Effects of Arterial Stiffness on Cerebral WM Integrity in Older Adults: A Neurite Orientation Dispersion and Density Imaging and Magnetization Transfer Saturation Imaging Study.

BACKGROUND AND PURPOSE: Arterial stiffness is reported to be able to cause axonal demyelination or degeneration. The present study aimed to use advanced MR imaging techniques to examine the effect of arterial stiffness on the WM microstructure among older adults. MATERIALS AND METHODS: Arterial stiffness was measured using the cardio-ankle vascular elasticity index (CAVI). The high-CAVI (mean CAVI ≥ 9 points) and the low-CAVI groups (mean CAVI < 9 points) were created. The neuronal fiber integrity of the WM was evaluated by neurite orientation dispersion and density imaging and magnetization transfer saturation imaging. Tract-Based Spatial Statistics and the tracts-of-interest analysis were performed. Specific WM regions (corpus callosum, internal capsule, anterior thalamic radiation, corona radiata, superior longitudinal fasciculus, forceps minor, and inferior fronto-occipital fasciculus) were selected in the tracts-of-interest analysis. RESULTS: In Tract-Based Spatial Statistics, the high-CAVI group showed a significantly lower myelin volume fraction value in the broad WM and significantly higher radial diffusivity and isotropic volume fraction values in the corpus callosum, forceps minor, inferior fronto-occipital fasciculus, internal capsule, corona radiata, and anterior thalamic radiation than the low-CAVI group. In tracts-of-interest analysis using multivariate linear regression, significant associations were found between the mean CAVI and radial diffusivity in the anterior thalamic radiation and the corona radiata; isotropic volume fraction in the anterior thalamic radiation and the corona radiata; and myelin volume fraction in the superior longitudinal fasciculus (P < .05). Additionally, partial correlation coefficients were observed for the significant associations of executive function with radial diffusivity and myelin volume fraction (P < .05). CONCLUSIONS: Arterial stiffness could be associated with demyelination rather than axonal degeneration.

An Investigation of Water Diffusivity Changes along the Perivascular Space in Elderly Subjects with Hypertension.

BACKGROUND AND PURPOSE: Hypertension may be related to alterations of the glymphatic system, a waste metabolite drainage system in the brain. We aimed to investigate analysis along the perivascular space index changes in elderly subjects with hypertension. MATERIALS AND METHODS: Diffusion-weighted images were acquired from 126 subjects, including 63 subjects with hypertension (25 men and 38 women; mean age, 72.45 years) and 63 age- and sex-matched controls (25 men and 38 women; mean age, 72.16 years). We calculated the analysis along the perivascular space index as a ratio of the mean of x-axis diffusivities in the projection and association areas to the mean of y-axis diffusivity in the projection area and z-axis diffusivity in the association area. The left, right, and mean analysis along the perivascular space indices of both hemispheres were compared between the hypertension and control groups using a Mann-Whitney U test. The Spearman correlation coefficient was used to assess the correlation between the left, right, and mean ALPS indices and blood pressure and pulse pressure. RESULTS: The left (P = .011) and mean (P = .024) analysis along the perivascular space indices of the hypertension group were significantly lower than that of the control group. The left, right, and mean analysis along the perivascular space indices of all subjects were significantly negatively correlated with blood pressure values (r = -0.200 to -0.278, P = .002-0.046) and pulse pressure values (r = -0.221 to -0.245, P = .006-0.013). CONCLUSIONS: Our results are consistent with a model in which hypertension causes glymphatic dysfunction.

Discussion of "Attitude of physicians towards automatic alerting in computerized physician order entry systems".

With these comments on the paper "Attitude of Physicians Towards Automatic Alerting in Computerized Physician Order Entry Systems", written by Martin Jung and co-authors, with Dr. Elske Ammenwerth as senior author [1], the journal wants to stimulate a broad discussion on computerized physician order entry systems. An international group of experts have been invited by the editor of Methods to comment on this paper. Each of the invited commentaries forms one section of this paper.

Data analysis and data mining: current issues in biomedical informatics.

