Search

Background The mechanisms underlying the association between obstructive sleep apnea (OSA) and cardiovascular disease may include accelerated vascular aging. The aim was to compare the magnitude of vascular aging in patients with high versus low risk of OSA. Methods and Results In 2 community-based studies, the PPS3 (Paris Prospective Study 3) and the Maastricht Study, high risk of OSA was determined with the Berlin questionnaire (a screening questionnaire for OSA). We assessed carotid artery properties (carotid intima-media thickness, Young's elastic modulus, carotid-femoral pulse wave velocity, carotid pulse wave velocity, carotid diameter using high precision ultrasound echography), and carotid-femoral pulse wave velocity (in the Maastricht Study only). Regression coefficients were estimated on pooled data using multivariate linear regression. A total of 8615 participants without prior cardiovascular disease were included (6840 from PPS3, 62% men, mean age 59.5 +/- 6.2 years, and 1775 from the Maastricht Study, 51% men, 58.9 +/- 8.1 years). Overall, high risk of OSA prevalence was 16.8% (n=1150) in PPS3 and 23.8% (n=423) in the Maastricht Study. A high risk of OSA was associated with greater carotid intima-media thickness (beta=0.21; 0.17-0.26), Young's elastic modulus (beta=0.21; 0.17-0.25), carotid-femoral pulse wave velocity (beta=0.24; 0.14-0.34), carotid pulse wave velocity (beta=0.31; 0.26-0.35), and carotid diameter (beta=0.43; 0.38-0.48), after adjustment for age, sex, total cholesterol, smoking, education level, diabetes mellitus, heart rate, and study site. Consistent associations were observed after additional adjustments for mean blood pressure, body mass index, or antihypertensive medications. Conclusions These data lend support for accelerated vascular aging in individuals with high risk of OSA. This may, at least in part, underlie the association between OSA and cardiovascular disease.

Background: Head and neck cancer is particular due to its infiltrative nature and lymphatic extension, with multidisciplinary treatment. Immunotherapy may be a brand-new therapeutic approach.Case P...

Background: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. Objective: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. Methods: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT‐associated variants and the entire coding sequence of MAPT were analyzed. Age‐, sex‐, and ethnicity‐adjusted analyses were performed to examine the association between MAPT, PD, and rapid eye movement sleep behavior disorder. Results: MAPT‐H2 variants were associated with PD (odds ratios: 0.62‐0.65; P = 0.010‐0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12‐2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48‐0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. Conclusions: Our results confirm the protective effect of the MAPT‐H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus.

The cohabitation of Drosophila melanogaster with humans is nearly ubiquitous. Though it has been well established that this fly species originated in sub-Saharan Africa, and only recently has spread globally, many details of its swift expansion remain unclear. Elucidating the demographic history of D. melanogaster provides a unique opportunity to investigate how human movement might have impacted patterns of genetic diversity in a commensal species, as well as providing neutral null models for studies aimed at identifying genomic signatures of local adaptation. Here, we use whole-genome data from five populations (Africa, North America, Europe, Central Asia, and the South Pacific) to carry out demographic inferences, with particular attention to the inclusion of migration and admixture. We demonstrate the importance of these parameters for model fitting and show that how previous estimates of divergence times are likely to be significantly underestimated as a result of not including them. Finally, we discuss how human movement along early shipping routes might have shaped the present-day population structure of D. melanogaster.

Specific clusters of metabolic syndrome (MetS) components impact differentially on arterial stiffness, indexed as pulse wave velocity (PWV). Of note, in several population-based studies participating in the MARE (Metabolic syndrome and Arteries REsearch) Consortium the occurrence of specific clusters of MetS differed markedly across Europe and the US. The aim of the present study was to investigate whether specific clusters of MetS are consistently associated with stiffer arteries in different populations. We studied 20,570 subjects from 9 cohorts representing 8 different European countries and the US participating in the MARE Consortium. MetS was defined in accordance with NCEP ATPIII criteria as the simultaneous alteration in >= 3 of the 5 components: abdominal obesity (W), high triglycerides (T), low HDL cholesterol (H), elevated blood pressure (B), and elevated fasting glucose (G). PWV measured in each cohort was "normalized" to account for different acquisition methods. MetS had an overall prevalence of 24.2% (4985 subjects). MetS accelerated the age-associated increase in PWV levels at any age, and similarly in men and women. MetS clusters TBW, GBW, and GTBW are consistently associated with significantly stiffer arteries to an extent similar or greater than observed in subjects with alteration in all the five MetS components - even after controlling for age, sex, smoking, cholesterol levels, and diabetes mellitus - in all the MARE cohorts. In conclusion, different component clusters of MetS showed varying associations with arterial stiffness (PWV). (C) 2014 Elsevier Ireland Ltd. All rights reserved., NIH -National Institutes of Health

