Particulate matter air pollution components and risk for lung cancer.

BACKGROUND: Particulate matter (PM) air pollution is a human lung carcinogen; however, the components responsible have not been identified. We assessed the associations between PM components and lung cancer incidence. METHODS: We used data from 14 cohort studies in eight European countries. We geocoded baseline addresses and assessed air pollution with land-use regression models for eight elements (Cu, Fe, K, Ni, S, Si, V and Zn) in size fractions of PM2.5 and PM10. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effect models for meta-analysis. RESULTS: The 245,782 cohort members contributed 3,229,220 person-years at risk. During follow-up (mean, 13.1 years), 1878 incident cases of lung cancer were diagnosed. In the meta-analyses, elevated hazard ratios (HRs) for lung cancer were associated with all elements except V; none was statistically significant. In analyses restricted to participants who did not change residence during follow-up, statistically significant associations were found for PM2.5 Cu (HR, 1.25; 95% CI, 1.01-1.53 per 5 ng/m(3)), PM10 Zn (1.28; 1.02-1.59 per 20 ng/m(3)), PM10 S (1.58; 1.03-2.44 per 200 ng/m(3)), PM10 Ni (1.59; 1.12-2.26 per 2 ng/m(3)) and PM10 K (1.17; 1.02-1.33 per 100 ng/m(3)). In two-pollutant models, associations between PM10 and PM2.5 and lung cancer were largely explained by PM2.5 S. CONCLUSIONS: This study indicates that the association between PM in air pollution and lung cancer can be attributed to various PM components and sources. PM containing S and Ni might be particularly important.

COX-2-dependent PGE(2) acts as a growth factor in mycosis fungoides (MF).

Cancer often originates from a site of persistent inflammation, and the mechanisms turning chronic inflammation into a driving force of carcinogenesis are intensely investigated. Cyclooxygenase-2 (COX-2) is an inducible key modulator of inflammation that carries out the rate-limiting step in prostaglandin synthesis. Aberrant COX-2 expression and prostaglandin E(2) (PGE(2)) production have been implicated in tumorigenesis. In this study we show that COX-2 is ectopically expressed in malignant T-cell lines from patients with cutaneous T-cell lymphoma (CTCL) as well as in situ in lymphocytic cells in 21 out of 22 patients suffering from mycosis fungoides (MF) in plaque or tumor stage. COX-2 is not expressed in lymphocytes of 11 patients with patch-stage MF, whereas sporadic COX-2 staining of stromal cells is observed in the majority of patients. COX-2 expression correlates with a constitutive production of PGE(2) in malignant T cells in vitro. These cells express prostaglandin receptors EP3 and EP4 and the receptor antagonist as well as small interfering RNA (siRNA) directed against COX-2, and specific COX-2 inhibitors strongly reduce their spontaneous proliferation. In conclusion, our data indicate that COX-2 mediated PGE(2) exerts an effect as a tumor growth factor in MF.

Structure of caesium disulfate at 120 and 273 K.

The crystal structures of Cs2S2O7 at 120 and 273 K have been determined from X-ray single-crystal data. Caesium disulfate represents a new structure type with a uniquely high number of independent formula units at 120 K: In one part caesium ions form a tube surrounding the disulfate ions, [Cs8(S2O7)6+]n; in the other part a disulfate double-sheet sandwiches a zigzagging caesium ion chain, [Cs2(S2O7)6-]n. Caesium disulfate shows an isostructural order-disorder transition between 230 and 250 K, where two disulfate groups become partially disordered above 250 K. The Cs+-ion arrangement shows a remarkable similarity to the high-pressure Rb(IV) metal structure.

Power spectral density changes and language lateralization during covert object naming tasks measured with high-density EEG recordings.

Our objective was to study changes in EEG time-domain power spectral density (PSDt) and localization of language areas during covert object naming tasks in human subjects with epilepsy. EEG data for subjects with epilepsy were acquired during the covert object naming tasks using a net of 256 electrodes. The trials required each subject to provide the names of common objects presented every 4 seconds on slides. Each trial comprised the 1.0 second before and 3.0 seconds after initial object presentation. PSDt values at baseline and during tasks were calculated in the theta, alpha, beta, low gamma, and high gamma bands. The spatial contour plots reveal that PSDt values during object naming were 10-20% higher than the baseline values for different bands. Language was lateralized to left frontal or temporal areas. In all cases, the Wada test disclosed language lateralization to the left hemisphere as well.

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome.