BACKGROUND: Medicine and biomedical sciences have become data-intensive fields, which, at the same time, enable the application of data-driven approaches and require sophisticated data analysis and data mining methods. Biomedical informatics provides a proper interdisciplinary context to integrate data and knowledge when processing available information, with the aim of giving effective decision-making support in clinics and translational research. OBJECTIVES: To reflect on different perspectives related to the role of data analysis and data mining in biomedical informatics. METHODS: On the occasion of the 50th year of Methods of Information in Medicine a symposium was organized, which reflected on opportunities, challenges and priorities of organizing, representing and analysing data, information and knowledge in biomedicine and health care. The contributions of experts with a variety of backgrounds in the area of biomedical data analysis have been collected as one outcome of this symposium, in order to provide a broad, though coherent, overview of some of the most interesting aspects of the field. RESULTS: The paper presents sections on data accumulation and data-driven approaches in medical informatics, data and knowledge integration, statistical issues for the evaluation of data mining models, translational bioinformatics and bioinformatics aspects of genetic epidemiology. CONCLUSIONS: Biomedical informatics represents a natural framework to properly and effectively apply data analysis and data mining methods in a decision-making context. In the future, it will be necessary to preserve the inclusive nature of the field and to foster an increasing sharing of data and methods between researchers.

Comparing a Japanese and a German hospital information system.

OBJECTIVES: To examine the architectural differences and similarities of a Japanese and German hospital information system (HIS) in a case study. This cross-cultural comparison, which focuses on structural quality characteristics, offers the chance to get new insights into different HIS architectures, which possibly cannot be obtained by inner-country comparisons. METHODS: A reference model for the domain layer of hospital information systems containing the typical enterprise functions of a hospital provides the basis of comparison for the two different hospital information systems. 3LGM(2) models, which describe the two HISs and which are based on that reference model, are used to assess several structural quality criteria. Four of these criteria are introduced in detail. RESULTS: The two examined HISs are different in terms of the four structural quality criteria examined. Whereas the centralized architecture of the hospital information system at Chiba University Hospital causes only few functional redundancies and leads to a low implementation of communication standards, the hospital information system at the University Hospital of Leipzig, having a decentralized architecture, exhibits more functional redundancies and a higher use of communication standards. CONCLUSIONS: Using a model-based comparison, it was possible to detect remarkable differences between the observed hospital information systems of completely different cultural areas. However, the usability of 3LGM(2) models for comparisons has to be improved in order to apply key figures and to assess or benchmark the structural quality of health information systems architectures more thoroughly.

Automatic DPC code selection from electronic medical records: text mining trial of discharge summary.

OBJECTIVES: We extracted index terms related to diseases recorded in hospital discharge summaries and examined the capability of the vector space model to select a suitable diagnosis with these terms. METHODS: By morphological analysis, we extracted index terms and constructed an original dictionary for the discharge summary analysis. We chose 125 different DPC (Japanese DRG system) codes for the diseases, each of which had more than 20 cases. We divided them into two groups. One group consisted of 5927 cases from 2004 fiscal year and was used to generate the document vector space according to the DPC. The other group of 3187 cases was collected to verify the automatic DPC selection by using data from 2005 fiscal year. The top 200 extracted index terms for each disease were used to calculate the weight of each disease. RESULTS: The DPC code obtained by the calculated similarity was compared with the original codes of patients for 125 DPCs of 3187 cases. Eighty percent of the cases matched the diagnosis of the DPC (first six digits) and 56% of the cases completely matched all 14 digits of the DPC. CONCLUSIONS: We demonstrated that we could extract suitable terms for each disease and obtain characteristics, such as the diagnosis, from the calculated vectors. This technique can be used to measure the qualification of discharge summaries and to integrate discharge summaries among different facilities. By the text mining technique, we can characterize the contents of electronic discharge summaries and deduce diagnoses with the data.

Commentaries on "Informatics and medicine: from molecules to populations".