The benefit of using individual head-related transfer functions (HRTFs) in binaural audio is well documented with regards to improving localization precision. However, with the increased use of binaural audio in more complex scene renderings, cognitive studies, and virtual and augmented reality simulations, the perceptual impact of HRTF selection may go beyond simple localization. In this study, the authors develop a list of attributes which qualify the perceived differences between HRTFs, providing a qualitative understanding of the perceptual variance of non-individual binaural renderings. The list of attributes was designed using a Consensus Vocabulary Protocol elicitation method. Participants followed an Individual Vocabulary Protocol elicitation procedure, describing the perceived differences between binaural stimuli based on binauralized extracts of multichannel productions. This was followed by an automated lexical reduction and a series of consensus group meetings during which participants agreed on a list of relevant attributes. Finally, the proposed list of attributes was then evaluated through a listening test, leading to eight valid perceptual attributes for describing the perceptual dimensions affected by HRTF set variations.

Background Since patients with diabetes mellitus have increased rates of cardiovascular morbidity and mortality, it is critical to evaluate cardiovascular risk perioperatively. Although several preoperative risk indices have been developed, including the Goldman and Detsky indices, none have been designed specifically for diabetic patients. In this study, we attempted to identify predictors of postoperative cardiac and noncardiac complications in diabetic patients undergoing elective general surgery. Study Design A cohort of 107 diabetic patients undergoing elective surgery was assembled. Basic demographic and clinical data were recorded perioperatively, and all patients were followed up prospectively daily for 7 days postoperatively. Patients were interviewed at 5 years postoperatively. Univariate and multivariate analyses were performed to identify predictors of postoperative complications and long-term cardiac and vascular morbidity and mortality. Results Total cardiac complications and myocardial infarction were predicted by the Goldman index. Wound complications were not predicted by any of the variables studied. At 5 years postoperatively, cardiac and vascular deaths and events were predicted by age, history of myocardial infarction or stroke, presence of vascular disease, Goldman index, duration of diabetes or hypertension, Charlson comorbidity score, and postoperative myocardial infarction or cardiac arrest. Blood sugar control during surgery was not predictive of any short- or long-term cardiovascular complications. Conclusions Total cardiac complications had a significant preoperative predictor: the Goldman index. Both preoperative and postoperative variables and indices predicted long-term cardiac and vascular complications. Further study is necessary to investigate these relationships to better assess and manage the diabetic patient in the perioperative setting.

PubMed ID: 25112663, Aims: Estimated central systolic blood pressure (cSBP) and amplification (Brachial SBP-cSBP) are non-invasive measures potentially prognostic of cardiovascular (CV) disease. No worldwide, multiple-device reference values are available. We aimed to establish reference values for a worldwide general population standardizing between the different available methods of measurement. How these values were significantly altered by cardiovascular risk factors (CVRFs) was then investigated. Methods and results: Existing data from population surveys and clinical trials were combined, whether published or not. Reference values of cSBP and amplification were calculatedas percentiles for 'Normal' (no CVRFs) and 'Reference' (any CVRFs) populations. We included 45 436 subjects out of 82 930 that were gathered from 77 studies of 53 centres. Included subjects were apparently healthy, not treated for hypertension or dyslipidaemia, and free from overt CV disease and diabetes. Values of cSBP and amplification were stratified by brachial blood pressure categories and age decade in turn, both being stratifiedbysex. Amplification decreased with age and more so in males than in females. Sex was the most powerful factor associated with amplification with 6.6 mmHg (5.8-7.4) higher amplification in males than in females. Amplification was marginally but significantly influenced by CVRFs, with smoking and dyslipidaemia decreasing amplification, but increased with increasing levels of blood glucose. Conclusion: Typical values of cSBP and amplification in a healthy population and a population free of traditional CVRFs are now available according to age, sex, and brachial BP, providing values included from different devices with a wide geographical representation. Amplification is significantly influenced by CVRFs, but differently in men and women. © 2014 Published on behalf of the European Society of Cardiology.