Sézary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3 in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-beta and suppress the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-kappaB (NF-kappaB) activity in reporter assays which is in keeping with a constitutive NF-kappaB activity in the malignant T cells. In conclusion, we show that the malignant T cells express low molecular splice forms of FOXP3 and function as Tregs. Furthermore, we provide evidence that FOXP3 splice forms are functionally different from wt FOXP3 and not involved in the execution of the suppressive function. Thus, this is the first description of FOXP3 splice forms in human disease.

Second generation complementary and alternative medicine physiologic data collection and monitoring research platform.

Progress on our second generation portable system specifically designed to collect 24 hour ambulatory physiologic data from human subjects is reported. The upgraded system has more sensor flexibility and better performance and is smaller, lighter, and simpler to use than our previous version. The new system continues to support a wide variety of sensors found useful for complementary and alternative medicine (CAM) research and has been designed using a modular approach for future expansion of capabilities. The system has improved data storage and supports popular physiologic data formats. Support for wireless control and real-time data monitoring has been added which demonstrates capabilities to be used for physiologic feedback control. The system was designed specifically to support the needs of investigators studying CAM mind-body interventions but could be used for a variety of research needs.

Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma.

Biopsies from patients with cutaneous T-cell lymphoma (CTCL) exhibit stage-dependent increase in angiogenesis. However, the molecular mechanisms responsible for the increased angiogenesis are unknown. Here we show that malignant CTCL T cells spontaneously produce the potent angiogenic protein, vascular endothelial growth factor (VEGF). Dermal infiltrates of CTCL lesions show frequent and intense staining with anti-VEGF antibody, indicating a steady, high production of VEGF in vivo. Moreover, the VEGF production is associated with constitutive activity of Janus kinase 3 (Jak3) and the c-Jun N-terminal kinases (JNKs). Sp600125, an inhibitor of JNK activity and activator protein-1 (AP-1) binding to the VEGF promoter, downregulates the VEGF production without affecting Jak3 activity. Similarly, inhibitors of Jak3 inhibit the VEGF production without affecting JNK activity. Downregulation of Stat3 with small interfering RNA has no effect, whereas curcumin, an inhibitor of both Jak3 and the JNKs, almost completely blocks the VEGF production. In conclusion, we provide evidence of VEGF production in CTCL, which is promoted by aberrant activation of Jak3 and the JNKs. Inhibition of VEGF-inducing pathways or neutralization of VEGF itself could represent novel therapeutic modalities in CTCL.

Geodesic photogrammetry for localizing sensor positions in dense-array EEG.

OBJECTIVE: An important goal for functional brain studies using EEG technology is to estimate the location of brain sources that produce the scalp-recorded signals. The accuracy of source estimates is dependent upon many variables, one of which is the accurate description of the scalp positions of the EEG sensors. The objective of the present research was to develop a photogrammatic method for sensor localization that is fast, accurate, and easy to use. METHODS: With the novel photogrammetric method, multiple cameras were arranged in a geodesic array, and images of the sensors on the subject's head were acquired allowing for the reconstruction of the 3D sensor positions. RESULTS: Data from the photogrammetric method were compared with data acquired with the conventional electromagnetic method. The accuracy of the photogrammatic method, quantified as RMS of the measured positions and the actual known positions, was similar (mean error = 1.27 mm) to the electromagnetic method (mean error = 1.02 mm), and both approximated the localization error of the calibration object (mean error = 0.56 mm). CONCLUSIONS: Accurate determination of 3D sensor positions can be accomplished with minimal demands on the time of the subject and the experimenter using the photogrammetric method.

Crystal structure and spectroscopic properties of CsVO2SO4.

Dark crystals of the V(V) compound CsVO(2)SO(4), suitable for X-ray investigations have been obtained from the catalytically important Cs(2)S(2)O(7)-V(2)O(5) system. By cooling of the mixture with the composition X(V)2(O)5 = 0.5, some crystals were obtained in the otherwise glassy sample. The compound crystallizes in the orthorhombic space group Pbca with a = 6.6688(13) A, b = 10.048(2) A, and c = 17.680(4) A at 20 degrees C and Z = 8. It contains a coordination sphere with a short V-O bond of 1.595(2) A and trans to this the closest VO distance at 3.4 A and four equatorial V-O bonds in the range 1.725(1)-1.984(2) A. The deformation of the VO(6) octahedron is thus much more pronounced compared to other known oxo sulfato V(V) compounds, and the coordination polyhedron of V(V) should be regarded as a tetragonal pyramid with the vanadium atom in the center. Each VO(2)(+) group is coordinated to the neighboring groups by oxygen and sulfate double bridges in a zigzag structure where two sulfate oxygens virtually remain uncoordinated-one is found at the very long nonbonding V-O distance from the neighboring chain. This is the first time that we find pentacoordination of vanadium in the 12 different V(III), V(IV), and V(V) compounds examined so far. The FTIR and Raman spectra of the compound are in agreement with the simple formula unit of the investigated compound.