OBJECTIVE: To discuss interdisciplinary research and education in the context of informatics and medicine by commenting on the paper of Kuhn et al. "Informatics and Medicine: From Molecules to Populations". METHOD: Inviting an international group of experts in biomedical and health informatics and related disciplines to comment on this paper. RESULTS AND CONCLUSIONS: The commentaries include a wide range of reasoned arguments and original position statements which, while strongly endorsing the educational needs identified by Kuhn et al., also point out fundamental challenges that are very specific to the unusual combination of scientific, technological, personal and social problems characterizing biomedical informatics. They point to the ultimate objectives of managing difficult human health problems, which are unlikely to yield to technological solutions alone. The psychological, societal, and environmental components of health and disease are emphasized by several of the commentators, setting the stage for further debate and constructive suggestions.

Activation of pulmonary T cells in corticosteroid-resistant and -sensitive interstitial pneumonitis in dermatomyositis/polymyositis.

To study the activation states and cytokine profiles of pulmonary T cells in corticosteroid-resistant and corticosteroid-sensitive interstitial pneumonitis (IP) in dermatomyositis (DM)/polymyositis (PM), we examined the activation markers and cytokine profiles of T cells in bronchoalveolar lavage fluids (BALF) from patients with IP in DM/PM before prednisolone therapy and then compared the activation states of T cells according to the therapeutic response of IP to prednisolone therapy. CD25+ CD4+ T cells in BALF were significantly increased in both corticosteroid-resistant and corticosteroid-sensitive IP in DM/PM as compared with those in controls without IP. Furthermore, CD25+ CD4+ T cells in BALF were significantly more increased in corticosteroid-resistant IP than those in cortico teroid- sensitive IP. Moreover, CD25+ CD8+ T cells in BALF were significantly increased only in corticosteroid-resistant IP, but not in corticosteroid-sensitive IP or controls without IP. IFN-gamma mRNA was detected in BALF T cells in corticosteroid-resistant and corticosteroid-sensitive IP but not in controls without IP, whereas IL-4 mRNA was virtually undetected in BALF T cells in both the IP groups. However, there were no significant differences in CD4/CD8 ratio of BALF T cells, HLA-DR+ BALF T cells or CD25+ and HLA-DR+ peripheral blood T cells between the two IP groups. These results indicate that activated Th1-type pulmonary T cells play an important role in the development of corticosteroid- resistant IP in DM/PM and that the increase in CD25+ CD8+ T cells in BALF is a useful indicator for corticosteroid-resistant IP in DM/PM and hence may be an indicator for early use of cyclosporin.

Osteonecrosis in patients with systemic lupus erythematosus develops very early after starting high dose corticosteroid treatment.

OBJECTIVES: To investigate the actual time of onset of osteonecrosis (ON) after high dose corticosteroid treatment in systemic lupus erythematosus (SLE). METHODS: 72 patients with active SLE, who received high dose corticosteroid for the first time, for the development of ON at hips and knees were monitored by magnetic resonance imaging for at least 12 months. RESULTS: ON lesions were detected in 32/72 patients (44%) between one and five months (3.1 months on average) after starting high dose corticosteroid treatment. No osteonecrotic lesion was newly detected from the sixth month of treatment until the end of the follow up period. CONCLUSION: The findings suggested that the actual time of onset of ON in SLE is within the first month of high dose corticosteroid treatment.

Enhancement of innate immunity against Mycobacterium avium infection by immunostimulatory DNA is mediated by indoleamine 2,3-dioxygenase.

Bacterial DNA and its synthetic immunostimulatory oligodeoxynucleotide analogs (ISS-ODN) activate innate immunity and promote Th1 and cytotoxic T-lymphocyte immune responses. Based on these activities, we investigated whether ISS-ODN could modify the course of Mycobacterium avium infection. M. avium growth in vitro was significantly inhibited by ISS-ODN treatment of human and mouse macrophages, and M. avium growth in vivo was similarly inhibited in C57BL/6 mice treated with ISS-ODN. This protective effect of ISS-ODN was largely independent of tumor necrosis factor alpha (TNF-alpha), interleukin 12 (IL-12), nitric oxide, NADPH oxidase, alpha/beta interferon (IFN-alpha/beta), and IFN-gamma. In contrast, we found that the induction of indoleamine 2,3-dioxygenase (IDO) was required for the antimycobacterial effect of ISS-ODN. To evaluate the potential for synergism between ISS-ODN and other antimycobacterial agents, treatment with a combination of ISS-ODN and clarithromycin (CLA) was tested in vitro and in vivo. ISS-ODN significantly enhanced the therapeutic effect of CLA in both human and mouse macrophages and in C57BL/6 mice. This study newly identifies IDO as being involved in the antimicrobial activity of ISS-ODN and suggests the usefulness of ISS-ODN when used in combination with conventional chemotherapy for microbial infections.

