Lipid phosphate phosphatase-1 dephosphorylates exogenous lysophosphatidate and thereby attenuates its effects on cell signalling.

The serum-derived phospholipid growth factor, lysophosphatidate (LPA), activates cells through a family of G-protein-coupled EDG receptors. The present article examines the role of lipid phosphate phosphatase-1 (LPP-1, or phosphatidate phosphate 2A) in regulating cell activation by LPA. Overexpressing LPP-1 approximately doubled the rate of dephosphorylation of exogenous LPA by Rat2 fibroblasts. The amount of LPA dephosphorylation was restricted to less than 10% of the total exogenous LPA. Over-expression of LPP-1 attenuated cell activation as indicated by diminished responses including cAMP, Ca2+, activation of phospholipase D and ERK, DNA synthesis and cell division. LPP-1 therefore provides a novel level of regulation for controlling cell signalling by exogenous LPA.

Efficacy of once-daily versus twice-daily administration of budesonide by Turbuhaler(R) in children with stable asthma.

We evaluated the efficacy of once-daily versus twice-daily treatment with budesonide, delivered by a Turbuhaler(R), in the management of children with stable asthma in a randomized, double-blind, parallel-group study involving 206 children (age 5-15 years). After a 2-week run-in period during which the children were maintained on their usual dose of budesonide (200 microg or 400 microg/day), patients were randomized to receive the same daily dose in either two daily administrations (morning and evening) or as a single dose in the morning over a period of 12 weeks. The primary efficacy variable was morning peak expiratory flow (PEF). The mean morning PEF during the run-in phase was 271 L/min in patients randomized to once-daily treatment and 264 L/min in those randomized to twice-daily treatment. The mean change from baseline to the last 2 weeks of the treatment period in the two groups was -0.3 L/min (95% confidence limits -6.6 to +6.0) and 2.5 L/min (-4.3 to +9.3). The estimated difference between the groups was -2.8 L/min, with 90% confidence limits of -10.4 + 4.5; these were close to the limits regarded as indicative of equivalence (-10 to +10), and hence the difference was not regarded as clinically relevant. Similarly, there were no significant differences between the groups in regard to secondary efficacy measures such as spirometric tests and symptom scores. Both treatments were well tolerated. We conclude that once-daily administration of budesonide by Turbuhaler(R) is as effective as twice-daily treatment in the management of stable asthma in children treated with inhaled steroids at doses of 200-400 microg/day.

Induced cervical ripening with Mifepristone in first trimester abortion. A double-blind randomized biomechanical study.

Mifepristone (RU 486; Roussel-Uclaf, Paris, France) is an antiprogesterone used for termination of very early pregnancy. The ripening effect of Mifepristone on the human pregnant cervix was studied in 42 healthy women from 7 to 11 weeks gestation. The women were randomly allocated to oral treatment of either 100 mg Mifepristone or placebo for 24 and 12 hours before vacuum aspiration. An objective method has been designed to measure the force necessary to step-wise dilate the cervix from 4 to 11 mm. Significant (p less than 0.05) changes in the stiffness of the cervix were demonstrated in patients treated with Mifepristone, reflecting ripeness. The treatment was simple and had no side effects.

Prediction of the outcome after hip fracture in elderly patients.

We report a prospective study of 232 consecutive patients with hip fractures. All were over 64 years of age and living independently before admission to a geriatric orthopaedic ward. We assessed the value, at admission, of predicting factors for independent living at one year after injury. The most important factors were: (1) preinjury function in activities of daily living (grade A or B on the Katz et al (1963) scale); (2) absence of other medical conditions which would impair rehabilitation; and (3) cognitive function better than 7 on the Pfeiffer (1975) mental questionnaire. The odds ratios (95% CI) for these three predictors were 3.5 (1.3 to 9.1), 2.9 (1.3 to 6.1) and 2.4 (1.9 to 4.9), respectively. When all predictors were positive at admission, 92% were living independently at one year; with one, two or three negative predictors, the percentages living independently were 76, 61 and 27, respectively. The median values of the total number of days in hospital, irrespective of diagnosis, during the first year were 12, 24, 29 and 149 days for the four groups. The mortality at one year was predictable on admission only by the number of medical conditions: with no other diagnosis than the fracture the mortality was 0%; with one or two additional conditions the mortality was 14%; and with three or more additional diagnoses it was 24%. These simple and robust predictors can be used to optimise resources for rehabilitation.

