Effectiveness of a real-life program (DIAfit) to promote physical activity in patients with type 2 diabetes: a pragmatic cluster randomized clinical trial.

Introduction: The aim of this study was to evaluate the effectiveness of a real-life clinical physical activity program (DIAfit) on improving physical fitness, body composition, and cardiometabolic health in an unselected population with type 2 diabetes mellitus, and to compare the effects of two variants a different exercise frequencies on the same outcomes. Research design and methods: This was a cluster randomized-controlled assessor-blind trial conducted in 11 clinical centres in Switzerland. All participants in the clinical program with type 2 diabetes were eligible and were randomized to either standard (3 sessions/week for 12 weeks) or alternative (1 session/week for the first four weeks, then 2 sessions/week for the rest of 16 weeks) physical activity program each consisting of 36 sessions of combined aerobic and resistance exercise. Allocation was concealed by a central office unrelated to the study. The primary outcome was aerobic fitness. Secondary outcome measures included: body composition, BMI, HbA1c, muscle strength, walking speed, balance, flexibility, blood pressure, lipid profile. Results: All 185 patients with type 2 diabetes (mean age 59.7 +-10.2 years, 48% women) agreed to participate and were randomized in two groups: a standard group (n=88) and an alternative group (n=97)). There was an 11% increase in aerobic fitness after the program (12.5 Watts; 95% CI 6.76 to 18.25; p<0.001). Significant improvements in physical fitness, body composition, and cardiometabolic parameters were observed at the end of the DIAfit program (improvements between 2-29%) except for lean body mass, triglycerides and cholesterol. No differences were observed between both programs, except for a larger weight reduction of -0.97kg (95% CI -0.04 to -1.91; p=0.04) in the standard program. Conclusions: Both frequency variants of the nation-wide DIAfit program had beneficial effects on physical fitness, HbA1c, body composition, and blood pressure in type 2 diabetes patients and differences were negligible. Clinical trial registration: clinicaltrials.gov, identifier NCT01289587.

Immunity-related GTPase M (IRGM) proteins influence the localization of guanylate-binding protein 2 (GBP2) by modulating macroautophagy.

The immunity-related GTPases (IRGs) are a family of proteins induced by interferon-γ that play a crucial role in innate resistance to intracellular pathogens. The M subfamily of IRG proteins (IRGM) plays a profound role in this context, in part because of the ability of its members to regulate the localization and expression of other IRG proteins. We present here evidence that IRGM proteins affect the localization of the guanylate-binding proteins (GBPs), a second family of interferon-induced GTP-binding proteins that also function in innate immunity. Absence of Irgm1 or Irgm3 led to accumulation of Gbp2 in intracellular compartments that were positive for both the macroautophagy (hereafter referred to as autophagy) marker LC3 and the autophagic adapter molecule p62/Sqstm1. Gbp2 was similarly relocalized in cells in which autophagy was impaired because of the absence of Atg5. Both in Atg5- and IRGM-deficient cells, the IRG protein Irga6 relocalized to the same compartments as Gbp2, raising the possibility of a common regulatory mechanism. However, other data indicated that Irga6, but not Gbp2, was ubiquitinated in IRGM-deficient cells. Similarly, coimmunoprecipitation studies indicated that although Irgm3 did interact directly with Irgb6, it did not interact with Gbp2. Collectively, these data suggest that IRGM proteins indirectly modulate the localization of GBPs through a distinct mechanism from that through which they regulate IRG protein localization. Further, these results suggest that a core function of IRGM proteins is to regulate autophagic flux, which influences the localization of GBPs and possibly other factors that instruct cell-autonomous immune resistance.

Importance of integrin LFA-1 deactivation for the generation of immune responses.

The dynamic regulation of ligand binding is considered crucial for integrin function. However, the importance of activity regulation for integrin function in vivo is largely unknown. Here, we have applied gene targeting to delete the GFFKR sequence of the lymphocyte function-associated antigen-1 (LFA-1) alpha(L) subunit cytoplasmic domain in mouse germline. Lymphocytes from Lfa-1(d/d) mutant mice showed constitutive activation of LFA-1-mediated cell adhesion and impaired de-adhesion from intercellular adhesion molecule-1 that resulted in defective cell migration. In contrast, signaling through LFA-1 was not affected in Lfa-1(d/d) cells. T cell activation by superantigen-loaded and allogeneic APCs, cytotoxic T cell activity, T-dependent humoral immune responses, and neutrophil recruitment during aseptic peritonitis were impaired in Lfa-1(d/d) mice. Thus, deactivation of LFA-1 and disassembly of LFA-1-mediated cell contacts seem to be vital for the generation of normal immune responses.

