE) ratios for creatinine, HGA, phenylalanine (PHE) and tyrosine (TYR) using standard calculations, for comparison between the AKU and the control groups. There were 225 AKU patients in the AKU group and 52 in the non-AKU control group. Circulating HGA increased with age (P

Currently, effective pharmacologic treatment to reduce severe oral mucositis (OM) resulting from high-dose myeloablative cytotoxic therapy in the pediatric population is not available. Palifermin has been proven to decrease the incidence and duration of severe OM in adults with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT). In the pediatric population, however, data on palifermin treatment are limited. A phase I dose-escalation study of palifermin in pediatric patients with acute leukemias undergoing myeloablative HSCT with total body irradiation, etoposide, and cyclophosphamide was performed to determine a safe and tolerable dose and to characterize the pharmacokinetic (PK) profile and efficacy of palifermin. Twenty-seven patients in 3 age groups (1 to 2, 3 to 11, and 12 to 16 years) and 3 dose levels (40, 60, and 80 μg/kg/day) were studied. There were no deaths, dose-limiting toxicities, or treatment-related serious adverse events. Long-term safety outcomes did not differ from what would be expected in this population. PK data showed no differences between the 3 age groups. Exposure did not increase with increase in dose. The maximum severity of OM (WHO grade 4) occurred in 6 patients (22%), none of whom was in the 80-μg/kg/day dosing group. This study showed that all doses were well tolerated and a good safety profile in all 3 pediatric age groups was seen.

Nitisinone inhibits the cytochrome P450 (CYP) subfamilies CYP2C9, CYP2D6, and CYP2E1 and the organic anion transporter (OAT) isoforms OAT1 and OAT3 in vitro. Since the effect of nitisinone on these enzymes and transporters in humans is still unknown, the purpose of this study was to evaluate the effect of nitisinone on these CYP subfamilies and OAT isoforms. This was an open-label, nonrandomized, two-arm, phase 1 study (EudraCT: 2016-004297-17) in healthy volunteers. The substrates (tolbutamide, metoprolol, and chlorzoxazone for the respective CYPs and furosemide for the OATs) were administered as single doses, before and after 15 days of once daily dosing of 80 mg nitisinone, to determine the AUC∞ ratios ([substrate+nitisinone]/[substrate]). Nitisinone pharmacokinetics, safety, and tolerability were also assessed, and blood and urine were collected to determine substrate and nitisinone concentrations by LC-MS/MS. Thirty-six subjects were enrolled with 18 subjects included in each arm. The least square mean ratio (90% confidence interval) for AUC∞ was 2.31 (2.11–2.53) for tolbutamide, 0.95 (0.88–1.03) for metoprolol, 0.73 (0.67–0.80) for chlorzoxazone, and 1.72 (1.63–1.81) for furosemide. Clinically relevant nitisinone steady-state concentrations were reached after 12 days: mean Cav,ss of 94.08 μM. All treatments were well tolerated, and no safety concerns were identified. Nitisinone did not affect CYP2D6 activity, was a weak inducer of CYP2E1, and was a weak inhibitor of OAT1 and OAT3. Nitisinone was a moderate inhibitor of CYP2C9, and treatment may therefore result in increased plasma concentrations of comedications metabolized primarily via this enzyme. EudraCT 2016-004297-17.

Background: Although nitisinone is successfully used to treat hereditary tyrosinemia type 1 (HT-1) with the recommended twice-daily dosing, data describing a long half-life motivate less frequent dosing. Therefore, in agreement with the Pharmacovigilance Risk Assessment Committee at the European Medicines Agency, this study was performed to investigate the switch to once-daily dosing.

With changing demands, the need of clinical competence development for district nurses' and child health care nurses' must keep pace. The aim of this study was to develop a model to clarify the nurses' function and their academic and experience based knowledge and to show the development and career possibilities. Steering documents and other literature concerning competence were reviewed by a network of nurses. The material was amalgamated and resulted in a model for competence development. This is described in four levels from Basic Competence to Research Competence. The model can be seen as working material for personal and professional development and for initiating change. Competence development should be kept stimulated during the nurses' whole career. Finally both patients and units will benefit from competence development.

