Simulation-based design study for the passive shielding of the COSINUS dark matter experiment.

The COSINUS (Cryogenic Observatory for SIgnatures seen in Next-generation Underground Searches) experiment aims at the detection of dark matter-induced recoils in sodium iodide (NaI) crystals operated as scintillating cryogenic calorimeters. The detection of both scintillation light and phonons allows performing an event-by-event signal to background discrimination, thus enhancing the sensitivity of the experiment. The choice of using NaI crystals is motivated by the goal of probing the long-standing DAMA/LIBRA results using the same target material. The construction of the experimental facility is foreseen to start by 2021 at the INFN Gran Sasso National Laboratory (LNGS) in Italy. It consists of a cryostat housing the target crystals shielded from the external radioactivity by a water tank acting, at the same time, as an active veto against cosmic ray-induced events. Taking into account both environmental radioactivity and intrinsic contamination of materials used for cryostat, shielding and infrastructure, we performed a careful background budget estimation. The goal is to evaluate the number of events that could mimic or interfere with signal detection while optimising the geometry of the experimental setup. In this paper we present the results of the detailed Monte Carlo simulations we performed, together with the final design of the setup that minimises the residual amount of background particles reaching the detector volume.

Geant4-based electromagnetic background model for the CRESST dark matter experiment.

The CRESST (Cryogenic Rare Event Search with Superconducting Thermometers) dark matter search experiment aims for the detection of dark matter particles via elastic scattering off nuclei in CaWO 4 crystals. To understand the CRESST electromagnetic background due to the bulk contamination in the employed materials, a model based on Monte Carlo simulations was developed using the Geant4 simulation toolkit. The results of the simulation are applied to the TUM40 detector module of CRESST-II phase 2. We are able to explain up to ( 68 ± 16 ) % of the electromagnetic background in the energy range between 1 and 40 keV .

Cardiac resynchronization therapy: a breakthrough in heart failure management.

Heart failure is now considered an epidemic. In patients with heart failure, electrical and mechanical dyssynchrony, evident primarily as prolongation of the QRS-complex on the surface electrocardiogram, is associated with detrimental effects on the cardiovascular system at several levels. In the past 10 years, studies have demonstrated that by stimulating both cardiac ventricles simultaneously, or almost simultaneously [cardiac resynchronization therapy (CRT)], the adverse effects of dyssynchrony can be overcome. Here, we provide a comprehensive overview of different aspects of CRT including the rationale behind and evidence for efficacy of the therapy. Issues with regard to gender effects and patient follow-up as well as a number of unresolved concerns will also be discussed.

Cellular internalization of proinsulin C-peptide.

Proinsulin C-peptide is known to bind specifically to cell membranes and to exert intracellular effects, but whether it is internalized in target cells is unknown. In this study, using confocal microscopy and immunostained or rhodamine-labeled peptide, we show that C-peptide is internalized and localized to the cytosol of Swiss 3T3 and HEK-293 cells. In addition, transport into nuclei was found using the labeled peptide. The internalization was followed at 37 degrees C for up to 1 h, and was reduced at 4 degrees C and after preincubation with pertussis toxin. Hence, it is concluded to occur via an energy-dependent, pertussis toxin-sensitive mechanism and without detectable degradation within the experimental time course. Surface plasmon resonance measurements demonstrated binding of HEK-293 cell extract components to C-peptide, and subsequent elution of bound material revealed the components to be intracellular proteins. The identification of C-peptide cellular internalization, intracellular binding proteins, absence of rapid subsequent C-peptide degradation and apparent nuclear internalization support a maintained activity similar to that of an intracrine peptide hormone. Hence, the data suggest the possibility of one further C-peptide site of action.

Specific cleavage of insulin-like growth factor-binding protein-1 by a novel protease activity.