Reduced notch activity is associated with an impaired marginal zone B cell development and function in Sly1 mutant mice.

MZ B cells represent a distinct lineage of naive B lymphocytes, apart from FO B cells and peritoneal B1 cells, and mediate humoral immune responses against blood-borne type 2 T-independent antigens. Regulation of MZ B cell development involves the Notch receptor signaling, the intensity of B cell receptor signals, and cell compartmentalization by adhesion and chemokine receptors. Our previous work showed that gene-targeted mice expressing a truncated form of the putative signaling adapter protein SLy1 exhibit reduced numbers of a splenic B cell population enriched in MZ B cells. Here, we demonstrate that Sly1(d/d) mice exhibit a partial, but selective, block in the transition from pre-MZ to mature MZ B cells. Development of both T1 and T2 precursor subsets and FO B cells was normal in Sly1(d/d) mice. Consistent with the loss of MZ B cells, the production of antigen-specific IgM antibodies following immunization with pneumococcal polysaccharides was severely impaired in Sly1(d/d) mice. Importantly, expression of the Notch signaling mediator RBP-J and the Notch target genes Hes-1 and Hes-5 was markedly reduced in MZ but not FO B cells of Sly1(d/d) mice. In contrast, B cell receptor signaling, expression and function of LFA-1 and alpha4-integrins, and expression of chemokine receptors appeared intact in Sly1(d/d) cells. Collectively, these results provide strong evidence that SLy1 is important for the generation and function of MZ B cells and suggest a novel link between SLy1 and the activity of the Notch pathway in the development of MZ B cells.

A 3-year follow-up study of a new corneal inlay: clinical results and outcomes.

PURPOSE: Here, we report the results of a 3-year follow-up analysis of the outcomes of the Flexivue Microlens corneal inlay. PATIENTS: Non-dominant eyes (n=31) of emmetropic presbyopic patients (spherical equivalent: -0.5 to 1.00 dioptre). METHODS: A Flexivue Microlens corneal inlay was implanted after the creation of a 300 µm deep stromal pocket using a femtosecond laser. Patients were followed up according to a clinical protocol involving refraction, anterior segment imaging analysis (Oculyser), optical quality analysis (OPD-Scan), monocular binocular uncorrected and corrected visual acuity tests, contrast sensitivity measurements (photopic and mesopic), satisfaction questionnaire results and adverse event reporting. RESULTS: Thirty patients were examined at the 3-year follow-up in this ongoing study. The mean uncorrected near visual acuity improved to Jaeger 1 in 76.9% of eyes treated with the inlays (vs 87.1% at the 1-year follow-up). All eyes improved four lines in all visits, except for four patients for whom the inlay was explanted. Patients reported that their near vision was good or excellent in 73.3% of cases (vs 90.3% in the first year). The UDVA remained stable over time. Three patients were explanted due to blurred vision for near-point and far-point distances. One patient developed a superficial corneal ulcer after 20 months. Two patients underwent cataract removal. Four patients underwent inlay exchange to increase near power correction. CONCLUSIONS: The Presbia Flexivue Microlens provided presbyopia treatment by improving near vision. Manageable complications may occur over the long term. CLINICAL TRIAL REGISTRATION NUMBER: U1111-1185-5684 and 0310451200000550.

Analyses of murine GBP homology clusters based on in silico, in vitro and in vivo studies.