Heroin impurity profiling. A harmonization study for retrospective comparisons.

Three laboratories present a harmonised system for the retrospective comparison of south west Asian heroin. It consists of an improved gas chromatographic (GC) profiling method and a computerised data retrieval. The investigations of the GC were necessary with a view to improve the reproducibility of the system. The necessity of a strict quality control is emphasized. The peaks of the GC profile were investigated for abundance, intensity, GC behaviour (reproducibility) and correlations; 16 of them were selected for describing the heroin profile in the database. The results from intra-lab profile comparisons are reported. The reproducibility of the analysis was good and the variation between the samples was large, thus, allowing conclusions with a high degree of certainty. The criteria of similarity were defined. The system is successfully running in all three labs. In connection with inter-laboratory comparison, the aspects of method harmonisation and standardisation are discussed. It appeared that the GC method is a very subtile one, urging for a strict standardisation between the three labs. Despite a long cooperation between three well-equipped and experienced labs, a more or less serious loss of reproducibility was noticed in the inter-lab results in comparison with the intra-lab results. The loss could for the greater part be attributed to the (limits of the) GC technique; a number of compounds, necessary for making the discrimination between samples, showed difficult chromatographic behaviour, leading to insufficient inter-lab reproducibility. Using the actual variables, improvements in performance can hardly be expected in the near future. The loss of reproducibilty implies that the number of false positive matches in a database search increases. This may strongly reduce the value of a relatively large, international database. The study shows that so far, the best option for international comparison is the analysis in a central laboratory. The idea of local determination at a large number of national labs and the use of a common database is not a realistic aim for this type of analysis.

Bone and cartilage formation in an experimental model of distraction osteogenesis.

OBJECTIVES: (a) To develop a reliable and reproducible system for distraction osteogenesis in the rat to establish a model for future investigations of bone repair and regeneration. (b) To describe and characterize the histological events in distraction osteogenesis in the rat and to determine whether cartilage development is a normal component of the process. STUDY DESIGN: Species-specific, longitudinal time study. METHODS: Twenty rats underwent production of a middiaphyseal femoral osteotomy and application of a monolateral external fixator specifically designed for distraction. Animals were divided into five groups based on the time and extent of lengthening. RESULTS: During distraction, gap tissue showed collagen bundles and fibroblasts that were oriented longitudinally to the direction of the distraction force. Woven bone appeared to be laid down on these collagen scaffolds, and the newly formed vascular sinuses appeared to be the sites from which bone formation was initiated within the distraction gap. All groups undergoing active distraction showed intramembranous ossification in the distraction gap and endochondral ossification peripherally. However, when distraction was discontinued, endochondral ossification was observed in the gap. CONCLUSION: Distraction produces an environment in the distraction gap that suppresses the formation of cartilage. The formation of cartilage by injured periosteum, however, is obligatory and does not appear to be influenced by distraction. Bone formation within the distraction gap occurs where angiogenesis develops.

Treatment of chronic leg ulcers with a hydrocolloid dressing.

The effects of a hydrocolloid dressing (Comfeel Ulcus) on the physical environment of chronic leg ulcers in 58 consecutive out-patients were investigated. Patients were subdivided into two groups of which Group 1 included 31 (53.4%) and Group 2, 27 (46.6%) patients. Twenty-three (39.7%) patients healed within 7 weeks (study period) and 49 (84.5%) within 1 year (follow-up period). Aerobic and anaerobic bacterial cultures as well as mycotic cultures were performed from ulcer bases of both groups of patients. In Group 1 a 3 mm punch biopsy was taken from the ulcer margins for histopathological examination. In Group 2 serum levels of iron, zinc, copper and selenium were measured and in these latter patients a mean temperature difference of 2.8 degrees C between the ulcer base and the skin surrounding the ulcer was found. There was no difference in ulcer pH in patients belonging to Group 2, independent of bacterial or fungal contamination. Low serum iron was found in 74.1% and anaemia in 40.7% of the patients in Group 2. No differences in ulcer healing were seen in these patients compared with those without iron-deficiency or anaemia. No differences were seen in serum iron, zinc, copper or selenium levels between good and poor healers. There were 22.2% ulcer relapses in Group 1 within a year of the start of the study, with no relapses in those 15 patients of Group 2 who used specially designed compression stockings.