Insulin-like growth factor-binding protein-1 (IGFBP-1) is secreted in a highly phosphorylated form that binds IGF-I with high affinity and is resistant to proteolysis. We have purified IGFBP-1-specific protease activity from the urine of an individual with multiple myeloma. This protease efficiently cleaves both phosphorylated and non-phosphorylated IGFBP-1 at Ile130-Ser131, generating fragments that together have higher association and dissociation rates for IGFs compared with intact IGFBP-1. The proteolytic fraction contained azurocidin, a protease homologue hitherto considered inactive. After cleavage of IGFBP-1, there was a lower affinity, but higher capacity for IGF-I binding, suggesting both N- and C-terminal fragments may interact with ligand independently. There was decreased inhibition of IGF-II-stimulated cell growth and glucose uptake. Alone, proteolysed IGFBP-1 stimulated glucose uptake in muscle. We conclude that specific cleavage of IGFBP-1 at target tissues is important in cellular growth and metabolism and opens novel strategies for targeting IGFBP-1 in treatment of disease.

Separate functional features of proinsulin C-peptide.

Proinsulin C-peptide influences a number of physiological parameters in addition to its well-established role in the parent proinsulin molecule. It is of interest as a candidate for future co-replacement therapy with insulin for patients with diabetes mellitus type 1, but specific receptors have not been identified and additional correlation with functional effects is desirable. Based on comparisons of 22 mammalian proinsulin variants, we have constructed analogues for activity studies, choosing phosphorylation of mitogen-activated protein kinases (MAPKs) in Swiss 3T3 fibroblasts for functional measurements. In this manner, we find that effective phosphorylation of MAPKs is promoted by the presence of conserved glutamic acid residues at positions 3, 11 and 27 of C-peptide and by the presence of helix-promoting residues in the N-terminal segment. Previous findings have ascribed functional roles to the C-terminal pentapeptide segment, and all results combined therefore now show the importance of different segments, suggesting that C-peptide interactions are complex or multiple.

The quality of perioperative care: development of a tool for the perceptions of patients.

AIM OF THE STUDY: To find out how surgical hospital patients (n=874) perceived the quality of perioperative care they received in an operating department and in the recovery room. BACKGROUND: Patients' perceptions of the perioperative care have not been included systematically in the improvement of the care. Accordingly, there is no standardized, valid, and reliable instrument or system in common use that we could use for the evaluation. The nursing care in operating departments has an important role in modern health care, and therefore more research concerning perioperative care quality is needed urgently and the development of the measurement tool is urgent. METHOD: The data were collected using a structured questionnaire in five operating departments in southern Finland during 1998. RESULTS: Physical activities (such as pain management and temperature maintenance) were rated as excellent, as were staff characteristics and the physical and social environment. The most critical comments were made with regard to supporting patient initiative, encouragement and educational activities. Patients stated they would have liked more information and it was felt that they should have been encouraged to ask more questions about unclear matters. Some of the patients said they had only very limited influence over their own care. The patients were very pleased with their care in the recovery room. There were only minor differences between the views of patients from different departments. CONCLUSIONS: Overall the quality of care was considered extremely good, but comparisons of different quality categories did reveal some problems. Although it has already proved to be a useful tool, the questionnaire needs to be developed and tested further.

p53 splice acceptor site mutation and increased HsRAD51 protein expression in Bloom's syndrome GM1492 fibroblasts.

GM1492 human diploid skin fibroblasts derived from a patient with Bloom's syndrome (BS), lack detectable p53 mRNA and protein as shown by Northern and Western blotting, and express an increased RecA-like activity. Here we demonstrate that the p53 gene is grossly intact in GM1492 cells according to Southern blotting. DNA sequencing did not reveal any mutations in the promoter region of p53. A highly sensitive RT-PCR produced a p53 cDNA fragment that was shorter than expected. DNA sequence analysis of p53 cDNA showed that exon 6 was missing, explaining the shorter PCR product. Furthermore, sequencing of genomic DNA revealed a base substitution at the nucleotide preceding the AG splice acceptor site of intron 5. The omission of exon 6 creates a frameshift at the junction of exons 5 and 7, and a premature stop codon in exon 7. The aberrant transcript is predicted to encode a truncated p53 protein containing 189 amino acid residues. Moreover, Western blotting demonstrated elevated HsRAD51 protein levels in GM1492 cells. The lack of sufficient levels of wild-type p53 and increased levels of HsRad51 protein may contribute to the elevated RecA-like activity in the GM1492 fibroblasts.

