Voluntary early retirement and mortality in patients with and without chronic diseases: a nationwide Danish Registry study.

OBJECTIVE: This study explores how the choice of voluntary early retirement (VER) affects mortality in a population where VER is available 5 years before regular retirement age. STUDY DESIGN: This retrospective cohort study uses a registry-based follow-up design with access to Nationwide Danish Registry Data. METHODS: The study includes all Danish individuals who between 2000 and 2015 were part of an unemployment insurance fund and working at the time of their 60th (P60) or 62nd (P62) birthday. Those alive 1 year from their 60th or 62nd birthday were included in the mortality analysis. Individuals were registered as VER recipients if they chose the benefit within 1 year from P60 or P62. Three-year mortality likelihood following the first year from inclusion was explored for both cohorts separately. Multiple subgroups were explored in the mortality analysis, including individuals with chronic obstructive pulmonary disease (COPD), heart failure, and diabetes. RESULTS: P60 included 627,278 individuals, and VER was chosen by 22.5%. P62 included 379,196 individuals, and VER was chosen by 33.4%. The likelihood of VER in the P60 was lower in healthy individuals (odds ratio [OR] 0.87, confidence interval [CI] 0.85-0.88) and higher in COPD (OR 1.15, CI 1.07-1.22) and heart failure patients (OR 1.15, CI 1.05-1.25). Three-year mortality was significantly higher in those choosing VER in P60 (OR 1.28, CI 1.22-1.34), which was also found for all health subgroups (healthy, OR 1.18, CI 1.07-1.30; COPD, OR 1.55, CI 1.16-2.07; heart failure, OR 1.42, CI 1.02-1.98; diabetes, OR 1.36, CI 1.12-1.65). The increased mortality risk was not found in the P62 cohort. CONCLUSION: The choice of VER is more likely in patients with COPD and heart failure. VER in the P60 cohort is associated with an increased mortality likelihood, which was not found in the P62 cohort, which may be explained by health selection bias.

The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015.

Since the year 2000, a concerted campaign against malaria has led to unprecedented levels of intervention coverage across sub-Saharan Africa. Understanding the effect of this control effort is vital to inform future control planning. However, the effect of malaria interventions across the varied epidemiological settings of Africa remains poorly understood owing to the absence of reliable surveillance data and the simplistic approaches underlying current disease estimates. Here we link a large database of malaria field surveys with detailed reconstructions of changing intervention coverage to directly evaluate trends from 2000 to 2015, and quantify the attributable effect of malaria disease control efforts. We found that Plasmodium falciparum infection prevalence in endemic Africa halved and the incidence of clinical disease fell by 40% between 2000 and 2015. We estimate that interventions have averted 663 (542-753 credible interval) million clinical cases since 2000. Insecticide-treated nets, the most widespread intervention, were by far the largest contributor (68% of cases averted). Although still below target levels, current malaria interventions have substantially reduced malaria disease incidence across the continent. Increasing access to these interventions, and maintaining their effectiveness in the face of insecticide and drug resistance, should form a cornerstone of post-2015 control strategies.

Granulocyte-monocyte adsorptive apheresis in pediatric inflammatory bowel disease: results, practical issues, safety, and future perspectives.

BACKGROUND: The purpose of the study was to collect data on granulocyte-monocyte adsorptive apheresis (GMA) for the treatment of corticosteroid-dependent (SD) or corticosteroid-resistant (SR) inflammatory bowel disease (IBD) in children from 3 Nordic countries to evaluate its efficacy and safety and to assess practical issues. METHODS: Retrospective data on 37 children treated with GMA were collected. In all, 22 children had ulcerative colitis (UC), 13 Crohn's disease (CD), and 2 had indeterminate colitis (IC). Their mean age was 13.2 years, range 5-17 years, and mean duration of disease was 2.4 years, range 1 month to 6 years. Indication for treatment in the UC group was SD in 11 cases, SR in 6 cases, and other reasons in 5 cases. The corresponding numbers in the CD group were SD in 8 cases, SR in 2 cases, and other reasons in 3 cases. In the IC group, 1 had SD and 1 was refractory to steroids, azathioprine, and infliximab. Efficacy was evaluated by severity indices: the Pediatric Ulcerative Colitis Activity Index (PUCAI) and the Pediatric Crohn's Disease Activity Index (PCDAI) and tapering of corticosteroids. RESULTS: PUCAI and PCDAI decreased significantly in both groups after 3 months (P = 0.0007, P = 0.025). The dosage of corticosteroid was significantly reduced in the UC group by the end of GMA (P = 0.004) and this response continued after 3 months. Relapse was seen in 2 patients with UC and 3 patients with CD after 3 months follow-up. CONCLUSIONS: GMA seems to be an effective and safe treatment in 81% of the SD or SR pediatric IBD patients, especially in those with UC.