The aim of this study was to investigate from the perspective of formal carers the care given to people aged 65 and over, who are cared for in their own homes by informal care. Thirty-three district nurses (DNs) and 20 home service assistants in a municipality with 13500 inhabitants (over 65 years old), were interviewed about the location of care recipients and 398 care recipients were located. Most of them were over 80 years old and had more than one disease (62%), mostly related to the circulatory system (27%). Dependence in three or more of the Katz ADL categories was seen in 30%, reduced mobility in 67%, reduced memory in 34% to a degree that restricted their everyday life and 34% of them could seldom or never be alone. Care had been given for three years or more for 57% of these people. The monitoring of the disabilities and reduced functional health status differed significantly between the diagnostic groups. Home help service was associated with the care recipients' ADL index but not with their need for continuous monitoring. The DNs' care did not relate to any of the variables. In conclusion, diagnoses, the care recipients ability to be alone and functional health status are important variables to include when assessing the demands for home care and when planning supplementary care for home care recipients and their informal caregivers.

Oral mucositis, a severe complication during chemo- and/or radiotherapy, is prevented with palifermin treatment, a recombinant human keratinocyte growth factor (KGF/FGF-7). The FGF family belongs to the larger family of heparin-binding growth factors. Because it has been shown that heparin modulates binding of KGF to the KGF receptor and subsequently affects cellular proliferation induced by the KGF mitogenic signal, it is critical to understand the drug-drug interactions between palifermin and heparin, particularly because of heparin's narrow therapeutic margin. Two studies were performed in healthy subjects to characterize the effect of palifermin on the pharmacodynamics of heparin (activated partial thromboplastin time) and evaluate the impact of heparin on the pharmacokinetics and pharmacodynamics (Ki67 staining of buccal mucosal tissue) of palifermin. Results demonstrated a pronounced pharmacokinetic interaction; heparin coadministration increased the palifermin AUC 4- to 5-fold and decreased its half-life by 40%-45%, suggesting an approximate 70%-80% decrease in palifermin clearance and volume of distribution. These changes in the pharmacokinetics of palifermin during coadministration of heparin, however, did not affect the pharmacodynamic effect of palifermin, or the anticoagulant activity of heparin, and did not lead to increased safety findings. Therefore, these results suggest that dose adjustments for heparin and palifermin are not warranted when administered concurrently.

PurposeThe purpose of this paper is to give an overview of the concept of HRCA – human resource costing and accounting – and to encourage debate in this research area. The knowledge dimensions or research areas of HRCA could be described by using a simple model or classification scheme. The model could be seen as a way to describe the links between accounting and financial calculation in company development, a development characterized as the innovation of the intrinsic area in a company. The three articles in this issue are also introduced, with a short overview of each of them.Design/methodology/approachThe objective is achieved by a pure theoretical approach. The subject of the paper is to try to explain the existence of the people dimension in the two knowledge areas of “accounting” and “costing” and link them to the “external” and “internal” organizational perspectives. In the HRCA area the aim is to see and understand the common body for these two areas of research: how to make people more transparent in a company's business. This is referred to as the “people dimension”.FindingsIn the article a model is reported which the author has found to be helpful when discussing the people dimension in organizational innovation. The model is helpful if one wishes to study and understand the innovation work going on in the most intrinsic and traditional parts of a company, usually driven in the same way, by rules and traditions, year after year.Originality/valueThe contribution of the paper is that it introduces the concept of the “people dimension” as the common interest for those dealing with accounting or costing in the forefront of development. The paper is of value for those dealing with trying to understand why human and intellectual capital has not become more accepted as something to be made more transparent in accounting and costing.