Corticosteroid therapy and need for hospital care in wheezing preschool children.

OBJECTIVES: To study the frequency of corticosteroid therapy and the use of inpatient care for preschool children with wheezing in two regions in Finland. METHODS: The Finnish Social Insurance Institution database on refundable asthma medication indicated that 1.18% of children in Tampere and 2.37% in Turku used inhaled corticosteroids regularly. To clarify the difference, hospital records of 800 randomly chosen 0.5-6.9-year-old children who had been treated for wheezing in Tampere or Turku University Hospital during 1995-1996 were retrospectively analysed. RESULTS: The incidences of wheezing-related emergency room (ER) index visits were 11.0 visits/year/1000 children both in Tampere and Turku. Oral corticosteroids were given to 2.5% versus 24.2% of children in ER and 10.6% versus 89.7% in hospital ward in Tampere and Turku, respectively. Hospitalisation rates were 44.8% in Tampere and 36.8% in Turku (95% confidence interval for the difference 1.2-14.8%). In both regions, children with prior inhaled corticosteroid therapy needed less inpatient care. Mean duration of hospitalisation was 3.4 days in Tampere and only 1.4 days in Turku. Recurrent visits in 6 months were more common in Tampere. CONCLUSIONS: There were marked regional differences in the management of preschool children with wheezing. On a population level, frequent use of corticosteroid therapy was associated with reduced hospital admissions.

Local heroes beat national champions: quality improvement in Finnish health care.

UNLABELLED: FINNISH HEALTH CARE: Although health care services in Finland are organized uniformly throughout the country, they, along with the application of total quality management (TQM)/continuous quality improvement (CQI), are the responsibility of municipalities. CASE 1: At the Helsinki City Health Organization, top management launched an organizationwide quality improvement (QI) initiative in 1993, entailing 150 CQI projects. Yet top and middle managers were not sufficiently dedicated to the initiative to provide adequate support to many of the quality projects. Only "islands of activity" were spotted. CASE 2: A physician in the pediatrics department of a hospital helped initiate CQI projects--for improvements in administration of x-rays for patients with antebrachium fractures, transport of samples to the microbiology laboratory, and admissions of patients with acute infectious disease. Successes led senior management in the hospital federation to issue a quality policy based on CQI management, showing the power of the good example. CASE 3: The first launch of CQI at the Helsinki University Central hospital was part of a management development project that did not have the full support of senior management and that, consequently, failed. A second initiative undertaken a year later, the quality council, was more successful. CASE 4: At a local center for social services and primary care, quality projects have strengthened the organization's team and network structures across two professional cultures. DISCUSSION: The four cases provide insight into the diffusion of TQM/QI and implementation strategies on the local level.

Diagnosis of Helicobacter pylori infection by using pyloriset EIA-G and EIA-A for detection of serum immunoglobulin G (IgG) and IgA antibodies.

We evaluated the performance of new enzyme immunoassay (EIA) kits (Pyloriset; Orion Corporation, Orion Diagnostica, Espoo, Finland) for the detection of immunoglobulin G (IgG) and IgA antibodies to Helicobacter pylori in serum. Serum samples from 195 patients with upper abdominal complaints were collected. Biopsy specimens of the gastric mucosae were taken for histological analysis and bacterial culture. The sensitivity, specificity, and positive and negative predictive values, and efficacy of the Pyloriset EIA-G in detecting IgG antibodies to H. pylori were 92, 84, 88, 90, and 89%, respectively, when compared with those of the reference methods used. The corresponding data for detection of IgA antibodies were 80, 89, 89, 79, and 84%, respectively. The overall prevalence of defined H. pylori positivity was 54%. Moreover, the antibody tests showed a very good correlation with the biopsy findings. IgG antibodies were found in 93% of sera from patients with documented gastritis and H. pylori positivity, whereas only 4% of the sera from patients with documented gastritis and H. pylori-negative patients was positive. The results obtained for IgA antibodies were 81 and 6%, respectively. We conclude that the Pyloriset EIA-G, the test for IgG antibodies, is a good and reliable test for the detection of antibodies to H. pylori and as an indication of H. pylori infection. The determination of IgA antibodies may be used as a test that complements the IgG antibody assay.