UNLABELLED: (99m)Tc-cAbVCAM1-5, a single-domain antibody fragment directed against mouse or human vascular cell adhesion molecule 1 (VCAM-1), recently has been proposed as a new imaging agent for the detection of inflamed atherosclerotic lesions. Indeed, in a mouse model of atherosclerosis, (99m)Tc-cAbVCAM1-5 specifically bound to VCAM-1-positive lesions, thereby allowing their identification on SPECT images. The purpose of the present study was to investigate (99m)Tc-cAbVCAM1-5 imaging sensitivity using a reference statin therapy. METHODS: Thirty apolipoprotein E-deficient mice were fed a western-type diet. First, the relationship between the level of VCAM-1 expression and (99m)Tc-cAbVCAM1-5 uptake was evaluated in 18 mice using immunohistochemistry and autoradiography. Second, longitudinal SPECT/CT imaging was performed on control (n = 9) or atorvastatin-treated mice (0.01% w/w, n = 9). RESULTS: (99m)Tc-cAbVCAM1-5 uptake in atherosclerotic lesions correlated with the level of VCAM-1 expression (P < 0.05).Atorvastatin exerted significant antiatherogenic effects, and (99m)Tc-cAbVCAM1-5 lesion uptake was significantly reduced in 35-wk-old atorvastatin-treated mice, as indicated by ex vivo γ-well counting and autoradiography (P < 0.05). SPECT imaging quantification based on contrast-enhanced CT was reproducible (interexperimenter intraclass correlation coefficient, 0.97; intraexperimenter intraclass correlation coefficient, 0.90), and yielded results that were highly correlated with tracer biodistribution (r = 0.83; P < 0.0001). Therefore, reduced (99m)Tc-cAbVCAM1-5 uptake in atorvastatin-treated mice was successfully monitored noninvasively by SPECT/CT imaging (0.87 ± 0.06 vs. 1.11 ± 0.09 percentage injected dose per cubic centimeter in control group, P < 0.05). CONCLUSION: (99m)Tc-cAbVCAM1-5 imaging allowed the specific, sensitive, and reproducible quantification of VCAM-1 expression in mouse atherosclerotic lesions. (99m)Tc-cAbVCAM1-5 therefore exhibits suitable characteristics for the evaluation of novel antiatherogenic agents.

For several years the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) decided not to produce their own guidelines on the diagnosis and treatment of hypertension but to endorse the guidelines on hypertension issued by the World Health Organization (WHO) and International Society of Hypertension (ISH)1,2 with some adaptation to reflect the situation in Europe. However, in 2003 the decision was taken to publish ESH/ESC specific guidelines3 based on the fact that, because the WHO/ISH Guidelines address countries widely varying in the extent of their health care and availability of economic resource, they contain diagnostic and therapeutic recommendations that may be not totally appropriate for European countries. In Europe care provisions may often allow a more in-depth diagnostic assessment of cardiovascular risk and organ damage of hypertensive individuals as well as a wider choice of antihypertensive treatment. The 2003 ESH/ESC Guidelines3 were well received by the clinical world and have been the most widely quoted paper in the medical literature in the last two years.4 However, since 2003 considerable additional evidence on important issues related to diagnostic and treatment approaches to hypertension has become available and therefore updating of the previous guidelines has been found advisable. In preparing the new guidelines the Committee established by the ESH and ESC has agreed to adhere to the principles informing the 2003 Guidelines, namely 1) to try to offer the best available and most balanced recommendation to all health care providers involved in the management of hypertension, 2) to address this aim again by an extensive and critical review of the data accompanied by a series of boxes where specific recommendations are given, as well as by a concise set of practice recommendations to be published soon thereafter as already done in 2003; …