The interactions between pathogens and hosts lead to a massive upregulation of antimicrobial host effector molecules. Among these, the 65 kDa guanylate binding proteins (GBPs) are interesting candidates as intricate components of the host effector molecule repertoire. Members of the GBP family are highly conserved in vertebrates. Previous reports indicate an antiviral activity of human GBP1 (hGBP1) and murine GBP2 (mGBP2). We recently demonstrated that distinct murine GBP (mGBP) family members are highly upregulated upon Toxoplasma gondii infection and localize around the intracellular protozoa T. gondii. Moreover, we characterised five new mGBP family members within the murine 65 kDa GBP family. Here, we identified a new mGBP locus named mGbp11. Based on bacterial artificial chromosome (BAC), expressed sequence tag (EST), and RT-PCR analyses this study provides a detailed insight into the genomic localization and organization of the mGBPs. These analyses revealed a 166-kb spanning region on chromosome 3 harboring five transcribed mGBPs (mGbp1, mGbp2, mGbp3, mGbp5, and mGbp7) and one pseudogene (pseudomGbp1), as well as a 332-kb spanning region on chromosome 5 consisting of six transcribed mGBPs (mGbp4, mGbp6, mGbp8, mGbp9, mGbp10, and mGbp11), and one pseudogene (pseudomgbp2). Besides the strikingly high homology of 65% to 98% within the coding sequences, the mGBPs on chromosome 5 cluster also exhibit a highly homologous exon-intron structure whereas the mGBP on chromosome 3 reveals a more divergent exon-intron structure. This study details the comprehensive genomic organization of mGBPs and suggests that a continuously changing microbial environment has exerted evolutionary pressure on this gene family leading to multiple gene amplifications. A list of links for this article can be found in the Availability and requirements section.

Impaired immune responses and prolonged allograft survival in Sly1 mutant mice.

Adaptive immunity is crucial for protective host defense and the development of immunological disorders. SLY1 was recently identified as an X-chromosomal SH3 protein that is serine phosphorylated (Ser27) upon B-and T-cell receptor engagement. Here, we demonstrate that SLY1 is localized in the cytoplasm and the nucleus of immunocytes. We generated mice expressing a mutant version of SLY1 lacking Ser27 and a functional nuclear localization signal. The defective SLY1 (SLY1(d)) protein is localized exclusively in the cytoplasm. B- and T-cell proliferation is attenuated and T-cell cytokine production is severely reduced. Sly1(d/d) mice exhibit reduced lymphoid organ sizes, diminished marginal zone B-cell numbers, and severely impaired antibody responses against T-dependent and -independent antigens. Importantly, survival of semi-identical cardiac allografts was substantially prolonged in Sly1(d/d) mice. These results define SLY1 as an essential molecular component for the full activation of adaptive immunity.

In silico and in vitro characterization of mGBP4 splice variants.

In a systematic approach to identify interferon-gamma (IFN-gamma)-regulated host effector molecules, we found several members of the 65 kDa guanylate-binding proteins (GBPs) highly upregulated. During extensive characterization of these guanosine triphosphatases (GTPases), we identified discrepancies between the cloned and published sequences of the murine GTPase mGBP4. Two splice variants of mGBP4 could be detected. One variant led to a premature stop codon after 312 bp. The second variant resulted in a transcript with a disrupted G2 domain and was deposited as mGBP4.1 to the GenBank. Interestingly, only mGBP4, not mGBP4.1 mRNA, was highly upregulated in mice after infection with Listeria monocytogenes.

Chronic liver disease is triggered by taurine transporter knockout in the mouse.

Taurine is an abundant organic osmolyte with antioxidant and immunomodulatory properties. Its role in the pathogenesis of chronic liver disease is unknown. The liver phenotype was studied in taurine transporter knockout (taut-/-) mice. Hepatic taurine levels were ~21, 15 and 6 mumol/g liver wet weight in adult wild-type, heterozygous (taut+/-) and homozygous (taut-/-) mice, respectively. Immunoelectronmicroscopy revealed an almost complete depletion of taurine in Kupffer and sinusoidal endothelial cells, but not in parenchymal cells of (taut-/-) mice. Compared with wild-type mice, (taut-/-) and (taut+/-) mice developed moderate unspecific hepatitis and liver fibrosis with increased frequency of neoplastic lesions beyond 1 year of age. Liver disease in (taut-/-) mice was characterized by hepatocyte apoptosis, activation of the CD95 system, elevated plasma TNF-alpha levels, hepatic stellate cell and oval cell proliferation, and severe mitochondrial abnormalities in liver parenchymal cells. Mitochondrial dysfunction was suggested by a significantly lower respiratory control ratio in isolated mitochondria from (taut-/-) mice. Taut knockout had no effect on taurine-conjugated bile acids in bile; however, the relative amount of cholate-conjugates acid was decreased at the expense of 7-keto-cholate-conjugates. In conclusion, taurine deficiency due to defective taurine transport triggers chronic liver disease, which may involve mitochondrial dysfunction.