Immunostimulatory DNA inhibits IL-4-dependent IgE synthesis by human B cells.

BACKGROUND: Immunostimulatory sequence oligodeoxynucleotide (ISS-ODN) is a potent antiallergic immunomodulating agent in mice. However, few studies have addressed its antiallergic potential in human subjects. OBJECTIVE: We sought to determine whether a phosphoro-thioate ISS-ODN could inhibit IL-4-dependent IgE synthesis by human B cells. METHODS: Initially, nonatopic- and atopic-donor PBMCs were incubated with ISS-ODN or mutated oligodeoxynucleotide, and cytokine production and B-cell expression of IFN-gamma receptor and IL-4 receptor were measured by using ELISA and flow cytometry, respectively. In subsequent studies atopic-donor PBMCs were incubated with IL-4 alone or with ISS-ODN or mutated oligodeoxynucleotide. After 14 days, IgE production and IgM, IgG, and IgA production were determined by using ELISA. In select IgE studies cytokines were neutralized with mAbs. RESULTS: ISS-ODN induced IL-12, IFN-alpha, IFN-gamma, IL-10, and IL-6 production from both nonatopic- and atopic-donor PBMCs. ISS-ODN also increased IFN-gamma receptor and inhibited IL-4 receptor expression on B cells from both donor populations. Furthermore, ISS-ODN inhibited IL-4-dependent IgE production by atopic-donor PBMCs. Neutralization of IL-12, IFN-alpha, IFN-gamma, and IL-10, but not IL-6, attenuated the inhibitory activity of ISS-ODN on IgE production. In contrast to its inhibition of IgE synthesis, ISS-ODN stimulated the production of IgM, IgG, and IgA. CONCLUSION: These in vitro studies demonstrate that phos-phorothioate ISS-ODN elicits an innate immune response by PBMCs, which inhibits IL-4-dependent IgE synthesis. In addition, these results provide further support for consideration of ISS-ODN therapy for the treatment of allergic disease in clinical practice.

Immunostimulatory DNA-based vaccines elicit multifaceted immune responses against HIV at systemic and mucosal sites.

Immunostimulatory DNA sequences (ISS, also known as CpG motifs) are pathogen-associated molecular patterns that are potent stimulators of innate immunity. We tested the ability of ISS to act as an immunostimulatory pathogen-associated molecular pattern in a model HIV vaccine using gp120 envelope protein as the Ag. Mice immunized with gp120 and ISS, or a gp120:ISS conjugate, developed gp120-specific immune responses which included: 1) Ab production; 2) a Th1-biased cytokine response; 3) the secretion of beta-chemokines, which are known to inhibit the use of the CCR5 coreceptor by HIV; 4) CTL activity; 5) mucosal immune responses; and 6) CD8 T cell responses that were independent of CD4 T cell help. Based on these results, ISS-based immunization holds promise for the development of an effective preventive and therapeutic HIV vaccine.

Selective reduction and recovery of invariant Valpha24JalphaQ T cell receptor T cells in correlation with disease activity in patients with systemic lupus erythematosus.