In vivo activation of STAT3 in cutaneous T-cell lymphoma. Evidence for an antiapoptotic function of STAT3.

A characteristic feature of neoplastic transformation is a perpetual activation of oncogenic proteins. Here, we studied signal transducers and activators of transcription (STAT) in patients with mycosis fungoides (MF)/cutaneous T-cell lymphoma (CTCL). Malignant lymphocytes in dermal infiltrates of CTCL tumors showed frequent and intense nuclear staining with anti-PY-STAT3 antibody, indicating a constitutive activation of STAT3 in vivo in tumor stages. In contrast, only sporadic and faint staining was observed in indolent lesions of patch and plaque stages of MF. Moreover, neoplastic lymphocytes in the epidermal Pautrier abscesses associated with early stages of MF did not express activated STAT3. To address the role of STAT3 in survival/apoptosis, CTCL tumor cells from an advanced skin tumor were transfected with either wild-type STAT3 (STAT3wt) or dominant-negative STAT3 (STAT3D). Forced inducible expression of STAT3D triggered a significant increase in tumor cells undergoing apoptosis, whereas forced expression of STAT3wt or empty vector had no effect. In conclusion, a profound in vivo activation of STAT3 is observed in MF tumors but not in the early stages of MF. Moreover, STAT3 protects tumor cells from apoptosis in vitro. Taken together, these findings suggest that STAT3 is a malignancy factor in CTCL.

Crystal structure and spectroscopic properties of Na(2)K(6)(VO)(2)(SO(4))(7).

Red-brown crystals of a new mixed alkali oxo sulfato vanadium(V) compound Na(2)K(6)(VO)(2)(SO(4))(7), suitable for X-ray determination, have been obtained from the catalytically important binary molten salt system M(2)S(2)O(7)-V(2)O(5) (M = 80% K and 20% Na). By slow cooling of a mixture with the mole fraction X(V(2)O(5)) = 0.24 from 325 degrees C, i.e., just below the liquidus temperature, to the solidus temperature of around 300 degrees C, a dark reddish amorphous phase was obtained containing crystals of the earlier described V(V)-V(IV) mixed valence compound K(6)(VO)(4)(SO(4))(8) and Na(2)K(6)(VO)(2)(SO(4))(7) described here. This compound crystallizes in the tetragonal space group P4(3)2(1)2 (No. 96) with a = 9.540(3) A, c = 29.551(5) A at 20 degrees C and Z = 4. It contains a distorted VO(6) octahedron with a short V-O bond of 1.552(6) A, a long one of 2.276(5) A trans to this, and four equatorial V-O bonds in the range 1.881(6)-1.960(6) A. The deformation of the VO(6) octahedron is less pronounced compared to that of the known oxo sulfato V(V) compounds. Each VO(3+) group is coordinated to five sulfate groups of which two are unidentately coordinated and three are bidentate bridging to neighboring VO(3+) groups. The length of the S-O bonds in the S-O-V bridges of the two unidentately coordinated sulfato groups are 1.551(6) A and 1.568(6) A, respectively, which are unusually long compared to our earlier measurements of sulfate groups in other V(III), V(IV), and V(V) compounds.

Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells.

Interleukin-2 (IL-2) is a growth factor which upon binding to high-affinity receptors (IL-2Ralphabetagamma) triggers mitogenesis in T cells. IL-2Ralpha expression is restricted to T cells which have recently encountered antigen, and in healthy individuals the majority (>95%) of peripheral T cells are IL-2Ralpha negative. An aberrant expression of IL-2Ralpha has recently been described in cutaneous T-cell lymphoma (CTCL). Here, we study the regulation of IL-2Ralpha expression and STATs in a tumor cell line obtained from peripheral blood from a patient with Sezary syndrome (SS), a leukemic variant of CTCL. We show that (1) STAT3 (a transcription factor known to regulate IL-2Ralpha transcription) is constitutively tyrosine-phosphorylated in SS tumor cells, but not in non-malignant T cells; (2) STAT3 binds constitutively to a STAT-binding sequence in the promotor of the IL-2Ralpha gene; (3) the Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel; and (4) tyrphostine AG490 inhibits IL-2 driven mitogenesis and triggers apoptosis in SS tumor cells. In conclusion, we provide the first example of a constitutive STAT3 activation in SS tumor cells. Moreover, our findings suggest that STAT3 activation might play an important role in the constitutive IL-2Ralpha expression, survival, and growth of malignant SS cells.

