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.

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.

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.

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.

Ceramide inhibition of mammalian phospholipase D1 and D2 activities is antagonized by phosphatidylinositol 4,5-bisphosphate.

Ceramides inhibit phospholipase D (PLD) activity in several mammalian cell types. These effects have been related to preventing activation by ARF1, RhoA, and protein kinase C-alpha and -beta and therefore indicate that PLD1 is inhibited. In the present work, we investigated the effects of ceramides in inhibiting both PLD1 and PLD2 and the interaction with another activator, phosphatidylinositol 4,5-bisphosphate (PIP2). PLD1 and PLD2 were overexpressed separately in Sf9 insect cells using baculovirus vectors. In our cell-free system, PLD1 activity was inhibited completely by C2-ceramide at sub-optimum concentrations of PIP2 (3 and 6 microM), whereas at supra-optimum PIP2 concentrations (18 and 24 microM) C2-ceramide did not inhibit PLD1 activity. Partially purified PLD2 exhibited an absolute requirement for PIP2 when the activity was measured using Triton X-100 micelles. Ceramides inhibited PLD2 activity, and this inhibition was decreased as PIP2 concentrations increased. However, C2-ceramide also reversibly inhibited the activity of PLD1 and PLD2 mutants in which binding of PIP2 was decreased, indicating that ceramides are interacting with the catalytic core of the mammalian PLDs. By contrast, C2-ceramide failed to produce a significant inhibition of PLDs from bacteria and plants. Our results provide a novel demonstration that ceramides reversibly inhibit mammalian PLD2 as well as PLD1 activities and that both of these actions are more pronounced when PIP2 concentrations are rate-limiting.

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.

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.

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.

Postoperative mental impairment in hip fracture patients. A randomized study of reorientation measures in 223 patients.

Mental impairment is a common and serious complication in geriatric surgery. We studied 223 hip fracture patients. They were over 64 years of age (mean 81), with no history of mental deterioration and acutely admitted to hospital from independent living conditions. They were randomized into two groups. One of these was subjected to reorientation measures during the perioperative phase, i.e., presurgery admission to the orthopedic ward, accompanied home visits during the hospital stay and access to reorientation devices--they received a large clock, calendar, radio, TV-set, telephone and were encouraged to wear their own clothing. Otherwise, there were no differences in the treatment given to the two groups. We used monitoring of cognitive function with the Short Portable Mental Status Questionnaire (SPMSQ) and a feedback program for evaluation of the treatment results. There was a low incidence of postoperative cognitive deterioration in both groups, compared with historical controls. However, no difference in mental status was noted when we compared the two groups. The conclusion is that attributes were less important than the psychological environment for postoperative mental deterioration. The mean total continuous hospitalization (transfers between departments and hospitals included) in the reorientation group was 22 (95% CI: 17-43) days, the corresponding figures for the controls were 30 (14-29) days.

Continuity, assessment and feedback in orthopaedic nursing care practice is cost-effective.

Hip fracture treatment and rehabilitation are often considered as separate issues and generally performed in different locations. The rapidly increasing proportion of patients that is old and very old now calls for a new approach. This is a prospective study of 909 consecutive hip fracture patients, over 64 years old, admitted to hospital from an independent living situation. In a specialized hip fracture unit, 256 patients were given an early and intense rehabilitation program. It focused on continuity, feedback, reorientation and continuous monitoring of cognitive function and activities of daily living (ADL). Eighty-five percent of the patients could return directly to their own home after the initial treatment period. The mean total utilization of health care resources during the first 4 months after the injury was lower (28 institutional days) than in 286 historical controls given conventional rehabilitation (39 days, p < 0.05). At 4 months, 81% of the patients still lived in their own home vs. 72% of the controls and the 1-year mortality was 14% (21% in the controls, p < 0.05). After the project had been completed 297 patients formed an additional control group. In this group the proportion discharged to their own home decreased to 44% and the number of bed-days during the first 4 months returned to the pre-study level (39 days). It thus appears to be cost-effective to allocate sufficient rehabilitation resources early in the treatment of elderly patients with hip fractures. Annual savings in the catchment area due to the intervention were calculated to approximately 5,000,000 SEK. Continuous assessment and adequate continuity gives the staff emotional feedback, which promotes their personal commitment.

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.

Prospective payment systems and hip fracture treatment costs.

We studied the health care consumption and costs after a hip fracture in 1,060 and 1,178 elderly patients admitted from their own home before and after the implementation of a prospective payment system in Stockholm. The total number of bed-days was estimated by merging the inpatient database and the municipal records of living accommodations for the elderly. By using a detailed patient-related accounting system and separating cost for surgery and "hotel" cost, we could compare costs in different types of rehabilitation. After the change in reimbursement system, the orthopedic stay was almost halved from 20 to 12 days. This was achieved by earlier and increased discharge to geriatric wards, where bed-day consumption doubled (107%), so that the total cost actually increased by 12%. This is not readily apparent from the official heath care statistics, which depict a more favorable cost development, as diagnosis-related registration for a large part of the geriatric care is no longer included. In contrast, a rehabilitation program in one of the acute hospitals, emphasizing continuity in the postoperative phase, reduced the total cost for treatment and rehabilitation by 12%. A prospective reimbursement aiming at reducing the costs of acute care does not necessarily result in overall savings.

The cost of a hip fracture. Estimates for 1,709 patients in Sweden.