The study aim was to determine the prevalence of repeated assaults on staff and other patients and characteristics of patients who commit repeated assaults in the Veterans Health Administration of the Department of Veterans Affairs.Patients in VA medical centers and freestanding outpatient clinics who committed two or more assaults in fiscal years 1995 and 1996 were identified through a survey of facility quality or risk managers. For each repeatedly assaultive patient, structured information, including incident reports, was obtained for all assault occasions.A total of 153 VA facilities responded, for a response rate of 99 percent. The survey identified 8,968 incidents of repeated assault by 2,233 patients, for a mean of 4.02 assaults per patient in the two-year study period. In 92 percent of the incidents, the assaultive patient had a primary or secondary psychiatric diagnosis. The mean age of the repeat assaulters was 62 years. Ninety-eight percent of the repeat assaulters were male, and 76.6 percent were Caucasian. At least 16 percent of the assaulters, 22 percent of the patients assaulted, and 20 percent of the staff assaulted required medical attention for injuries, which, along with the number of lost work days, indicates that repeated assaults are costly.Repeatedly assaultive patients represent major challenges to their own safety as well as to that of other patients and staff. Identifying patients at risk for repeated assaults and developing intervention strategies is critically important for ensuring the provision of health care to the vulnerable population of assaultive patients.

To more clearly define the scope and impact of violence in health care facilities, national data on assaults in VA medical centers and freestanding clinics were examined.A survey was distributed to all VA medical centers and freestanding clinics asking for cumulative data for one fiscal year (October 1990 through September 1991). Data were obtained on number, types, and locations of physical assaults and other assaultive behavior; the types of staff assaulted and number of workdays lost due to injuries; diagnoses of perpetrators; recommendations made after the incidents were reviewed; training in prevention and management of assaultive behavior; and the impact of training on rates of assaultive behavior.During the survey year, 24,219 incidents of assaultive behavior were reported by 166 VA facilities; 8,552 incidents involved battery or physical assault. Weapon possession by perpetrators was common (8.5 percent of incidents), and weapons were used in 130 assaults (1.5 percent of assaults). Assaults occurred most frequently in psychiatric units (43.1 percent), followed by long-term-care units (18.5 percent) and admitting or triage areas (13.4 percent). Assault-related injuries were most common among nursing personnel. Perpetrators of assaults were most typically diagnosed as having psychoses, substance use disorders, or dementia. On inpatient psychiatry units, an inverse correlation was found between expenditures on staffing and the frequency of assaultive incidents. Staff training on management of assaultive behavior varied widely.Assaultive behavior is a significant problem for health care workers. Staff in all clinical areas need to be prepared to deal with assaultive patients. More research is needed on staff training and interventions for preventing and limiting assaults.

Staphylokinase (Sak), a 16-kDa bacterial protein, forms a 1:1 stoichiometric complex with the serine proteinase domain of human plasmin, which in turn converts other plasminogen molecules into plasmin. To identify amino acid residues critical for generating the Sak:plasmin activator complex, alanine-scanning mutagenesis was performed on phage-displayed micro-plasminogen (microPlg). Substitution of Arg719 with Ala [microPlg(R719A)] disrupted complex formation, although the sensitivity of phage-displayed microPlg(R719A) to activation by urokinase and the amidolytic activity of the micro-plasmin derivative [microPli(R719A)] remained unaffected. Likewise, the soluble microPlg(R719A) molecule did not generate a functional activator complex with Sak, whereas quantitative activation into plasmin was obtained upon incubation with either urokinase or the Sak:plasmin complex. Real-time biospecific affinity measurements revealed that the Arg --> Ala substitution at position 719 increased the equilibrium dissociation constant between microPlg(R719A) and Sak from 46 nM to 1 microM, primarily by reducing the association rate constant. Arg719 has recently also been implied in the functional complex formation between human plasmin and streptokinase [Dawson, K. M., Marshall, J. M., Raper, R. H., Gilbert, R. J., and Ponting, C. P. (1994) Biochemistry 33, 12042-12047.], suggesting that both bacterial cofactors may share common structural and/or mechanistic aspects for plasminogen activation.

The effectiveness of clozapine treatment in a treatment-refractory sample of older adult veterans with primary psychosis was examined.Data were collected over a five-year period for patients age 55 and older who were given clozapine because of a history of treatment-refractory or treatment-intolerant psychosis. At initiation of clozapine therapy, baseline demographic, clinical, and psychopathology data were collected. At baseline and quarterly, patients' psychopathology was rated with the Brief Psychiatric Rating Scale (BPRS), and involuntary movements were rated with the Abnormal Involuntary Movement Scale (AIMS).The 329 patients age 55 or older who received clozapine during the study period represented 10 percent of all patients on clozapine therapy in the VA system. Of the 312 patients for whom demographic information was available, 294 were men and 18 were women. Overall, patients improved on clozapine therapy, although wide variation in drug response was observed. Complete BPRS and AIMS data were available for 97 patients. The 55- to 64-year-old group had a mean improvement in total BPRS score of 19.8 percent, with 42.6 percent showing more than a 20 percent improvement; those age 65 and older had a mean improvement of 5.7 percent, with 17.2 percent showing an improvement greater than 20 percent. The 97 patients with complete AIMS data showed a mean improvement of 16.6 percent in total score.Clozapine is an important therapeutic agent for older adults with treatment-refractory psychosis. Patients between the ages of 55 and 64 may have a better response than those age 65 and older.