[Can readmission after apoplexy be prevented? Post-hospital follow-up intervention for apoplexy patients]. / Kan genindlaeggelse af apopleksiramte forebygges? Resultater af et randomiseret interventionsstudium. Posthospital opfølgende indsats til apopleksipatienter.

INTRODUCTION: The aim of this study was to evaluate two models of an organised postdischarge follow-up service for stroke survivors in comparison with standard aftercare. METHODS: One hundred and fifty-five stroke patients discharged to their homes with lasting impairment were randomised as follows: 54 to follow-up home visits by a physician (INT1-HVP), 53 to instruction by a physiotherapist in their home (INT2-PI), and 48 to standard aftercare (control). Six months after discharge, data on readmission were collected. RESULTS: The readmission rate over the six-month period was 26% in the INT1-HVP group, 34% in the INT2-PI group, and 44% for the controls (p = 0.028). Multivariate analysis of the readmission risk showed a significant, favourable effect of intervention in interaction with the length of hospital stay (p = 0.0332), which indicates that the effect of intervention was strongest for patients with a long inpatient rehabilitation. DISCUSSION: Follow-up intervention after discharge seems to be a way of preventing readmission, especially for patients with a long inpatient rehabilitation.

Oligonucleotide fishing for STAT6: cross-talk between IL-4 and chemokines.

Signal transducer and activator of transcription 6 (STAT6) is essential for the biological activities of interleukin-4 (IL-4) and the development of allergic responses in mice. Here we report on a sensitive and specific assay for STAT6 activation in response to IL-4. We took advantage of double-stranded oligonucleotide probes containing a STAT6-binding gene-sequence from the promotor of the immunoglobulin heavy chain germline epsilon transcript to study the IL-4-induced DNA binding of STAT6. Using these probes, we show that repeated adjacent STAT6-binding sites result in enhanced STAT6-DNA binding. Moreover, the distance between the binding sites is critical for STAT-DNA binding, i.e. STAT6 binding is decreased at distances above 20 nucleotides between neighbouring binding sites. Using this assay to study cross-talk between IL-4 and chemokines, we provide evidence that MIP-1beta and MIG inhibit IL-4-induced STAT6 activation, whereas other chemokines and cytokines do not. In conclusion, our data show that oligonucleotide fishing is a supplementary tool for studying cytokine cross-talk at a genomic level.

HbAlc in an unselected population of 4438 people with type 2 diabetes in a Danish county.

OBJECTIVE: To describe the use and level of HbA1c in a large unselected Type 2 diabetic population in Denmark. In addition, to describe the characteristics of the patients and the general practitioners in relation to the monitoring of HbA1c. DESIGN: Data were collected from public data files for the period January 1993 to December 1997. SETTING: The County of Vejle with a background population of 342,597 citizens, 303,250 of whom were listed with participating general practitioners. PATIENTS: The Type 2 diabetic population alive and resident in the county on 1 January 1997. RESULTS: In a population of 4438 Type 2 diabetics, 73% had a minimum of one annual HbA1c measurement in 1997. No HbA1c measurement was associated with a long history of diabetes, diet treatment or old age. Poor glycaemic regulation was found in 65% of the Type 2 diabetics in 1997. Poor glycaemic regulation was associated with tablet or insulin treatment, age under 70 years and long history of diabetes. The interpractice variation was huge. CONCLUSION: The quality of HbA1c monitoring of Type 2 diabetics needs to be improved. Possibilities for improvement seem to be present.

Regional head tissue conductivity estimation for improved EEG analysis.

We develop a method for estimating regional head tissue conductivities in vivo, by injecting small (1-10 microA) electric currents into the scalp, and measuring the potentials at the remaining electrodes of a dense-array electroencephalography net. We first derive analytic expressions for the potentials generated by scalp current injection in a four-sphere model of the human head. We then use a multistart downhill simplex algorithm to find regional tissue conductivities which minimize the error between measured and computed scalp potentials. Two error functions are studied, with similar results. The results show that, despite the low skull conductivity and expected shunting by the scalp, all four regional conductivities can be determined to within a few percent error. The method is robust to the noise levels expected in practice. To obtain accurate results the cerebrospinal fluid must be included in the forward solution, but may be treated as a known parameter in the inverse solution.