Tissue distribution of two NMDA receptor antagonists, [3H]CGS 19755 and [3H]MK-801, after intrathecal injection in mice.

The tissue distribution of [3H]cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) and [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne (NK-801) was investigated after a single IT injection into lumbar spinal cord of mice. The level of radioactivity was analyzed in the lumbar, thoracic, and cervical spinal cord, brainstem, frontal cortex, liver, lungs, kidneys, stomach, intestine, spleen, heart, and blood from 5 min up to 6 h after injection. Within the CNS, [3H]CGS 19755 redistributed slowly from the site of injection toward the brainstem and cortex, peaking in the cortex 3-4 h after IT injection. At no time, however, did the relative level per gram of tissue in the frontal cortex exceed 10% of the relative level in the lumbar region of the spinal cord. The highest peripheral level of [3H]CGS 19755 was found in the kidneys. [3H]MK-801 redistributed rapidly from the spinal cord injection site to the peripheral organs. The highest peripheral levels of [3H]MK-801 were found in the lungs and liver, where the radioactivity peaked at 10 and 30-60 min, respectively, after injection. The relative levels of [3H]CGS 19755 were consistently higher in CNS tissues (except for the first 15 min in the frontal cortex) and blood than the corresponding levels of [3H]MK-801. The opposite relationship was true in the liver, lungs, kidneys, stomach, intestine, spleen, and heart. The effect on the response latency in the hot-plate test was quantified in the same animals immediately prior to sacrifice for the distribution study.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term effects of syrup medications for recurrent otitis media on the dental health of 6- to 8-year-old children.

The dental response to repeated antimicrobial and antihistamine medications was studied by comparing the dental health of 64 adenoidectomized children 5 years after surgery to that of 212 untreated controls. Annual dental recordings starting from the age of 3 years were obtained from health care centers. As expected, the proportion of children who had several (> or = 11) syrup medications was significantly higher (p < 0.001) in the adenoidectomized than in the control group. Sucrose-containing syrup medications were prescribed twice as often for the children of the adenoidectomized as for the control group (p < 0.001). However, the average amount of antimicrobial syrup medications prescribed was 19.2 +/- (SD) 13.0 per child for the adenoidectomized as compared to 8.5 +/- 8.3 for the control children (p < 0.001). The dmf value of the adenoidectomized children at the age of 3 years (mean +/- SEM: 0.5 +/- 0.1) was significantly (p < 0.005) lower than that of the controls (1.1 +/- 0.2). The difference was still significant (p < 0.01) at the age of 4 years, but disappeared thereafter. In conclusion, the antibacterial syrup medication seemed to be associated with a significant decline in dental caries at first. The simultaneous use of antihistamines was, however, thought to delay normal tooth maturation, so that after discontinuation of the antimicrobial medication, accelerated formation of new carious lesions took place.

Swedish dioxin survey: evaluation of the H-4-II E bioassay for screening environmental samples for dioxin-like enzyme induction.

The H-4-II E enzyme induction bioassay was used for testing both pure reference substances and extracts of wildlife samples. Polychlorinated naphthalenes were found to be as active as enzyme inducers as certain coplanar polychlorinated biphenyls (PCBs). Also a mixture of polybrominated diphenyl ethers (Bromkal 70-5DE) was shown to induce enzyme activity. In extracts of herring, containing polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), bioassay and chemically derived TCDD-equivalents (TEQs) were nearly identical. When extracts containing other types of dioxin-like compounds as well were tested, the bioassay TEQs for most of them agreed well with chemical TEQs calculated for PCDDs, PCDFs and non-ortho PCBs. However, for ringed seal and whitefish, TEQs obtained from the bioassay were higher than those from the chemical analysis. Our results indicate that this bioassay is an excellent complement to chemical residue analysis and a useful tool in understanding the complex interactions of halogenated hydrocarbons. For risk assessment, such results should, however, be used most carefully as they are measured in vitro.

Mutagenic activity of photoreaction products formed from chlorinated ethenes and nitrogen dioxide.