Computer aided retrieval of common-batch members in Leuckart amphetamine profiling.

Comparison of profiles is a well established way to find links between confiscated drugs. It is a laborious and time consuming task to manually compare large numbers of profiles to find common-batch links. To facilitate the comparison a computerized method has been developed. It is described and applied to a set of amphetamine impurity profiles. From each profile, areas of selected peaks are fed to the computer. By using quotients of corresponding peaks, the computer finds pairs of closely related profiles. With a sufficient numbers of peaks, the method is tolerant to variations in intensity between profiles, random peak area variations and a few strongly deviating peak areas. The program was written in Q-basic from Microsoft and may be run on any IBM-compatible personal computer. The method may also be used for analyzing data from other forensic objects, when the descriptors chosen are affected by errors like those described in the text.

Bodyloading on atrophied bone and bone mineral content. An experimental study in the rabbit.

The quality of a cortical bone, as reflected in the bone mineral content, has been studied in rabbit tibiae during an experimental atrophy process, and following recovery and adaptation to increased loading. Atrophy of the bone was induced by a rigid internal fixation plate applied to the tibia for 12 weeks. During the process of recovery after the plate had been removed, the bone mineral content was studied by means of an ashing procedure. The bone mineral content per unit volume cortical bone remained unchanged both at maximum atrophy and during the subsequent process of recovery.

The influence of nylon cerclage on diaphyseal bone strength: an experimental evaluation of Partridge bands on rabbits.

Partridge-designed nylon bands which are used for the cerclage of fractured osteoporotic bones. These bands were given elevations on their inner surfaces to raise the band from the bone surface and thus minimize the negative effects on the periosteal blood circulation. It has previously been shown that the Partridge bands, when applied to a diaphyseal bone, cause a mechanical irritation to the periosteum resulting in an increased callus formation by comparison with the case when corresponding bands with no elevations are applied. It has been suggested that the increased amount of callus would result in increased strength. We have studied the effect of bands designed in accordance with Partridge, compared with corresponding bands having no elevations, in terms of torsion strength (maximum torque capacity), on intact rabbit femora. The results show an increased torsion strength in the femora to which Partridge bands had been applied for eight weeks, while the femora to which corresponding plain nylon bands had been applied had decreased in strength. The experimental study performed supports Partridge's recommendation to use the bands as cerclage in the internal fixation of fractured osteoporotic bones, preferably in combination with further internal fixation materials.

Intramedullary reaming and nailing: its early effects on cortical bone vascularization.

The early effect of reaming the medullary cavity prior to intramedullary nailing using Küntscher's method, on human cortical bone vascularization in the femur is discussed. In sections of the femur where the medullary tissue had been totally reamed, the inner two-thirds of the cortical bone tube was completely avascularized one week after the reaming. In the outer third of the cortex the vascularization was only moderately decreased. In the parts of the femur where the medullary tissue was not totally destroyed there was a marginal effect on the amount of intact cortical vessels. The observation is thus in accordance with corresponding results from experimental studies on animals. Microcracks, and cracks in the cortical wall, caused by the reaming and procedure are also described in the article.

The effect of athletic activity on the bone mass in human diaphyseal bone.

Both humeri of seven professional tennis players and seven controls were examined with x-ray spectrophotometry, and computed tomography. Both the bone mineral content and the cortical cross-sectional area were found to be larger in the dominant arm of the tennis players than in their non-dominant arm, and in comparison to both arms of the controls. The increase in cortical cross-sectional area was a result of an increased outer diameter of the diaphysis.

Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk.

The aim of this study was to compare the frequency of human leukocyte antigen (HLA) genotypes in 1-18-year-old patients with type 1 diabetes newly diagnosed in 1986-1987 (n = 430), 1996-2000 (n = 342) and in 2003-2005 (n = 171). We tested the hypothesis that the HLA DQ genotype distribution changes over time. Swedish type 1 diabetes patients and controls were typed for HLA using polymerase chain reaction amplification and allele specific probes for DQ A1* and B1* alleles. The most common type 1 diabetes HLA DQA1*-B1*genotype 0501-0201/0301-0302 was 36% (153/430) in 1986-1987 and 37% (127/342) in 1996-2000, but decreased to 19% (33/171) in 2003-2005 (P \ 0.0001). The 0501-0201/0501-0201 genotype increased from 1% in 1986-1987 to 7% in 1996-2000 (P = 0.0047) and to 5% in 2003-2005 (P > 0.05). This study in 1-18-year-old Swedish type 1 diabetes patients supports the notion that there is a temporal change in HLA risk.