Ocular wavefront aberrations in patients after diffuse lamellar keratitis.

PURPOSE: To study ocular wavefront aberrations after laser in situ keratomileusis (LASIK) in patients who developed diffuse lamellar keratitis (DLK). METHODS: A case-control evaluation of 47 patients with DLK and 30 uneventful LASIK-operated controls. Measurements of visual acuities, cycloplegic refraction, eye's wave aberrations using a LADARWAVE aberrometer (up to eighth order), and corneal topography were obtained after LASIK treatment. All of the surgeries were performed using the Hansatome or the Moria microkeratome and the LadarVision excimer laser system. RESULTS: Mean follow-up interval from the day of the operative procedure to the examination day was 6.26 (DLK group; range, 2-13 months) and 6.23 months (control group; range, 3-9 months). Mean preoperative spherical equivalent was -3.7 D in patients with DLK and -3.7 D in controls. High-order aberration S7+7 (P = 0.015) was statistically different in the DLK group from that in controls. High-order aberrations S3+3 (P = 0.091) and S8+4 (chi = 8.014, P = 0.046) showed a tendency to be different from controls. Loss of best-corrected visual acuity was greater in patients with DLK. CONCLUSIONS: The occurrence of DLK after LASIK surgery may not significantly affect the visual outcome.

One-Year Clinical Outcomes of a Corneal Inlay for Presbyopia.

PURPOSE: To report the results of a 1-year follow-up analysis of the safety and efficacy of the Flexivue Microlens corneal inlay. METHODS: The Flexivue Microlens corneal inlay was implanted in the nondominant eye of patients with emmetropic presbyopia (a spherical equivalent of -0.5 to 1.00 diopter) after the creation of a 300-µm deep stromal pocket, using a femtosecond laser. The patients were followed up according to a clinical protocol involving refraction, anterior segment imaging analysis (Oculyzer), and optical quality analysis (OPD-Scan). RESULTS: Thirty-one patients were enrolled in this ongoing study. The mean age was 50.7 years (range 45-60 yrs), and 70% of the patients were female. The mean uncorrected near visual acuity improved to Jaeger 1 in 87.1% of the eyes treated with the inlays. All eyes improved 4 lines at all visits. The binocular uncorrected distance visual acuity was 20/20 in all patients. Ninety percent of the patients reported that their near vision was good or excellent. Some of the patients (16.1%) lost more than 3 lines of corrected distance visual acuity. At the latest follow-up, induction of a corneal spherical aberration to improve near visual acuity was statistically significant. No other intraoperative or postoperative complication was noted. CONCLUSIONS: The Flexivue Microlens provided patients with improved near vision, as a result of a negative spherical aberration. A significant loss of corrected distance visual acuity in the operated eyes was observed. Overall, this intracorneal inlay was an effective alternative to other procedures for the correction of presbyopia.

Complete depigmentation of a small aperture corneal inlay implanted for compensation of presbyopia.

We describe a case of late-onset remarkable depigmentation of a small aperture corneal inlay implanted for presbyopia compensation. The patient was a participant in a clinical trial designed to evaluate the safety and efficacy of the AcuFocusTM ACU-10R160, which is a 10 µm-thick polyimide film tinted with an organic dye. Inlay implantation occurred under mechanical microkeratome Lasik flaps set for a depth of 120 µm. The patient returned to the clinic 11 years after surgery and reported loss of near-vision acuity. Clinical examination showed the complete absence of pigments in the device and the total loss of the initial effect on near vision, despite normal distance vision. Manifest refraction remained stable during the follow-up period. Scheimpflug images characterized the loss of the small aperture effect on incoming light. Confocal analysis revealed small hyper-reflective round images on the endothelium and no signs of inflammation.

Postprandial modulation of serum paraoxonase activity and concentration in diabetic and non-diabetic subjects.