Pharmacokinetics of rectal paracetamol after repeated dosing in children.

Twenty-three children (aged between 9 weeks and 11 yr) were given paracetamol suppositories 25 mg kg-1 every 6 h (maximum 5 days) after major surgery and serum and saliva concentrations were measured. There was a good correlation (r = 0.91, P < 0.05) between saliva and serum concentrations. A one-compartment linear model with first-order elimination and absorption and lag-time was fitted to the data (ADAPT II). At steady state, the mean (SD) concentration was 15.2 (6.8) mg litre-1. Mean (SD) time to reach 90% of the steady state concentration was 11.4 (8.6) h. Body weight, age and body surface area were well correlated (P < 0.05) with clearance and apparent volume of distribution. There was no evidence of accumulation leading to supratherapeutic concentrations during this dosing schedule for a mean of approximately 2-3 days.

Molecular cloning, genomic organization, developmental regulation, and a knock-out mutant of a novel leu-rich repeats-containing G protein-coupled receptor (DLGR-2) from Drosophila melanogaster.

After screening the Berkeley Drosophila Genome Project database with sequences from a recently characterized Leu-rich repeats-containing G protein-coupled receptor (LGR) from Drosophila (DLGR-1), we identified a second gene for a different LGR (DLGR-2) and cloned its cDNA. DLGR-2 is 1360 amino acid residues long and shows a striking structural homology with members of the glycoprotein hormone [thyroid-stimulating hormone (TSH); follicle-stimulating hormone (FSH); luteinizing hormone/choriogonadotropin (LH/CG)] receptor family from mammals and with two additional, recently identified mammalian orphan LGRs (LGR-4 and LGR-5). This homology includes the seven transmembrane region (e.g., 49% amino acid identity with the human TSH receptor) and the very large extracellular amino terminus. This amino terminus contains 18 Leu-rich repeats-in contrast with the 3 mammalian glycoprotein hormone receptors and DLGR-1 that contain 9 Leu-rich repeats, but resembling the mammalian LGR-4 and LGR-5 that each have 17 Leu-rich repeats in their amino termini. The DLGR-2 gene is >18.6 kb pairs long and contains 15 exons and 14 introns. Four intron positions coincide with the intron positions of the three mammalian glycoprotein hormone receptors and have the same intron phasing, showing that DLGR-2 is evolutionarily related to these mammalian receptors. The DLGR-2 gene is located at position 34E-F on the left arm of the second chromosome and is expressed in embryos and pupae but not in larvae and adult flies. Homozygous knock-out mutants, where the DLGR-2 gene is interrupted by a P element insertion, die around the time of hatching. This finding, together with the expression data, strongly suggests that DLGR-2 is exclusively involved in development.

Can readmission after stroke be prevented? Results of a randomized clinical study: a postdischarge follow-up service for stroke survivors.

BACKGROUND AND PURPOSE: About 50% of stroke survivors are discharged to their homes with lasting disability. Knowledge, however, of the importance of follow-up services that targets these patients is sparse. The purpose of the present study was to evaluate 2 models of follow-up intervention after discharge. The study hypothesis was that intervention could reduce readmission rates and institutionalization and prevent functional decline. We report the results regarding readmission. METHODS: This randomized study included 155 stroke patients with persistent impairment and disability who, after the completion of inpatient rehabilitation, were discharged to their homes. The patients were randomized to 1 of 2 follow-up interventions provided in addition to standard care or to standard aftercare. Fifty-four received follow-up home visits by a physician (INT1-HVP), 53 were provided instructions by a physiotherapist in their home (INT2-PI), and 48 received standard aftercare only (controls). Baseline characteristics for the 3 groups were comparable. Six months after discharge, data were obtained on readmission and institutionalization. RESULTS: The readmission rates within 6 months after discharge were significantly lower in the intervention groups than in the control group (INT1-HVP 26%, INT2-PI 34%, controls 44%; P=0.028). Multivariate analysis of readmission risk showed a significant favorable effect of intervention (INT1-HVP or INT2-PI) in interaction with length of hospital stay (P=0.0332), indicating that the effect of intervention was strongest for patients with a prolonged inpatient rehabilitation. CONCLUSIONS: Readmission is common among disabled stroke survivors. Follow-up intervention after discharge seems to be a way of preventing readmission, especially for patients with long inpatient rehabilitation.