Diabetic ketoacidosis and cerebral oedema in Sweden--a 2-year paediatric population study.

AIM: The aim of this study was to investigate diabetic ketoacidosis (DKA) and cerebral oedema in the Swedish paediatric diabetes population, and to measure laboratory parameters during treatment. METHODS: The Swedish National Paediatric Diabetes Registry (SWEDIABKIDS) indicates that 16% of patients < 18 years during 2000 to 2004 had DKA at onset of diabetes. Data from 1999 and 2000 was collected retrospectively from all of Sweden by questionnaire. RESULTS: We identified 292 cases of DKA (pH < 7.30) in 265 children (149 at diabetes onset), aged 0.8-19.9 years. The incidence of DKA in patients with previously diagnosed diabetes was 1.4/100 patient years in 1999 and 1.7/100 in 2000. Two patients, both 11 years old with newly diagnosed diabetes, had overt symptoms of cerebral oedema and one developed neurological sequelae. This corresponds to an incidence of 0.68% (2/292) with no mortality. Symptoms of subclinical cerebral oedema after admission (headache, vomiting, lethargy) were recorded in a further 16 cases. In two of these mannitol was given, and both recovered within 1-2 h. Laboratory data was available from 253/292 episodes. During treatment for DKA, hypokalaemia (< 3.5 mmol/l) was significantly more common at onset of diabetes than in patients with established diabetes (65 vs. 28%, P < 0.001; initial prescription of potassium was 20 mmol/l). CONCLUSIONS: We conclude that 16% of children with new-onset diabetes presented with DKA at diagnosis and that the incidence of DKA in children with established diabetes was 1.6/100 patient years. Cerebral oedema occurred in 0.68% of the DKA episodes.

Statistical molecular design of building blocks for combinatorial chemistry.

The reduction of the size of a combinatorial library can be made in two ways, either base the selection on the building blocks (BB's) or base it on the full set of virtually constructed products. In this paper we have investigated the effects of applying statistical designs to BB sets compared to selections based on the final products. The two sets of BB's and the virtually constructed library were described by structural parameters, and the correlation between the two characterizations was investigated. Three different selection approaches were used both for the BB sets and for the products. In the first two the selection algorithms were applied directly to the data sets (D-optimal design and space-filling design), while for the third a cluster analysis preceded the selection (cluster-based design). The selections were compared using visual inspection, the Tanimoto coefficient, the Euclidean distance, the condition number, and the determinant of the resulting data matrix. No difference in efficiency was found between selections made in the BB space and in the product space. However, it is of critical importance to investigate the BB space carefully and to select an appropriate number of BB's to result in an adequate diversity. An example from the pharmaceutical industry is then presented, where selection via BB's was made using a cluster-based design.

[Measuring corneal thickness in photo-keratectomy with a reflectometry incorporated into the laser beam of the excimer laser]. / Messung der Hornhautdicke bei der Photo-Keratektomie mit einem in den Strahlengang des Excimer-Lasers integrierten Reflektometer.