OBJECTIVE: To study the regulatory role of CD4-CD8- double-negative (DN) invariant T cell receptor (TCR) Valpha24JalphaQ T cells, a human counterpart of murine NK 1 + T cells, in the autoimmune process of systemic lupus erythematosus (SLE). METHODS: We carried out a 2 step frequency analysis of DN Valpha24JalphaQ T cells in patients with SLE before and after prednisolone therapy; the frequency of DN Valpha24+ T cells was determined by 3 color FACS analysis and subsequently the frequency of Valpha24JalphaQ rearrangement among DN Valpha24+ T cells was determined by sequencing. RESULTS: DN Valpha24+ T cells were significantly increased in patients with active SLE compared to healthy subjects. In healthy subjects, invariant Valpha24JalphaQ TCR dominated in DN Valpha24+ T cells at a high frequency (93-100%). However, the invariant Valpha24JalphaQ TCR was not detected in DN Valpha24+ T cells from patients with active SLE, and instead 2 to 9 Jalpha genes other than the invariant JalphaQ were oligoclonally expanded in the patients. In inactive SLE induced by prednisolone therapy, the invariant Valpha24JalphaQ TCR could be detected in DN Valpha24+ T cells from all the patients and dominated in most of the patients. Further, oligoclonally expanded Valpha24+ clones other than the invariant JalphaQ gene in active disease states were significantly decreased by prednisolone therapy. CONCLUSION: The selective reduction of DN invariant Valpha24JalphaQ T cells is related to the disease progression of SLE, while DN TCR Valpha24 T cells other than Valpha24JalphaQ T cells constitute autoaggressive T cells in SLE.

Increased interleukin-17 production in patients with systemic sclerosis.

OBJECTIVE: To determine the role of a novel T cell-derived cytokine, interleukin-17 (IL-17), which activates fibroblasts and endothelial cells, in the pathogenesis of systemic sclerosis (SSc). METHODS: We examined IL-17 production by lymphocytes from the peripheral blood (PBL) and from fibrotic lesions of the skin and lungs of SSc patients by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. We also studied the effect of IL-17 on the proliferation of fibroblasts and on the production of cytokines and the expression of adhesion molecules on endothelial cells in vitro. RESULTS: IL-17 messenger RNA was expressed in unstimulated PBL and lymphocytes from the skin and lungs of SSc patients, but not in similar samples from patients with systemic lupus erythematosus (SLE) or polymyositis/dermatomyositis or from healthy donors. IL-17 levels were also increased in the serum of SSc patients, but not in that of SLE patients or healthy donors. IL-17 overproduction was significantly related to the early stage of SSc, but not to other clinical features of SSc. Moreover, IL-17 enhanced the proliferation of fibroblasts and induced the expression of adhesion molecules and IL-1 production in endothelial cells in vitro. CONCLUSION: IL-17 is overproduced by T cells from the peripheral blood and fibrotic lesions of the skin and lungs in SSc patients. These results suggest that IL-17 overproduction plays an important role in the pathogenesis of SSc, especially in the early stages of the disease, by inducing the proliferation of fibroblasts and the production of IL-1 and the expression of adhesion molecules on endothelial cells.

Sustained hemostatic abnormality in patients with steroid-induced osteonecrosis in the early period after high-dose corticosteroid therapy.

To determine whether the development of steroid-induced osteonecrosis in collagen disease patients was related to hemostatic abnormality after corticosteroid administration, we examined levels of thrombin-antithrombin III complex (TAT) and plasmin-alpha2-plasmin inhibitor complex (PIC) in 32 patients who were treated with high-dose corticosteroid. All were prospectively followed for osteonecrosis, with serial magnetic resonance imaging (MRI), for at least 12 months from the beginning of corticosteroid therapy. MRI was performed on bilateral hips and knees. Of the 32 patients, 17 (53.1%) had osteonecrosis in the hip or knee. Osteonecrosis was detected on MRI at an average 3.1 months after the start of high-dose corticosteroid therapy. PIC levels were significantly higher in the group of 17 patients with osteonecrosis (ON group) than in the group of 15 patients without osteonecrosis (non-ON group) (P < 0.0001). The difference in PIC levels was most prominent 20 days after the start of the high-dose corticosteroid therapy. Moreover, the number of osteonecrotic joints was significantly correlated with PIC levels (P < 0.0001). The sustained hemostatic abnormality after corticosteroid therapy in the ON group suggests that microvascular coagulation participates in the development of osteonecrosis.

Conjugation of protein to immunostimulatory DNA results in a rapid, long-lasting and potent induction of cell-mediated and humoral immunity.