OBJECTIVES: To analyse the HDL associated anti-oxidant enzyme paraoxonase-1, during postprandial hyperlipaemia. METHODS AND RESULTS: Type 2 diabetic patients (n=72), glucose intolerant patients (n=10) and controls (n=38) consumed a high fat:high carbohydrate meal. Blood samples were collected up to 4h and analysed for lipids and paraoxonase-1. In vitro studies examined HDL function with respect to the enzyme. There were significant postprandial increases in serum triglycerides. Paraoxonase-1 activity decreased significantly throughout the postprandial phase. Concentrations of the enzyme initially decreased significantly, but returned to fasting concentrations at 4h. Specific activities were significantly lower at 4h, compared to fasting. The decrease in specific activity was linked to the dynamic phase of postprandial lipoprotein metabolism. Apo AI limited loss of paraoxonase-1. HDL isolated after being subjected to postprandial conditions in vitro had reduced capacity to associate with and stabilise PON1. CONCLUSIONS: Postprandial hyperlipaemia was associated with changes to serum paraoxonase-1, consistent with a reduced anti-oxidant potential of HDL. No differences were observed between diabetic and non-diabetic patients, suggesting that the effect was linked to postprandial hyperlipaemia. Modifications to paraoxonase-1 could contribute to increased risk of vascular disease associated with postprandial lipaemia, particularly in diabetic patients, who are already deficient in serum paraoxonase-1.

Regulation and function of the CGRP receptor complex in human granulopoiesis.

OBJECTIVE: Anatomic studies and animal experiments suggest that neuropeptides such as calcitonin gene-related peptide (CGRP) may be involved in hematopoiesis. Here, we examined the regulation and function of the CGRP receptor in human granulopoiesis. MATERIALS AND METHODS: Expression of CGRP receptor components on CD34(+) cells, peripheral blood granulocytes, and in vitro differentiated CD34(+) cells was analyzed at the mRNA level and by measuring the signaling capacity of the receptor. The function of CGRP in human hematopoiesis was investigated by clonal colony formation assays. RESULTS: mRNA transcripts for the cell surface CGRP receptor subunits receptor activity-modifying protein-1 (RAMP-1) and calcitonin receptor-like receptor (CRLR) as well as for the intracellular adapter protein CGRP-receptor component protein (CGRP-RCP) were found in CD34(+) cells from 4/4 donors tested. CGRP-RCP mRNA was expressed in peripheral blood granulocytes of 8/15 donors, whereas RAMP-1 and CRLR were not detectable. CD34(+) cells, but not granulocytes, exhibited a marked elevation of cellular cAMP after CGRP stimulation, thereby confirming the mRNA expression data. Both RAMP-1 and CRLR mRNA expression and CGRP receptor signaling capacity were lost during in vitro granulocytic differentiation of CD34(+) cells. Consistent with a role of CGRP in hematopoiesis, we show that CGRP significantly enhances the formation of granulomonocytic, but not erythroid or mixed, colonies by purified human CD34(+) cells. CONCLUSION: The CGRP receptor is expressed on CD34(+) hematopoietic progenitor cells and is downregulated during granulocytic differentiation. CGRP directly acts on CD34(+) cells to promote formation of granulomonocytic colonies. Thus, CGRP may have a function in directing hematopoiesis.

Complete depigmentation of a small aperture corneal inlay implanted for compensation of presbyopia / Despigmentação completa de um implante corneano de pequena abertura para correção da presbiopia

ABSTRACT We describe a case of late-onset remarkable depigmentation of a small aperture corneal inlay implanted for presbyopia compensation. The patient was a participant in a clinical trial designed to evaluate the safety and efficacy of the AcuFocusTM ACU-10R160, which is a 10 µm-thick polyimide film tinted with an organic dye. Inlay implantation occurred under mechanical microkeratome Lasik flaps set for a depth of 120 µm. The patient returned to the clinic 11 years after surgery and reported loss of near-vision acuity. Clinical examination showed the complete absence of pigments in the device and the total loss of the initial effect on near vision, despite normal distance vision. Manifest refraction remained stable during the follow-up period. Scheimpflug images characterized the loss of the small aperture effect on incoming light. Confocal analysis revealed small hyper-reflective round images on the endothelium and no signs of inflammation.