PURPOSE: To integrate a newly developed OLCR instrument into the optical system of the excimer laser. The instrument is designed to perform corneal pachymetry before, during, and after corneal photoablation and thus allow for a precise and continuous on-line measurement of the corneal photoablation process. METHODS: The conditions required to integrate the OLCR instrument into the excimer laser optics were investigated. With a technical setting providing on-line data of corneal thickness, three groups of 8-10 corneae received central keratectomies of 27 (group 1), 82 (group 2) and 163 (group 3) microns calculated central depth and 7.38 mm diameter. All measurements were performed with OLCR and ultrasound. RESULTS: The OLCR instrument was coupled into the optical system of the excimer laser and a useful signal obtained at SLD power levels of 40 microW incident on the cornea. Individual corneal thickness measurements were obtained before, during and after the photoablation procedure. In group 1, the ablation was 50.3 (40-68) microns measured with ultrasound and 30.2 (27-38) microns measured with OLCR. In group 2, the ablation was 101.1 (80-113) microns measured with ultrasound and 93.3 (76-109) microns measured with OLCR. In group 3, the ablation was 210.6 (190-227) microns measured with ultrasound and 188.4 (181-197) microns measured with OLCR. The precision (standard deviation) for measurements of individual corneas was 1-2 microns with OLCR and up to 12 mm in Ultrasound measurements. CONCLUSION: With this interferometric method, continuous, non-contact measurement of corneal thickness before, during and after excimer laser photoablation were performed. By establishing a feed-back control between the pachymetric measurements and the photoablation process, the precision of excimer ablation may possibly be further increased.

Toxicity in vitro of some silicon carbides and silicon nitrides: whiskers and powders.

The objectives of this work were to investigate the toxicity of silicon carbide whiskers and powders and silicon nitride whiskers and powders and to compare their toxicity with the toxicity of crocidolite. The effects studied were inhibition of the cloning efficiency of V79 cells, formation of DNA strand breaks by means of a nick translation assay, formation of oxygen radicals in three different assays, and the ability to stimulate neutrophils to produce hydroxyl radicals. All materials showed concentration-dependent inhibition of the cloning efficiency of V79 cells. The inhibition by the most toxic whiskers was in the same order of magnitude as that of crocidolite. Milled whiskers and powders were less toxic than the whiskers. There was a high DNA breaking potential for crocidolite and four of the silicon carbide whiskers and a rather low one for the other materials. Formation of hydroxyl radicals was found for crocidolite and one of the silicon carbide whiskers. In the neutrophil activation test, there was a great variation in the different materials' abilities to activate neutrophils. There was also a good correlation between chemiluminescence and H2O2 formation. The highest activation was found in neutrophils exposed to two of the silicon carbide whiskers and one milled whisker. The conclusion of the investigation is that some of the ceramic materials studied had damaging biological effects comparable to or greater than those of crocidolite. The results from the investigation clearly imply that caution is needed in the introduction of new ceramic fiber materials, so that the correct precautions and protective devices are used in order to avoid harm to the personnel handling the material.

Modelling of the biological activity for a set of ceramic fibre materials: a QSAR study.

The objective was to develop quantitative structure-activity relationships (QSARs) for a set of nine ceramic raw materials. The samples were characterized by a chemical analysis (both X-ray fluorescence and neutron activation analysis) and the morphology was determined by electron microscopy in combination with automated image analysis. Further, the fibre samples were subjected to two biological activity assays, measuring cytotoxicity and hydroxyl radical production. To investigate the produced data structures, principal component analysis (PCA) and partial least squares (PLS) were applied together with rigorous validation techniques. Significant QSARs were found for both biological activity assays. The morphology of the fibres plays an important role for the cytotoxicity and their trace element background is related to the hydroxyl radical production.

Proinsulin levels in newborn siblings of type 1 (insulin-dependent) diabetic children and their mothers.