We calculated the costs related to hip fractures and estimated the potential cost savings from preventing hip fractures. Subjects for this retrospective study were 1,709 hip fracture patients admitted for a primary hip fracture during 1992 in Stockholm, Sweden. Direct costs were compiled for the services of hospital orthopedics, hospital geriatrics, nursing homes, home for the elderly, group living, other acute hospital care, and municipal home help. The direct costs per patient during 1 year after a fracture amounted to about USD 40,000. The county council was responsible for 59% of the direct costs during 1 year after a hip fracture, while the remaining 41% were referred to the municipality. In the morbidity group, the potential cost savings per patient from preventing hip fractures was about USD 22,000.

The appearance and disappearance of cognitive impairment in elderly patients during treatment for hip fracture.

We studied the natural course of cognitive state in 256 consecutive hip fracture patients who were admitted from an independent living situation. We employed a treatment programme that focused on preventing postoperative cognitive impairment. Cognitive function was assessed with the SPSMQ screening test. The incidence of postoperative cognitive impairment among those lucid on admission was 13%, which generally was reversed before discharge. Thirty-seven percent were cognitively impaired on admission; of those, 51% reached normal test scores while in hospital. Those who recovered within the first week had as good a prognosis during the first year as those who remained lucid throughout the hospital stay. Cognitive impairment was associated with an increased complication rate, e.g. a three-fold increase of early fracture displacement and a four-fold increase of wound infection. This increased risk was present even in patients with mild/moderate cognitive impairment and could not entirely be explained by age. Our results suggest that it is possible to decrease postoperative cognitive impairment by routine monitoring of cognitive status, a high level of continuity and a reorientation programme. The routine assessment of the cognitive function is recommended in geriatric patients who are admitted for surgery.

Decreasing admissions for childhood asthma to a Swedish county hospital.

Hospital admission rates for childhood asthma have increased in many countries. To study if this is also true for Norrköping Hospital, paediatric admission rates for asthma every fifth year were examined for the period 1973 to 1993. Admission rates were found to have fallen over the last 10 years, especially in children of school age. Among the younger age groups (below 5 years of age) a fall in admission rates was also observed over the last 5 years. This fall occurred in spite of reported increases in the prevalence of childhood asthma. The relative risk for admission due to asthma thus decreased from 1 in 1973 to 0.09 in 1993. The readmission rate has been stable. The mean length of stay in hospital for asthma decreased significantly. The observed decreasing trend in hospital admissions for childhood asthma is contrary to that found in many other countries. Possible explanations are discussed.

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.

Atopic allergy and delayed hypersensitivity in children with diabetes.

The prevalence of atopy was studied in 61 children with type I insulin-dependent diabetes mellitus (IDDM) and 72 age- and sex-matched control subjects. The two groups had a similar prevalence of atopic disease and did not differ significantly with respect to history, clinical findings, skin prick test results, total serum IgE levels, or presence of circulating IgE antibodies to allergen. We also studied delayed-type hypersensitivity reactions in 37 of the children with IDDM and 46 of the control subjects. Children with IDDM, as compared with those without IDDM, more often had other autoimmune diseases in their family histories (p < 0.01). They also had significantly stronger delayed hypersensitivity reactions than the control subjects, as determined with tetanus toxoid (p < 0.05) and mumps antigen (p < 0.01). The reactivity to purified protein derivate of tuberculin and Candida antigen was similar in the two groups. The study does not confirm previous suggestions of an inverse relationship between IDDM and atopic disease but does not confirm previous suggestions of an inverse relationship between IDDM and atopic disease but does confirm that IDDM is associated with other immunologic disturbances. The different genetic and immunologic traits do not prevent allergic manifestations in children with diabetes.

Nedocromil sodium 2% eye drops for twice-daily treatment of seasonal allergic conjunctivitis: a Swedish multicentre placebo-controlled study in children allergic to birch pollen.

This was a multicentre, double-blind, randomized group comparative study in which 77 children, aged 6-16 years, received 2% nedocromil sodium eye drops and 72 received placebo, one drop into each eye twice daily. The treatment period was 4 weeks, covering the peak birch pollen season. Prior to the start of the season, patients who had attended the clinic the previous 2 years because of seasonal allergic conjunctivitis (SAC) to birch pollen, entered a one week baseline period during which symptoms were assessed, dairy cards completed, and routine sampling of blood and urine carried out. The double-blind treatment period then commenced at the onset of the birch pollen season. Patients/parents kept daily diary record cards of eye symptom severity and concomitant therapy. Conjunctivitis was mild in both treatment groups but nedocromil sodium was more effective than placebo in controlling symptoms. During the 2-3 weeks of peak pollen counts, this therapeutic effect was statistically significant for itching (P < 0.01), watering (P < 0.05) and total symptom score (P < 0.01), but was not significant for grittiness (P = 0.08) or redness (P = 0.06). Global opinions of efficacy showed no difference between treatments, due to a high placebo effect (however, the diary card data indicated a significant improvement with nedocromil sodium). We therefore conclude that nedocromil sodium 2% eye drops, administered twice daily, is an effective treatment for SAC in children.

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.

Enhancement of bone formation in rabbits by recombinant human growth hormone.

We studied the effect of human recombinant growth hormone on diaphyseal bone in 40 adult rabbits. The diaphyseal periosteum of one femur in each animal was mechanically stimulated by a nylon cerclage band. The bands induced an increase in bone formation, bone mineral content, and maximum torque capacity of the diaphyseal bone at 1 and 2 months. Growth hormone enhanced the anabolic effect of the cerclage bands on bone metabolism, evidenced by a further increase in torsional strength of the femurs.