The mutagenicity in Salmonella, strain TA 100, of photoreaction products from chlorinated alkenes and nitrogen dioxide, was studied after a mean reaction time of 40 min with UV-irradiation and an exposure time of 20 hr. Only vinyl chloride (monochloroethene) gave rise to significantly mutagenic photoreaction products. Of the other chloroethenes, 1,1-dichloroethene and tetrachloroethene, but not 1,2-dichloro- or trichloroethene, formed slightly mutagenic products. Bacteriotoxic effects occurred at low doses, especially with tri- and tetrachloroethene.

Glutathione and glutathione-metabolizing enzymes in the erythrocytes of healthy children and in children with insulin-dependent diabetes mellitus, juvenile rheumatoid arthritis, coeliac disease and acute lymphoblastic leukaemia.

Oxidative biotransformation of xenobiotics and endogenous substances involves glutathione in reduced form as an integral component through two mechanisms: glutathione peroxidase catalysing the reduction of hydrogen peroxide and organic hydroperoxides, and glutathione-S-transferases catalysing the conjugation of oxygenated derivatives with glutathione. We studied glutathione and glutathione-related enzyme activities in haemolysed venous blood samples from 49 healthy children and from 11 children with diabetes mellitus, 10 children with rheumatoid arthritis, seven children with active coeliac disease, and seven children with acute lymphoblastic leukaemia. Among the healthy children glutathione content and the activities of glutathione reductase, glutathione peroxidase, and glutathione-S-transferase were unrelated to sex; age-dependent differences were also minor. The patients with diabetes mellitus had decreased activity of glutathione reductase. The patients with acute lymphoblastic leukaemia had increased activity of both glutathione peroxidase and glutathione-S-transferase, possibly reflecting an adaptive response to free-radicals. The patients with active coeliac disease had control levels of all measured parameters of glutathione-related reactions indicating, since we earlier found decreased activities of glutathione peroxidase in intestinal mucosa of celiacs, that blood may not always reflect tissue-specific changes.

Iron deficiency in coeliac disease is mild and it is detected and corrected by gluten-free diet.

In 54 children with coeliac disease, mild iron deficiency anaemia or evidence of iron deficiency without anaemia were common at the time of diagnosis. Treatment with a gluten-free diet without iron medication eliminated all evidence of iron deficiency and completely normalized laboratory values. Subsequent challenge with gluten resulted in the rapid reappearance of suboptimal iron balance as evidenced by a decrease in serum ferritin concentration.

Immunochemical detection of human liver cytochrome P450 forms related to phenobarbital-inducible forms in the mouse.

Polyclonal antibodies generated to four distinct mouse liver phenobarbital-inducible cytochrome P450 isoforms were used to analyse related forms in human liver. N-terminal sequence analysis and biochemical properties of the P450s used as antigens suggest that they belong to P450 subfamilies IIB (P450PBI), IA (P450PBII), IIC (P450PBIII) and IIA (P450Coh). In immunoblot analysis, anti-P450PBII detected a single protein presumed to be P450IA2 in all the human livers tested. No proteins corresponding with P450IA1 could be detected. Anti-PBIII and anti-P450Coh antibodies each detected one band (54 and 48 kDa, respectively) in the liver samples. No bands were revealed by anti-P450PBI antibody. Protein dot-immunobinding analysis showed that P450s immunodetectable by anti-P450PBII, anti-P450PBIII and anti-P450Coh antibodies are expressed in human liver (range 9 to 69 pmol P450/mg protein). In immunoinhibition experiments the activity of 7-ethoxyresorutin O-deethylase (EROD) was blocked up to 90% by the anti-P450PBII antibody. Aryl hydrocarbon hydroxylase (AHH) was inhibited only by anti-P450PBIII, and coumarin 7-hydroxylase (COH) only by anti-P450Coh antibody. Testosterone hydroxylations in positions 6 beta, 7 alpha, 15 alpha and 16 alpha were not affected significantly by any of the antibodies. These data suggest that the human liver P450IA2 is responsible for most of the elevated EROD activity, P450s in the IIC subfamily for constitutive AHH and P450s in the IIA subfamily for all of COH activity.