Elevated proinsulin levels have been observed in healthy first degree relatives of Type 1 (insulin-dependent) diabetic patients. This elevation could reflect a sequele after a previous attack on the beta-cells not necessarily leading to diabetes, or represent a family trait related to the development of diabetes. When cord plasma levels of proinsulin, insulin and C-peptide from 14 newborn siblings of Type 1 diabetic patients were compared with 21 newborn control siblings unrelated to diabetic subjects, no differences were observed. Neither were any differences observed between their mothers at delivery when comparing the same parameters. In cord plasma the proinsulin levels (median and range) were higher than those in plasma from 35 adult fasting women unrelated to diabetic subjects (10, 5-83 pmol/l vs 4, 2-33 pmol/l; p < 0.001) whereas the C-peptide levels (median and range) were lower (0.20, 0.11-0.56 nmol/l vs 0.37, 0.21-0.69 nmol/l; p < 0.001). No differences in insulin levels using a highly specific insulin assay were observed. The results suggest that newborn children have high proinsulin and low C-peptide levels unrelated to heredity of diabetes and that the previously described elevated proinsulin level observed in older first degree relatives of diabetic subjects occurs later in life.

Heterogeneity of molecular weight and apolipoproteins in low density lipoproteins of healthy human males.

The molecular weights of five low density lipoprotein (LDL) subfractions from four normal healthy males were determined by analytic ultracentrifuge sedimentation equilibria. Protein content of each subfraction was determined by elemental CHN analysis, and weights of apoprotein peptides were calculated. Molecular weights in subfractions of increasing density were 2.92 +/- 0.26, 2.94 +/- 0.12, 2.68 +/- 0.09, 2.68 +/- 0.28 and 2.23 +/- 0.22 million Da, and protein weight percentages were 21.05, 21.04, 22.05, 23.10 and 29.10, in subfractions 1, 2, 3, 4 and 5, respectively. Total mean apoprotein weights for respective subfractions were 614 +/- 53, 621 +/- 45, 588 +/- 9, 637 +/- 83 and 645 +/- 62 KDa. In addition to a single apoprotein B-100 (apo B-100) peptide with a mean carbohydrate content of 7.1% and a molecular weight of 550 KDa per LDL particle, there may be one or more apoprotein E peptides of 34 KDa and/or apoprotein C-III of 9 KDa. In addition, subfractions 4 and 5 may contain 3-7% apolipoprotein (a). There is considerable heterogeneity among LDL subfractions as well as within the same fraction from different individuals. This heterogeneity may relate to differences in origin, metabolism and/or atherogenicity as a result of their content of apoproteins other than apo B-100.

The interaction of smoking and noise on temporary threshold shifts.

Four separate experiments examined the effects of cigarette smoking on temporary threshold shifts (TTS) following noise exposure. One experiment compared smokers and non-smokers after the subjects had abstained from smoking for at least 6 h. A second experiment tested only smokers who smoked a cigarette just before noise exposure, during the noise exposure and in a control condition during which they did not smoke. A third experiment tested only non-smokers who were exposed to noise after chewing nicotine gum or after a control condition in which they rested without chewing the gum. A fourth experiment tested smokers and non-smokers in one condition which required them to smoke a cigarette just prior to noise exposure and in another condition which prevented them from smoking. The results indicate that smokers consistently evidence slightly smaller TTS than do non-smokers. Non-smokers evidenced significantly greater TTS at one frequency after they had chewed nicotine gum than when they had not. These results suggest that the smaller TTS associated with cigarette smoking is related to both the chronic and the acute effects of smoking and that these effects may be more attributable to carbon monoxide than to nicotine.

Associations of lipoproteins and apolipoproteins with gradient gel electrophoresis estimates of high density lipoprotein subfractions in men and women.

We examined the relations of gender and lipoproteins to subclasses of high density lipoproteins (HDLs) in a cross-sectional sample of moderately overweight men (n = 116) and women (n = 78). The absorbance of protein-stained polyacrylamide gradient gels was used as an index of mass concentrations of HDL at intervals of 0.01 nm across the entire HDL particle size range (7.2-12 nm). At least five HDL subclasses have been identified by their particle sizes: HDL3c (7.2-7.8 nm), HDL3b (7.8-8.2 nm), HDL3a (8.2-8.8 nm), HDL2a (8.8-9.7 nm), and HDL2b (9.7-12 nm). Men had significantly higher HDL3b and significantly lower HDL2a and HDL2b than did women. Correlations of HDL subclasses with concentrations of other lipoprotein variables were generally as strong for gradient gel electrophoresis as for analytical ultracentrifugation measurements of HDL particle distributions. In both sexes, high levels of HDL3b were associated with coronary heart disease risk factors, including high concentrations of triglycerides, apolipoprotein B, small low density lipoproteins, intermediate density lipoproteins, and very low density lipoproteins and low concentrations of HDL2 cholesterol and HDL2 mass. Plasma concentrations of HDL3 cholesterol were unrelated to protein-stained HDL3b levels. HDL3 cholesterol concentrations also did not exhibit the sex difference or the relations with lipoprotein concentrations that characterized HDL3b. Thus, low HDL3b levels may contribute in part to the low heart disease risk in men and women who have high HDL cholesterol. Measurements of HDL3 cholesterol may not identify clinically important relations involving HDL3b.