This article is based on a content analysis of intellectual capital (IC) in annual reports from 1998 to 2002. The aim of the study was to compare the content of voluntary information on IC in the corporate annual reports covering a period of 4 years. The results from the study, based on 15 Swedish companies in the retail sector, show that for the year 2002 the information on human capital in the annual reports was, on average, 8.4% of the total text mass, with 14.9% pertaining to external capital, 21.2% to process capital and 7.4% about innovation capital. Further, the amount of IC information in 2002 increased when compared with the amount of information in 1998. The findings indicate that companies dealing with daily goods provide more information about IC in their annual reports than fashion companies.

In this paper a study of a career planning project launched by the Swedish National Tax Board is reported. The project, named Propeller, was initiated in 1998 as a joint endeavour among three agencies: the Swedish National Tax Board, the Regional Stockholm Tax Office and the Enforcement Authority. The intention was to create a common micro labour market in order to encourage employees to become more aware of their own development, as well as to create a competence exchange in and between the agencies, i.e. create greater mobility among the agencies. In this paper the focus is on the follow‐up study of the project. The program for career counselling contained at most eight hours of consultation over a period of six weeks to three months when the employee or Propellers “customer” met with an external consultant. The consultation should terminate with an action and time schedule that includes concrete steps to be taken to reach the specific goals set by the employee. The study is based on both a written questionnaire administered to 72 respondents and interviews with 46 persons who had finished the career‐counselling program during the first half‐year of the Propeller project. The results indicated that the model for career planning used by the Swedish National Tax Board was exceedingly effective and that all the goals of the project were successfully completed. In summary, the model was found to increase the mobility among the three agencies included in the Propeller project. The results showed that, by the end of the study, 43% (20 of 46) of those persons who used the program during the first year had already moved internally between departments within an agency or had changed affiliation from one agency to another. Additionally, 11 persons planned to change or move from their position to another sometime in the next few years. This rate of changing position or location implies that the mobility effect could be expected to become as high as 67%. The managers evaluated the project and felt that this sort of initiative for active career planning would increase the attraction of the agency on the labour market. Moreover, it implies a higher employability among those persons that took part in the evaluation. According to the managers, the relatively small sum of money used for the career planning project was seen as a good investment in personnel.

Alkaptonuria (AKU) is a serious genetic disease due to a defect in tyrosine metabolism, leading to increased serum levels of homogentisic acid (HGA). Nitisinone decreases HGA in AKU, but the concentration-response relationship has not been previously reported.To determine the relationship between serum concentrations of nitisinone and the effect on both HGA and tyrosine; secondly to determine steady-state pharmacokinetics of nitisinone in AKU patients.Thirty-two patients with AKU received either 1, 2, 4, or 8 mg nitisinone daily. Urine and serum HGA and serum tyrosine and nitisinone were measured during 24 h at baseline (before first dose) and after 4 weeks of treatment.Nitisinone pharmacokinetics (area under the curve [AUC] and maximum concentrations [C max]) were dose proportional. The median oral clearance determined in all patients, irrespective of dose, was 3.18 mL/h·kg (range 1.6-6.7).Nitisinone decreased urinary excretion of HGA in a concentration-dependent manner, with a maximum effect seen at average nitisinone concentrations of 3 μmol/L. The association between nitisinone and tyrosine concentrations was less pronounced. Serum levels of HGA at Week 4 were below the limit of quantitation in 65% of samples, which prevented determination of the relationship with nitisinone concentrations.Nitisinone exhibits dose-proportional pharmacokinetics in the studied dosage interval. Urinary excretion of HGA decreases in a concentration-dependent manner, while the increase in tyrosine is less clearly related to nitisinone concentrations.

Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650–85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.

Background Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied. Methods Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA 24 ) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone. Findings A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA 24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively. For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA 24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of nitisinone therapy. Conclusions In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range. Trial registration number EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463.