RESUMO Descrevemos um caso de importante despigmentação de início tardio de implante corneano de pequena abertura implantada para compensação de presbiopia. O paciente foi um dos participantes de ensaio clínico destinado a avaliar a segurança e eficácia do AcuFocusTM ACU-10R160, uma película de poliimida de 10 microns de espessura, tingida com um corante orgânico. A implantação ocorreu sob um flap de Lasik criado por microcerátomo mecânico ajustado para profundidade de 120 µm. O caso aqui descrito foi avaliado 11 anos após a cirurgia, relatando diminuição de acuidade de visão para perto. O exame clínico mostrou ausência total de pigmentos no dispositivo e perda total do efeito inicial na visão de perto, apesar da visão normal para distância. A refração manifesta permaneceu estável durante o período de seguimento. As imagens de Scheimpflug caracterizaram a perda do efeito da abertura pequena na luz entrante. A análise de microscopia confocal revelou pequenas imagens hiper-reflexivas redondas sobre o endotélio, sem sinais de inflamação.

Isoform-selective interaction of the adaptor protein Tks5/FISH with Sos1 and dynamins.

The adaptor protein Tks5/FISH (tyrosine kinase substrate 5/five SH3 domains, hereafter termed Tks5) is a crucial component of a protein network that controls the invasiveness of cancer cells and progression of Alzheimer's disease. Tks5 consists of an amino-terminal PX domain that is followed by five SH3 domains (SH3A-E), and two different splice variants are expressed. We identified son of sevenless-1 (Sos1) as a novel binding partner of Tks5 and found colocalization of Tks5 with Sos1 in human epithelial lung carcinoma (A549) cells and in podosomes of Src-transformed NIH 3T3 cells. We observe synergistic binding of SH3A and SH3B to Sos1 when peptide arrays are used, indicating that the tandem SH3A and SH3B domains of Tks5 can potentially bind in a superSH3 binding mode, as was described for the homologous protein p47phox. These results are further corroborated by pull-down assays and isothermal titration calorimetry showing that both intact SH3 domains are required for efficient binding to the entire proline-rich domain of Sos1. The presence of a basic insertion between the SH3A and SH3B domains in the long splice variant of Tks5 decreases the affinity to Sos1 isoforms about 10-fold as determined by analytical ultracentrifugation. Furthermore, it leads to an alteration in the recognition of binding motifs for the interaction with Sos1: While the insertion abrogates the interaction with the majority of peptides derived from the proline-rich domains of Sos1 and dynamin that are recognized by the short splice isoform, it enables binding to a different set of peptides including a sequence comprising the splice insertion in the long isoform of Sos1 (Sos1_2). In the absence of the basic insertion, Tks5 was found to bind a range of Sos1 and dynamin peptides including conventional proline-rich motifs and atypical recognition sequences. Hereby, the tandem SH3 domains in Tks5 employ two distinct types of binding modes: One class of peptides is recognized by single SH3 domains, whereas a second class of peptides requires the presence of both domains to bind synergistically. We conclude that the tandem SH3A and SH3B domains of Tks5 constitute a versatile module for the implementation of isoform-specific protein-protein interactions.

Photorefractive keratectomy with mitomycin-C for consecutive hyperopia after radial keratotomy.

PURPOSE: To evaluate the safety, efficacy, and stability of excimer laser photorefractive keratectomy (PRK) and mitomycin-C (MMC) 0.02% for consecutive hyperopia after radial keratotomy (RK). METHODS: A prospective, nonrandomized, noncomparative interventional case series of 35 eyes (22 patients) with consecutive hyperopia after RK. All eyes were treated with PRK, using a single intraoperative topical application of MMC 0.02% for 60 seconds. Uncorrected visual acuity, best spectacle-corrected visual acuity, refraction, slit-lamp evidence of corneal haze, and endothelial cell counts were evaluated for up to 18 months after surgery. RESULTS: Postoperative follow-up was 9.6 +/- 5.5 months (ranged from 3 to 18 months). The mean spherical equivalent was +3.36 +/- 1.94 diopters preoperatively and +0.27 +/- 1.38 diopters 12 months after surgery. The uncorrected visual acuity was > or =20/30 in 37.1% of the eyes at 1 month and 78.6% of the eyes at 12 months. At 12 months, 14% of the eyes lost up to 1 line of Snellen acuity in the best spectacle-corrected visual acuity. No corneal haze was observed and the endothelial cell counts remained unchanged postoperatively (P > 0.05). CONCLUSION: PRK with MMC 0.02% for consecutive hyperopia after RK seems to be a safe and effective procedure at least in the short-term period of 6 months.