The influence of eye colour on susceptibility to TTS in humans.

In order to investigate the function of the inner ear melanin, noise-induced temporary hearing loss (temporary threshold shift, TTS) was studied in humans with either blue or brown iris colour. Sixty-eight normally hearing teenage boys participated in this study. Hearing thresholds before and after exposure were established with a computerized sweep frequency audiometer in the frequency range 0.8-8 kHz. The noise exposure consisted of a 1/3 octave band-filtered noise with centre frequency 2 kHz at 105 dB SPL for 10 min. The mean TTS in the frequency range 2-8 kHz showed a significant difference with the brown-eyed subjects developing least TTS, and the blue-eyed subjects most TTS.

Glucose-induced insulin response is reduced and proinsulin response increased in healthy siblings of type 1 diabetic patients.

Glucose-stimulated insulin and proinsulin responses, and insulin sensitivity, were studied in 30 HLA identical, 38 HLA haplo-identical, and 25 HLA non-identical, healthy islet-cell-antibody negative siblings of Type 1 diabetic patients. The results were compared with 41 age- and sex-matched healthy subjects with no diabetes in the family. The proinsulin-corrected insulin response to an intravenous glucose infusion test was significantly lower among siblings when insulin sensitivity was taken into account (1.65 (inter-quartile range 1.20-2.64) vs 2.18 (1.65-3.28) nmol mmol-1 min, p = 0.04). Proinsulin values were consistently higher among siblings than among control subjects (peak values 50.0 vs 38.0 pmol l-1 (p = 0.004)). When proinsulin release was corrected for individual insulin sensitivity this difference remained. The results suggest disturbed islet B-cell function, unrelated to HLA identity or the presence of circulating islet cell antibodies.

Minimum analogue peptide sets (MAPS) for quantitative structure-activity relationships.

The information contents in previously published peptide sets was compared with smaller sets of peptides selected according to statistical designs. It was found that minimum analogue peptide sets (MAPS) constructed by factorial or fractional factorial designs in physiochemical properties contained substantial structure-activity information. Although five to six times smaller than the originally published peptide sets the MAPS resulted in QSAR models able to predict biological activity. The QSARs derived from a MAPS of nine dipeptides, and from a set of 58 dipeptides inhibiting angiotensin converting enzyme were compared and found to be of equal strength. Furthermore, for a set of bitter tasting dipeptides it was found that an incomplete MAPS of 10 dipeptides gave just as good a model as the model based on a set of 48 dipeptides. By comparison other non-designed sets of peptides gave QSARs with poor predictive power. It was also demonstrated how MAPS centered on a lead peptide can be constructed as to specifically explore the physiochemical and biological properties in the vicinity of the lead. It was concluded that small information-rich peptide sets MAPS can be constructed on the basis of statistical designs with principal properties of amino acids as design variables.

Effect of a salmon diet on the distribution of plasma lipoproteins and apolipoproteins in normolipidemic adult men.