Immunostimulatory DNA sequences (ISS) are a potent Th1 adjuvant. We hypothesized that conjugation of ISS to protein antigens would strongly enhance their immunogenicity because both antigen and adjuvant (ISS) would be delivered to the same locale/antigen-presenting cell. To test this hypothesis, we conjugated a 22-mer immunostimulatory oligodeoxynucleotide (ISS-ODN) to two test antigens of differing intrinsic immunogenicity, namely Escherichia coli beta-galactosidase and the HIV-1 envelope glycoprotein gp120. We show that the antigen-ISS conjugates rapidly induce Th1 cells secreting high levels of IFN-gamma, strong CTL activity, and high titer IgG2a and HIV-neutralizing antibodies, exceeding gene and protein vaccination alone or immunization with mixtures of antigen and ISS-ODN. The data suggest that this procedure generates a novel and unique vaccine that rapidly triggers strong humoral and cell-mediated immunity.

Conjugation of immunostimulatory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity.

BACKGROUND: Allergen immunotherapy is inconvenient and associated with the risk of anaphylaxis. Efforts to improve the safety of immunotherapy by means of chemical modification of allergens have not been successful because it greatly reduced their antigenicity. Recently, immunostimulatory DNA sequences (ISS or CpG motifs) have been shown to act as strong T(H)1 response-inducing adjuvants. OBJECTIVE: We sought to determine whether conjugation of ISS to the major short ragweed allergen Amb a 1 results in enhanced immunotherapeutic potential in mice and decreased allergenicity in human subjects. METHODS: A 22-mer ISS oligodeoxynucleotide (ISS-ODN) was coupled to Amb a 1 and used for immunization of mice, rabbits, and monkeys. RESULTS: In mice the Amb a 1-ISS conjugate induced a T(H)1 response (IFN-gamma secretion), whereas Amb a 1 induced a T(H)2 response (IL-5 secretion). The T(H)1 response was not observed with an Amb a 1-non-ISS conjugate. Coinjection of Amb a 1 with ISS-ODN was much less effective in inducing a T(H)1 response. In mice primed for a T(H)2 response, injection with Amb a 1-ISS conjugate induced a de novo T(H)1 response and suppressed IgE antibody formation after challenge with Amb a 1. Amb a 1-ISS conjugate induced high-titer anti-Amb a 1 IgG antibodies in rabbits and cynomolgus monkeys, whereas Amb a 1 alone or Amb a 1 coinjected with ISS-ODN did not induce a detectable response. Amb a 1-ISS conjugate was less allergenic than Amb a 1 alone, as shown by a 30-fold lower histamine release from human basophils of patients with ragweed allergy, whereas mixing ISS-ODN with Amb a 1 did not reduce histamine release. CONCLUSION: Amb a 1-ISS conjugate has an enhanced T(H)1-biased immunogenicity and reduced allergenicity. It may offer a more effective and safer approach for allergen immunotherapy than currently available methods.

Immunostimulatory DNA-based vaccines induce cytotoxic lymphocyte activity by a T-helper cell-independent mechanism.

Immunostimulatory DNA sequences (ISS) contain unmethylated CpG dinucleotides within a defined motif. Immunization with ISS-based vaccines has been shown to induce high antigen-specific cytotoxic lymphocyte (CTL) activity and a Th1-biased immune response. We have developed a novel ISS-based vaccine composed of ovalbumin (OVA) chemically conjugated to ISS-oligodeoxynucleotide (ODN). Protein-ISS conjugate (PIC) is more potent in priming CTL activity and Th1-biased immunity than other ISS-based vaccines. Cytotoxic lymphocyte activation by ISS-ODN-based vaccines is preserved in both CD4-/- and MHC class II-/- gene-deficient animals. Furthermore, PIC provides protection against a lethal burden of OVA-expressing tumor cells in a CD8+ cell-dependent manner. These results demonstrate that PIC acts through two unique mechanisms: T-helper-independent activation of CTL and facilitation of exogenous antigen presentation on MHC class I. This technology may have clinical applications in cancer therapy and in stimulating host defense in AIDS and chronic immunosuppression.