Background The “charged cluster–to-alanine” substitution variants SakSTAR(K35A,E38A,K74A,E75A,R77A) and SakSTAR(K74A,E75A,R77A,E80A,D82A), previously identified as SakSTAR.M38 and SakSTAR.M89, respectively, induce less antibody formation in patients than wild-type recombinant staphylokinase (SakSTAR), but their specific activities are reduced by 50%. Therefore, the effect of the reversal of one or more of these substituted amino acids on the ratio of activity to antigenicity was studied. Methods and Results Fourteen mutants with one to four “alanine-to–wild-type” reversals were expressed in Escherichia coli and highly purified (>95%). In rabbits immunized with wild-type SakSTAR, the combined K35,E38,K74,E75,R77 or K74,E75,R77,E80,E82 epitope accounted for only 30% of antibody absorption from plasma, and no clear immunodominant residue could be identified. In baboons immunized with SakSTAR, the K35,E38 and K74,E75,R77 epitopes or the K74,E75,R77 and E80,D82 epitopes contributed equally to account for 50% of total antibody binding, but no immunodominant residues were apparent. In pooled plasma from patients with peripheral arterial occlusion treated with wild-type SakSTAR, about 40% of the antibodies depended on K74 of epitope K74,E75,R77 for binding, whereas epitopes K35,E38 and E80,D82 had a negligible contribution toward antibody recognition. Conclusions The recognition pattern by SakSTAR variants of antibodies induced with wild-type SakSTAR differs markedly among species. This implies that a systematic evaluation of reduced antigen recognition and antibody induction in humans will require the development of human or humanized systems. Surprisingly, SakSTAR(K 74 ), with a single substitution of Lys74 with Ala, had an intact specific activity but did not absorb 40% of the antibodies induced in patients by treatment with wild-type SakSTAR.

We describe a novel phage display system that affords the surface expression and hence affinity selection of cDNAs. The strategy is based on a new approach to functionally display proteins on filamentous phage through the attachment to the C-terminus of the minor coat protein VI. The utility of the method was evaluated using a cDNA library derived from the parasite Ancylostoma caninum. cDNA sequences were fused in each of the three reading frames to the 3'-end of the M13 gene VI expressed by a phagemid vector. Phages rescued from this cDNA expression library were subjected to biopanning against two serine proteases, trypsin and the human coagulation factor Xa. This led to the identification of cDNAs encoding novel members of two different families of serine protease inhibitors. The authenticity of the cDNA selected with trypsin as the target was demonstrated by purifying the encoded potent Kunitz-type inhibitor from an Ancylostoma caninum extract. The rapid isolation of specific cDNAs with the protein VI monovalent display system should facilitate the search for novel biologically important ligands.

International audience; Lentiviral vectors are effective tools for gene transfer and integrate variable numbers of proviral DNA copies in variable proportions of cells. The levels of transduction of a cellular population may therefore depend upon experimental parameters affecting the frequency and/or the distribution of vector integration events in this population. Such analysis would require measuring vector copy numbers (VCN) in individual cells. To evaluate the transduction of hematopoietic progenitor cells at the single-cell level, we measured VCN in individual colony-forming cell (CFC) units, using an adapted quantitative PCR (Q-PCR) method. The feasibility, reproducibility and sensitivity of this approach were tested with characterized cell lines carrying known numbers of vector integration. The method was validated by correlating data in CFC with gene expression or with calculated values, and was found to slightly underestimate VCN. In spite of this, such Q-PCR on CFC was useful to compare transduction levels with different infection protocols and different vectors. Increasing the vector concentration and re-iterating the infection were two different strategies that improved transduction by increasing the frequency of transduced progenitor cells. Repeated infection also augmented the number of integrated copies and the magnitude of this effect seemed to depend on the vector preparation. Thus, the distribution of VCN in hematopoietic colonies may depend upon experimental conditions including features of vectors. This should be carefully evaluated in the context of ex vivo hematopoietic gene therapy studies.