Comparison of skin microvascular reactivity with hemostatic markers of endothelial dysfunction and damage in type 2 diabetes.

AIM: Patients with non-insulin-dependent diabetes mellitus (NIDDM) are at increased cardiovascular risk due to an accelerated atherosclerotic process. The present study aimed to compare skin microvascular function, pulse wave velocity (PWV), and a variety of hemostatic markers of endothelium injury [von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (t-PA), tissue factor pathway inhibitor (TFPI), and the soluble form of thrombomodulin (s-TM)] in patients with NIDDM. METHODS: 54 patients with NIDDM and 38 sex- and age-matched controls were studied. 27 diabetics had no overt micro- and/or macrovascular complications, while the remainder had either or both. The forearm skin blood flow was assessed by laser-Doppler imaging, which allowed the measurement of the response to iontophoretically applied acetylcholine (endothelium-dependent vasodilation) and sodium nitroprusside (endothelium-independent vasodilation), as well as the reactive hyperemia triggered by the transient occlusion of the circulation. RESULTS: Both endothelial and non-endothelial reactivity were significantly blunted in diabetics, regardless of the presence or the absence of vascular complications. Plasma vWF, TFPI and s-TM levels were significantly increased compared with controls only in patients exhibiting vascular complications. Concentrations of t-PA and PAI-1 were significantly increased in the two groups of diabetics versus controls. CONCLUSION: In NIDDM, both endothelium-dependent and -independent microvascular skin reactivity are impaired, whether or not underlying vascular complications exist. It also appears that microvascular endothelial dysfunction is not necessarily associated in NIDDM with increased circulating levels of hemostatic markers of endothelial damage known to reflect a hypercoagulable state.

Extensive characterization of IFN-induced GTPases mGBP1 to mGBP10 involved in host defense.

IFN-gamma orchestrates a potent antimicrobial host response. However, the underlying molecular basis for this immunological defense system is largely unknown. In a systematic approach to identify IFN-gamma-regulated host effector molecules, a notable number of transcripts with consensus GTP-binding motives were obtained. Further extensive transcriptome and genome analyses identified five novel family members of murine guanylate-binding proteins (mGBPs) now designated mGBP6, 7, 8, 9, and 10. Moreover, in this study, all 10 mGBP members (mGBP1-10) were extensively characterized. mGBPs are selectively up-regulated in vitro by a set of proinflammatory cytokines and TLR agonists as well as in vivo after Listeria monocytogenes and Toxoplasma gondii infection. After IFN-gamma stimulation, mGBP1, 2, 3, 6, 7, and 9 are associated with intracellular Toxoplasma parasites and, interestingly, virulent Toxoplasma interfere with mGBP recruitment. Taken together, mGBPs comprise an important set of host defense molecules.

Primary malignant tumors of the aorta: clinical presentation, treatment, and course of different entities.

OBJECTIVE: The objective of this study was to analyze possible correlations between the clinical presentation and the course of patients with different types of primary malignant aortic tumors. METHODS: A single academic center's experience was reviewed retrospectively. RESULTS: Four patients with primary malignant tumors of the aorta were treated in an 11-year period. Three different histologic entities were found: malignant fibrous histiocytoma, epitheloid angiosarcoma, and unclassified sarcoma. Two female patients presenting with clinical symptoms of vasculitis proved to have epitheloid aortic sarcoma. Both developed diffuse metastasis to bone and skin with initial lymphatic disease in the groin. The other patients developed local recurrence and pulmonary metastasis. Survival of the 4 patients was 11, 20, and 51 months, 1 patient with metastatic disease is still alive 6 months after surgery. CONCLUSION: Different types of malignant aortic tumors seem to have different clinical presentation and course.