International audience; Objectives:Preterm infants often experience suboptimal growth, which can affect organ development. The aim of this study was to improve growth by treatment with bile salt–stimulated lipase (BSSL), naturally present in breast milk, but lost after pasteurization, and absent in formula.Methods:Two clinical trials were performed with a predefined analysis of combined data to investigate the effects of recombinant human BSSL (rhBSSL) treatment on growth velocity and fat absorption in preterm infants. The studies were randomized and double-blinded comparing 7-day treatment with rhBSSL and placebo, administered in pasteurized breast milk or formula, using a crossover design.Results:Sixty-three infants were evaluated for safety. At randomization, the mean (standard deviation) weight was 1467 (193) g and mean postmenstrual age was 32.6 (0.5) weeks. Sixty and 46 infants were evaluated for growth velocity and fat absorption, respectively. rhBSSL treatment significantly improved mean growth velocity by 2.93 g · kg−1 · day−1 (P

There are several ways to implement and work with the Balanced Scorecard (BSC). The company Ericsson Data AB was one of the pioneers in employing the BSC in Sweden. As early adopters, they were interested in obtaining an evaluation performed by external researchers. We were fortunate to have that opportunity. During the autumn of 1998, Majvor Karlsson and Ellen Sharma had full access to the developmental department dealing with the implementation of BSC at the company. The present article is based on interviews with managers and developers with the aim to determine how the BSC was implemented and how it functions in the day‐to‐day life of the company. The BSC model introduced in Ericsson was given the name Cockpit. As one might expect, implementing BSC requires a great deal of time and energy. We found that it resembles the process in other organisational changes as well. In our research, we found that there were many aspects of the implementation of BSC with which we could interpret and explain our observations with the help of theories of organisational change. Our findings led us to formulate a theory concerning the implementation process of the BSC. It was a relief to discover that we could use a method that allowed us to listen and learn from the persons involved in the implementation process at Ericsson Data.

In this article, the author discusses the implications of a 6+6‐hour model for the production economy of the Finnish Company Essilor Oy. The theory of returns to scale has been used to analyse the results of the change from one 8‐hour shift to the 6+6‐hour‐shift system. It is shown that the company Essilor attained a better production economy and increased profit by introducing a 6+6‐hour‐shift system in one of their departments. The operation time increased by 72%. The wages per month were unreduced and seven new persons were recruited.

In the beginning of 1990s preparations were underway in Sweden to enact a law aimed at making accounting on personnel in the annual reports compulsory. An official investigation resulted in a special report on how to design and report on it. The expectations and the discussions that followed resulted in considerable voluntary implementation of “personnel economics reports” or “human resources accounting reports” (HRA reports) in companies and municipalities. Preparations were made through education and training to acquaint people with the new procedure of reporting on personnel. The present article gives a description of one the most frequently used models of accounting on personnel elaborated during the 1990s in Sweden. In this article the experiences from a training programme with the aim of implementing this model for a group of hospital clinics, The Hospital Sector in Northwest of Stockholm, are described and analysed.

The increasing demand for more effective work procedures also affects work such that the entire 24h window is exploited for work and the work pattern ceases to be stable and predictable and instead becomes directly tailored to short term variation in production/service demand (termed “flexible ”). This results in increased night work, increased duration of shifts (often demanded by employees) and work hour fragmentation. We seem to know that night work and long hours are negative factors for health. However, summarizing a number of studies we find a need for reinterpretation. Thus, permanent night work may often be more acceptable than rotating hours, particularly if the night shift ends early. Long work shifts (12h) seemed to be preferable to normal (8h) ones, at least as long as not more than 2–3 shifts are worked in a row before rest and sleep was not interfered with. Furthermore, the ability to chose one’s shift schedule has strong positive effects. And, finally, reduced work hours with full pay has profound effects on social functioning, but very limited effects on health. The results suggest that influence on schedules and provisions for rest may improve most work schedules.