Clozapine therapy for 2,996 patients with treatment-refractory schizophrenia was examined over a five-year period in the Veterans Affairs health care system. Patients were assessed with the Brief Psychiatric Rating Scale (BPRS) and the Abnormal Involuntary Movement Scale (AIMS). BPRS scores, which were available for 522 patients, indicated a significant improvement, as did AIMS scores, which were available for 252 patients. Compared with individuals who showed a modest improvement, those with a more robust response to clozapine had higher initial BPRS scores and were three times more likely to have been suicidal in the month before starting clozapine therapy.

International audience; Wiskott–Aldrich syndrome (WAS) is an immune deficiency with thrombopenia resulting from mutations in the WASP gene. This gene normally encodes the Wiskott–Aldrich syndrome protein (WASP), a major cytoskeletal regulator expressed in hematopoietic cells. Gene therapy is a promising option for the treatment of WAS, requiring that clinically applicable WASP gene transfer vectors demonstrate efficacy in preclinical studies. Here, we describe a self-inactivating HIV-1-derived lentiviral vector encoding human WASP and show that it effectively transduced bone marrow progenitor cells of WASP knockout (WKO) mice. Transplantation of these transduced cells into lethally irradiated WKO recipients led to stable expression of WASP and correction of immune, inflammatory and cytoskeletal defects. Splenic T-cell proliferation was restored, podosomes were reinstated on bone-marrow-derived dendritic cells and colon inflammation was reduced. This shows for the first time (a) that cytoskeletal defects can be corrected in WKO mice, (b) that human WASP is biologically active in mice and (c) that a lentiviral vector is effective to express human WASP in vivo over several months. These data support further development of such lentiviral vectors for the gene therapy of WAS.

Cardiovascular morbidity and mortality in disadvantaged populations remains high. Few innovative strategies or services to treat chronic diseases have been critically analyzed in these patients. We evaluated our initial experiences with a newly established multidisciplinary clinic For the treatment of difficult-to-control hypertension and describe reasons for poor blood pressure control as well as treatment strategies. Patients with blood pressures greater than 140/90 despite concurrent treatment with three or more medications for at least three months were referred to our clinic. Data regarding sociodemographic characteristics, health beliefs and behaviors were collected. Two physicians jointly proposed an explanation for lack of blood pressure control. A multidisciplinary team of physicians, nurses, pharmacists, and nutritionists aggressively assessed and reinforced educational objectives tailored to individual needs. 58% of patients achieved target blood pressure at six months, but 22% were lost to follow-up. The most common reasons for previous treatment failure were volume overload and poor medication adherence. We conclude that a multidisciplinary clinic for difficult-to-control blood pressure can be successful in a large, urban hospital serving a disadvantaged minority population. However, more study is needed to delineate the specific reasons for success and further refine treatment strategies.

Recombinant staphylokinase (SakSTAR) variants obtained by site-directed substitution with cysteine, in the core (lysine 96 [Lys96], Lys102, Lys109, and/or Lys135) or the NH(2)-terminal region that is released during activation of SakSTAR (serine 2 [Ser2] and/or Ser3), were derivatized with thiol-specific (ortho-pyridyl-disulfide or maleimide) polyethylene glycol (PEG) molecules with molecular weights of 5,000 (P5), 10,000 (P10), or 20,000 (P20). The specific activities and thrombolytic potencies in human plasma were unaltered for most variants derivatized with PEG (PEGylates), but maleimide PEG derivatives had a better temperature stability profile. In hamsters, SakSTAR was cleared at 2.2 mL/min; variants with 1 P5 molecule were cleared 2-to 5-fold; variants with 2 P5 or 1 P10 molecules were cleared 10-to 30-fold; and variants with 1 P20 molecule were cleared 35-fold slower. A bolus injection induced dose-related lysis of a plasma clot, fibrin labeled with 125 iodine ((125)I-fibrin plasma clot), and injected into the jugular vein. A 50% clot lysis at 90 minutes required 110 microg/kg SakSTAR; 50 to 110 microg/kg of core-substitution derivatives with 1 P5; 25 microg/kg for NH(2)-terminal derivatives with 1 P5; 5 to 25 microg/kg with derivatives with 2 P5 or 1 P10; and 7 microg/kg with P20 derivatives. Core substitution with 1 or 2 P5 molecules did not significantly reduce the immunogenicity of SakSTAR in rabbits. Derivatization of staphylokinase with a single PEG molecule allows controllable reduction of the clearance while maintaining thrombolytic potency at a reduced dose. This indicates that mono-PEGylated staphylokinase variants may be used for single intravenous bolus injection.