The effects of n-3 fatty acids on plasma lipids, lipoproteins and apoproteins have usually been studied in humans after feeding of purified fish oil. This study describes the effect of a natural diet, containing salmon as the source of n-3 fatty acids, on these parameters as compared to a diet very low in n-3 fatty acids. The subjects were nine normolipidemic, healthy males who were confined to a nutrition suite for 100 days. During the first 20 days of the study the participants were given a stabilization diet consisting of 55% carbohydrates, 15% protein, and 30% fat. The n-3 content of this diet was less than 1%, and it contained no 20- or 22-carbon n-3 fatty acids. After the stabilization period the men were split into two groups, one group continued on the stabilization diet while the other received the salmon diet that contained approximately 2.1 energy percent (En%) of calories from 20- and 22-carbon n-3 fatty acids. Both diets contained equal amounts of n-6 fatty acids. This regime continued for 40 days, then the two groups switched diets for the remainder of the study. Plasma triglycerides were lowered significantly (p less than 0.01) and high density lipoprotein cholesterol (HDL-C) was significantly elevated (p less than 0.01) after the men consumed the salmon diet for 40 days. The very low density lipoproteins (VLDL) were lowered, but the trend did not reach statistical significance during the intervention period.(ABSTRACT TRUNCATED AT 250 WORDS)

A multivariate representation and analysis of DNA sequence data.

A new way to represent and analyze DNA sequence data is described. This approach complements methods currently used, in that it allows the systematic part of the variation between different sequences to be modeled. This can prove as informative as absence of variation (homology), which is the most widely used criterion for comparing sequence data. A multivariate sequence-activity model (SAM), for DNA-promoter sequences is presented, by which the relative promoter strength is modeled in terms of the primary DNA-sequence. The model is shown to have a good predictive capability. The coefficients from the model are interpreted, and used to design new structures predicted to be strong promoters in the system investigated. The approach described is also applicable to other kinds of sequence data, e.g. RNAs, proteins or peptides.

Insulin sensitivity and glucose-induced insulin response changes during adolescence.

Recently we reported that insulin resistance and glucose induced insulin release are inversely correlated to age in young healthy siblings of diabetic patients. To confirm this pattern of change with age, the subjects were reexamined after two years. The study was limited to the age groups with the lowest insulin sensitivity, i.e. 14.0-15.9 years for females and 16.0-17.9 years for males. All five girls and four of five boys showed an increased insulin sensitivity as measured by the somatostatin-insulin-glucose infusion test (p = 0.02). All subjects showed a decrease in fasting levels of insulin-like growth factor 1 (IGF-1) (p less than 0.01) during the observation period. All except one showed an increase in the levels of dehydroepiandrosterone sulphate (DHEA-S) (p less than 0.01). These data confirm that insulin sensitivity increases in the late teenage period. The parallelism to the changes of IGF-1 indicate that the pubertal changes in insulin sensitivity may partly be caused by growth hormone. Our data contradict the hypothesis that the low insulin sensitivity of puberty is due to the increased levels of DHEA-S.

A comparison of the variability in thresholds measured with insert and conventional supra-aural earphones.

The purpose of this study was to evaluate the reliability and comparability of the commercially available insert earphone Etymotic Research ER-3A and the commonly available supra-aural TDH earphone. Thirteen subjects were tested five times with the ER-3A and five times with TDH-49P with MX-41/AR cushions. Threshold determinations were obtained utilizing a sweep-frequency audiometer in the range 0.25-8 kHz. The results showed that the reliability of the ER-3A earphone as measured by intra-individual variation, was comparable to that obtained with the TDH earphone. No evidence was found indicating an increased variability due to the positioning of the insert earphone's coupling device in the ear canal. Comparison of thresholds obtained with both devices indicated that the manufacturer's suggested correction values were appropriate.

The influence of inner ear melanin on susceptibility to TTS in humans.

In order to investigate the function of the inner ear melanin, the relationship between skin pigmentation and noise-induced temporary hearing loss (TTS) was studied. Forty-four normal-hearing Caucasian subjects were divided into three groups according to their sun sensitivity. Hearing thresholds before and after exposure were ascertained with a computerized sweep frequency audiometer in the frequency range 2-8 kHz. The noise exposure consisted of a 1/3-octave band-filtered noise with a centre frequency of 2 kHz at 105 dB SPL for 10 min. The mean TTS in the frequency range 2-8 kHz showed statistically significant differences between the three groups, i.e. the most pigmented subjects developed least TTS, and the least pigmented subjects most TTS.