SUMO4 M55V polymorphism affects susceptibility to type I diabetes in HLA DR3- and DR4-positive Swedish patients.

SUMO4 M55V, located in IDDM5, has been a focus for debate because of its association to type I diabetes (TIDM) in Asians but not in Caucasians. The current study aims to test the significance of M55V association to TIDM in a large cohort of Swedish Caucasians, and to test whether M55V is associated in those carrying human leukocyte antigen (HLA) class II molecules. A total of 673 TIDM patients and 535 age- and sex-matched healthy controls were included in the study. PCR-RFLP was performed to identify the genotype and allele variations. Our data suggest that SUMO4 M55V is not associated with susceptibility to TIDM by itself. When we stratified our patients and controls based on heterozygosity for HLA-DR3/DR4 and SUMO4 genotypes, we found that presence of SUMO4 GG increased further the relative risk conferred by HLA-DR3/DR4 to TIDM, whereas SUMO4 AA decreased the risk. From the current study, we conclude that SUMO4 M55V is associated with TIDM in association with high-risk HLA-DR3 and DR4, but not by itself.

IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5.

In a large case-control study of Swedish incident type I diabetes patients and controls, 0-34 years of age, we tested the hypothesis that the GIMAP5 gene, a key genetic factor for lymphopenia in spontaneous BioBreeding rat diabetes, is associated with type I diabetes; with islet autoantibodies in incident type I diabetes patients or with age at clinical onset in incident type I diabetes patients. Initial scans of allelic association were followed by more detailed logistic regression modeling that adjusted for known type I diabetes risk factors and potential confounding variables. The single nucleotide polymorphism (SNP) rs6598, located in a polyadenylation signal of GIMAP5, was associated with the presence of significant levels of IA-2 autoantibodies in the type I diabetes patients. Patients with the minor allele A of rs6598 had an increased prevalence of IA-2 autoantibody levels compared to patients without the minor allele (OR=2.2; Bonferroni-corrected P=0.003), after adjusting for age at clinical onset (P=8.0 x 10(-13)) and the numbers of HLA-DQ A1*0501-B1*0201 haplotypes (P=2.4 x 10(-5)) and DQ A1*0301-B1*0302 haplotypes (P=0.002). GIMAP5 polymorphism was not associated with type I diabetes or with GAD65 or insulin autoantibodies, ICA, or age at clinical onset in patients. These data suggest that the GIMAP5 gene is associated with islet autoimmunity in type I diabetes and add to recent findings implicating the same SNP in another autoimmune disease.

Diagnostic accuracy of the atopy patch test and the skin-prick test for the diagnosis of food allergy in young children with atopic eczema/dermatitis syndrome.

AIM: To evaluate the diagnostic value of the skin-prick test and the atopy patch test in diagnosing basic food allergy in young children suffering from atopic eczema/dermatitis syndrome. METHODS: 141 children, the majority under 2 y of age (mean 16 mo) with atopic eczema/dermatitis syndrome were investigated using skin-prick and atopy patch tests for milk, egg, wheat and rye. Open diagnostic elimination challenge was done since this has been reported to be a reliable method in young children. RESULTS: A positive challenge response was found to milk in 63 (45%), egg in 78 (55%), wheat in 61 (43%) and rye in 61 (43%). Sensitivity/specificity of the atopy patch test was 60%/97% for milk, 71%/97% for egg, 90%/94% for wheat and 93%/90% for rye. For the skin-prick test the corresponding figures were 41%/99%, 60%/97%, 13%/98% and 15%/99%. CONCLUSION: Patch testing was found to be a more sensitive method than the skin-prick test in diagnosing food allergy in children with atopic eczema/dermatitis syndrome, especially in those under 2 y of age. Many children with a negative skin-prick test result have a positive patch test result, especially in the case of cereals. A diagnosis of food allergy should be confirmed by elimination and in the research setting also by challenge.