A procedure is described to screen panels of hybridomas or purified monoclonal antibodies using antigen displayed on the surface of filamentous bacteriophage. In this system, samples containing murine monoclonal antibodies are incubated with phage-displayed antigen in microtiter plates coated with rabbit anti-mouse IgG, and bound antibody–phage complex is detected with horseradish peroxidase–sheep anti-phage M13 conjugate. The assay has been validated with a panel of 16 monoclonal antibodies directed against human plasminogen, using phage-displayed miniplasmin(ogen) (amino acids Ala 444 through Asn 791 comprising kringle 5 and the proteinase domain of plasminogen) or microplasminogen (amino acids Ala 543 through Asn 791 comprising the proteinase domain). Six monoclonal antibodies were identified directed against miniplasminogen and miniplasmin; this was confirmed using a microtiter plate coated with antigens. One of these monoclonal antibodies (MA-42B12) did not react with microplasminogen, suggesting that its epitope is comprised within the kringle 5 domain. This test is rapid and sensitive (detecting 10–20 ng/ml of monoclonal antibody), and screening can be performed using phage-displayed zymogens or active enzymes or selected domains thereof. The procedure eliminates the need for large amounts of purified antigen for screening. Furthermore, immunization can be performed with partially purified antigen because only antibodies raised against the antigen of interest will be identified with the use of phage-displayed antigen. Therefore, this test may offer distinct advantages over the classical one-site enzyme-linked immunosorbent assay using antigen-coated microtiter plates.

To determine the reproducibility of radial artery mass (RAM), in hypertensive patients.In 49 patients, RAM was measured using a high resolution echotracking device (Nius-02) which allows noninvasive measurement of diameter and wall thickness of the radial artery. RAM was validated in vitro by comparing weight of arterial segments to ultrasonographic measurement and determined as RAM = r (pi Re2-pi Ri2) where r is the arterial wall density (1.06 g/cm3), and Re and Ri are values of internal and external radii, respectively. Repeatability coefficient (RC2 = SDi2/n) was 1.3 mg.Blood pressure was (mean +/- SD) 146 +/- 19/85 +/- 15 mmHg, radial arterial diameter was 2,449 +/- 376 microns, radial wall thickness was 302 +/- 68 microns, RAM was 28 +/- 9 mg (range 13-43 mg).These results indicate that radial artery mass can be measured using a high resolution echotracking device.

The structure of arteries changes with age. Gradual disappearance of elastic fibres facilitates dilatation of the arterial lumen and increase in length of the vessels. Simultaneously, the arterial wall becomes thicker, but it is often difficult to distinguish the changes due to ageing from those caused by atherosclerosis. These structural alterations result in a greater rigidity of the arteries, which can now be evaluated by non-invasive segmental methods. This shows that ageing does not have the same functional effects on wide-caliber elastic arteries and on middle-sized muscular arteries. The increase of systolic arterial pressure observed in the elderly is a consequence of structural and functional changes in the arterial system.

The authors describe a training program on prevention and management of violent behavior for the staff of a Veterans Administration hospital. The one-day workshop focuses on preventive identification of potentially violent situations and on methods of verbal and physical management of violent behavior. A study of workshop participants showed that trainees had improved knowledge about and performance in handling violent behavior after completing the program. Future developments in training in prevention and management of violent behavior should include greater availability of educational resource materials and incorporation of the subject in undergraduate and graduate health care training.