Objectives: The study examined the relation between daily workhours and the occurrence of neck-shoulder or back pain in physically demanding care work. Methods: Unpublished data were obtained from three intervention projects in care institutions. The projects had been conducted independently in Oslo (46 participants, 175 referents before and 158 referents after the intervention), Helsingborg (60 participants, 89 referents) and Stockholm (41 participants, 22 referents) between 1995 and 1998. The intervention was a reduction of daily workhours from ≥7 or more to 6 hours (or 30 hours weekly). Full-time salary was retained, and extra personnel were employed to compensate for the reduction in workhours. Data were collected by self-administered questionnaires before and during the intervention periods, lasting from 12 to 22 months. Results: The prevalence of neck-shoulder pain decreased from 40.9% to 25.6% in Oslo and from 57.1% to 39.1% in Helsingborg after 1.5 years with a 6-hour workday; for Stockholm the decrease was from 81.6% to 68.3% after 1 year. No decrease was observed in the reference groups. The prevalence of back pain did not show the same consistent pattern. Conclusions: The shortening of regular workdays from ≥7 hours to 6 hours may considerably reduce the prevalence of neck-shoulder pain among persons with physically demanding care work. The potential health benefits should encourage intervention studies also in other occupations with increased risk of work-related musculoskeletal disorders.

Background: Tolterodine is an antimuscarinic agent for the treatment of overactive bladder, a chronic condition that is particularly common in women. Given the prevalence pattern of overactive bladder and the widespread use of oral contraception, circumstances are likely to arise in which physicians may wish to prescribe tolterodine for patients already taking oral contraceptives. Based on a search of MEDLINE from 1990 to 2001, there have been no studies of whether concomitant use of these agents entails a risk of drug—drug interaction or conception. Objective: This study investigated the effects of tolterodine on the pharmacokinetics and pharmacodynamics of a low-dose combination oral contraceptive (ethinyl estradiol 30 μg/levonorgestrel 150 μg). Methods: This was an open-label, randomized, 2-period crossover study in healthy women. Oral contraception was given for 21 days either alone or in combination with oral tolterodine 2 mg BID (on days 1–14) over two 28-day contraceptive cycles. Pharmacokinetic assessments were performed on day 14 based on plasma levels of ethinyl estradiol and levonorgestrel up to 24 hours after dosing and serum tolterodine levels at 1 to 3 hours after dosing. The potential for pharmacodynamic interaction was assessed in terms of the risk of failure of suppression of ovulation based on serum levels of estradiol and progesterone measured throughout each cycle. Results: Twenty-four healthy women (age, 23–41 years [mean, 30 years]; height, 155–178 cm [mean, 167 cm]; body weight, 51–75 kg [mean, 64 kg]) participated in the study. There was no evidence of a pharmacokinetic interaction between tolterodine and the steroid hormones in the oral contraceptive used, nor did the oral contraceptive show any relevant pharmacokinetic interaction with tolterodine. Serum levels of estradiol and progesterone indicated suppression of ovulation in both treatment periods. Conclusion: In this selected population, coadministration of tolterodine did not affect the contraceptive efficacy of a low-dose combination oral contraceptive containing ethinyl estradiol and levonorgestrel.

To determine whether food intake influences the pharmacokinetics of a new, once daily, extended release (ER) capsule formulation of tolterodine in healthy volunteers, and to compare its bioavailability with that of the existing immediate release (IR) tablet.Open, randomised, 3-way crossover trial.17 healthy volunteers (3 females, 14 males) aged between 19 and 50 years. With the exception of 1 male volunteer, all participants were classified as extensive metabolisers by cytochrome P450 2D6 genotyping.Volunteers received single oral doses of tolterodine L-tartrate ER 8 mg (2 x 4 mg capsules) on an empty stomach or with a standardised high-fat breakfast. Reference therapy comprised tolterodine L-tartrate IR 4 mg (2 x 2 mg tablets), administered in the fasting state. Serum concentrations of tolterodine, its active 5-hydroxymethyl metabolite (5-HM) and the active moiety (sum of unbound tolterodine + 5-HM) were measured for up to 72 hours post-dose. Safety endpoints were also determined.No effect of food on the bioavailability of tolterodine ER capsules was apparent and there was no sign of dose-dumping with meals. The geometric mean fed:fasting ratio of area under the serum concentration-time curve to infinity (AUCinfinity) of the active moiety, for all volunteers combined, was 0.95 (90% confidence interval 0.88 to 1.03). Equivalence with respect to AUCinfinity (dose-corrected) was also found for the ER capsule compared with the IR tablet, although uncorrected maximum serum concentrations were around 50% lower despite the fact that the capsule dose was twice as high. Seven volunteers reported adverse events, predominantly headache. No volunteer reported dry mouth. Overall, there were no safety concerns.The new ER formulation of tolterodine shows no pharmacokinetic interaction with food. On the basis of these results, patients with overactive bladder may, therefore, be advised to take the drug without regard to the timing of meals, maximising convenience during therapy.

The objective of this study was to investigate the influence of food on the pharmacokinetics of tolterodine, its active 5-hydroxymethyl metabolite (5-HM), and exposure to the active moiety (sum of unbound tolterodine + 5-HM) in healthy volunteers. Serum concentrations of tolterodine and 5-HM were measured for up to 12 hours after a single oral dose (2 mg) of tolterodine L-tartrate, administered either on an empty stomach or with a standardized medium-fat breakfast. All 23 subjects completing the study were classified as extensive metabolizers (phenotyped with debrisoquine). Pharmacokinetic data on tolterodine and the active moiety were evaluable for 22 subjects; all completing subjects were evaluable for 5-HM pharmacokinetics. Based on Cmax and AUC(infinity) ratios, relative bioavailability of tolterodine in the presence of food was 1.49 (90% confidence interval [CI], 1.35-1.71) and 1.53 (1.35-1.72), respectively. The pharmacokinetics of 5-HM and the active moiety were unaffected by food, as were the rates of drug absorption and terminal half-lives of tolterodine and 5-HM. Given that bioequivalence was observed for the active moiety underfed and fasting conditions, the authors concluded that coadministration of tolterodine with food is not expected to have any clinically relevant effects.

The Swedish government decided in 1994, as part of the so‐called 50,000 Swedish crowns scheme, to set aside a portion of the labour market budget for the further training and retraining of local government and country council employees. The present article reports on the experiences of the training effort that took place in 1994–1995 and provides a theoretical framework for discussing staff training as an alternative to redundancies in the case of “economic overstuffing” and as part of a strategy for lifelong learning. Staff training and further development can be viewed as direct labour market measures instead of as redundancies. This article is based on a large empirical study in municipalities and county councils that have used these measures. In the study it was shown that these market measures can be defended both economically and humanly in the sense that both contribute to strengthening internal mobility and increasing the worker's adaptability to the external labour market. At the same time, this conform part of a strategy for a more flexible structuring of working time.

Seven strains of mycoplasma have been characterized by two-dimensional polyacrylamide gel electrophoresis in combination with immunoblotting. The two-dimensional patterns of the strains were compared and similarities and differences are discussed. Hyperimmune rabbit antisera were used in the immunoblotting experiment to study the immunological cross-reactivity between the species. Sera from goats, naturally and experimentally infected with mycoplasma, were also used in the immunoblotting experiment to study the immune responses of the infected animals.

The pharmacokinetics of iohexol, a new nonionic, water-soluble contrast medium, have been determined after intravenous injection in 20 healthy volunteers, at four different dose levels (125-500 mg I/kg). The apparent volume of distribution was 0.27 1/kg, indicating distribution in the extracellular water. The biologic half-life was 121 minutes, comparable with that of other intravascular contrast media. Iohexol was excreted completely unmetabolized in the urine, with a 100% recovery 24 hours after injection. A comparison of iohexol and chromium-51 (51Cr)-EDTA clearances indicates that iohexol is mainly excreted by glomerular filtration. The 51Cr-EDTA clearance was the same when injected separately and concomitantly with iohexol, indicating that glomerular filtration rate is not affected by iohexol. No dose dependency was observed in the investigated parameters t1/2 alpha, t1/2 beta, Vd, ClT or ClR. Iohexol pharmacokinetics are in correspondence with previously reported data on intravascular contrast media.

PhastSystem, an integrated system for horizontal electrophoresis and isoelectric focusing in small gels, including automated staining and destaining, is described. Buffers for electrophoresis are supplied to the gel from buffer strips made of agarose. The separation bed is cooled by Peltier elements. All conditions of significance to the results, both during separation and development, are controlled by a microprocessor. For separation, nine programs are available, each with 9 steps; for development, there are nine programs with 20 steps each. In this paper, we also report results using PhastSystem for purity checking and characterization of monoclonal antibodies after affinity chromatography and also for determining their digestion rate with papain.

The suitability for multiple dosing of two acetylsalicylic acid (ASA) preparations was compared in 8 healthy volunteers. During this study a marked decrease in serum salicylate concentrations with time was observed in 7 of the subjects. These results are presented here. On day 16 of medications, levels were 60-80 % of those on day 6. On day 38, when the study was discontinued, the levels had fallen to 50-65% of the values on day 6. The decrease in salicylate concentrations is probably due to induction of the salicyluric acid formation, one of the saturable pathways of salicylate elimination. Because of a narrow therapeutic range and large interindividual differences in salicylate concentrations with the same dose, determination of serum salicylate levels is an important tool in the adjustment of optimum individual ASA therapy. Our findings further emphasize this fact. They indicate that serum salicylate determinations should preferably be repeated a few times after initiation of ASA therapy.

An improved procedure, "thermoblotting", is described for transferring proteins by diffusion from PhastGel Gradient media to an immobilizing matrix after horizontal sodium dodecyl sulfate-polyacrylamide gel electrophoresis. After electrophoresis the gels were left on the separation bed of PhastSystem, the blotting matrix was applied and a transfer temperature was selected between 5-70 degrees C. An experimental series at fixed diffusion times showed that the transfer yield was significantly increased with temperature. The evaluation was done visually after staining of the blots with colloidal gold. An evaluation study comparing nitrocellulose, nylon, and polyvinylidenedifluoride of different pore sizes is also reported. Finally, the transfer efficiencies for 125I-labelled bovine serum albumin and soybean trypsin inhibitor were estimated using four different blotting procedures: two diffusion blotting techniques and two electrophoretic blotting techniques (tank vs. semi-dry).

The absorption of iohexol from the subarachnoid space was studied in 9 patients. Serum concentrations of iohexol were measured for a minimum of 24 hours after injection. Peak serum concentrations were observed after 2.2 (1.7–2.7) hours. The half-life of the subsequent decrease in serum concentrations was 3.4 (2.2–7.9) hours. Concentrations of iohexol in cerebrospinal fluid were 0.29–4.3 mg I/ml 24 hours after injection (7 patients). Serum and cerebrospinal fluid concentrations of iohexol are comparable to those found after intrathecal injection of metrizamide.

Four cases of adenocarcinoid of the appendix were studied. Two tumours were found among 28 cases primarily diagnosed as appendiceal carcinoids. They showed characteristic histological structures with features of both a conventional carcinoid tumour and a mucinproducing adenocarcinoma with goblet cells. All tumours were small and ill-defined; three were associated with fibrous obliteration of the appendiceal lumen. All were diagnosed incidentally by the pathologist in appendices removed “en passant” or because of acute appendicitis. Three of the tumours appeared well differentiated with a low degree of malignancy similar to that of the conventional carcinoid tumour. In one case however, the tumour was less differentiated with atypical foci and a high mitotic count and had metastasised to peritoneum and both ovaries.

To investigate whether the personal attention paid to a patient can affect his or her subjective recovery from acute tonsillitis, a controlled study was performed on 100 patients consulting a doctor for this disease. At the consultation a randomly assigned experimental group (n = 50) was given more detailed information about the diagnosis, treatment and prognosis and also a more extensive physical examination than a control group (n = 50). At a follow-up interview two days later significantly more of the experimental group felt that their symptoms had improved (P less than 0.005) than the control group, significantly more felt that the treatment had helped them (P less than 0.005) and significantly more felt they had received sufficient information about their illness and treatment (P less than 0.001). A deliberate attempt to maximize the expectation effect was thus shown to influence the clinical course of acute tonsillitis, recorded as the degree of subjective improvement.