The relationship between steady-state plasma concentration and clinical response was studied in 22 hospitalized unipolar depressed patients. In a double-blind format the patients were randomly assigned to receive amitriptyline or nortriptyline. Dosage was adjusted based on plasma level with the aim of achieving a concentration of 60-180 ng/ml. By week 4 of treatment, 83% of amitriptyline patients and all nortriptyline patients were within the targeted plasma range. Based on final ratings of clinical state, the drug level adjustment improved the outcome for nortriptyline-treated patients, but not amitriptyline-treated patients. Nortriptyline patients with plasma levels of 60-230 ng/ml had lower Hamilton Rating Scale depression scores than patients outside that range. By contrast, amitriptyline plasma levels were not associated with depression ratings. After 1 week, patients treated with nortriptyline had a significantly greater mean reduction in Hamilton depression score, i.e., 55% compared to 25% for amitriptyline patients.

Cholangiocarcinoma (CC) represent 3% of all gastrointestinal tumours and can be classified anatomically in 3 types: intrahepatic (ICC), perihilar (PCC) and distal (DCC) cholangiocarcinomas. Resection is the treatment of choice but is only achieved in a few cases (20%) because of invasion of the biliary tract and/or vascular structures. The outcome of advanced CC is poor with an overall survival (OS) of maximum 15 months with chemotherapy. In the 1990s, CC was regarded as a contraindication for liver transplantation (LT). LT has recently been proposed as potentially curative option for ICC and PCC. Careful patient selection has changed OS. This article provides an update on current status of LT for patients with unresectable CC.

The dosage of urinary catecholamines and their metabolites is a main element of diagnosis in the research of a pheochromocytoma in patients with high blood pressure. The literature reports high values of these compounds in patients treated with labetalol (an alpha/beta-blocker). An analytical interference has been evoked to explain these misleading results, which have not been observed with other beta-blockers. The goal of this work was to look for this eventual analytical interference in the dosage of urinary metanephrine by reversed phase liquid chromatography coupled with electrochemical detection, in patients with high blood pressure. Eighteen hypertensive patients, 52 +/- 14 years old, were included in the study. In 8 patients, a dosage of metanephrine, normetanephrine and creatinine on a 24 hours urine sample was performed before (D1) and 24 hours after (D3) the prescription of labetalol (200 mg twice a day). In the other group, labetalol was not prescribed but dosage was made in the same conditions. Urinary excretion of these compounds (metanephrine+normetanephrine) divided by urinary creatinine was not modified in the treated group (0.16 +/- 0.08 vs 0.14 +/- 0.04), nor in the reference group (0.17 +/- 0.08 vs 0.17 +/- 0.08). This study shows that administration of labetalol in patients with essential hypertension does not interfere with urinary metanephrine and normetanephrine determination after 48 hours of treatment. This implies that research for a pheochromocytoma is possible in patients with hypertension and receiving labetalol, by using reversed phase liquid chromatography coupled with an electrochemical detector for the dosage of urinary metanephrine and normetanephrine.

Local Pulse Pressure (PP) is an independent determinant of carotid artery wall thickness, stronger than mean BP. The present study was designed to assess whether a beta-adrenoceptor antagonist or an ACE inhibitor-based treatment was able to reduce carotid artery wall hypertrophy through the reduction in carotid PP rather than by lowering mean BP, and whether the influence of local PP reduction could also be detected at the site of a muscular artery, the radial artery.Ninety-eight essential hypertensive patients were randomised to 9 months of double-blind treatment with either celiprolol or enalapril. Arterial parameters were determined with high resolution echotracking systems. PP was measured locally with PP applanation tonometry, and independently of mean BP. After 9 month's treatment, mean BP, carotid PP and intima-media thickness (IMT) decreased significantly, with no difference between the tow groups. The reduction in carotid pression pulsée, but not in mean BP, was a major independent determinant of the reduction in carotid IMT. Radial artery IMT and PP decreased significantly with both treatments. However, the reduction in radial artery IMT was not related to the changes in radial artery PP.The regression of carotid artery wall hypertrophy during long-term antihypertensive treatment was dependent on the reduction in local PP rather than on the lowering of mean BP. The effect of PP lowering on IMT reduction was observed at the site of an elastic artery but not at the site of a muscular artery.

Colorectal cancer (CRC) is a leading cause of cancer related death in the western countries. It remains an important health problem, often under-diagnosed. The symptoms can appear very late and about 25% of the patients are diagnosed at metastatic stage. Familial adenomatous polyposis (FAP) is an inherited colorectal cancer syndrome, characterized by the early onset of hundred to thousands of adenomatous polyps in the colon and rectum. Left untreated, there is a nearly 100% cumulative risk of progression to CRC by the age of 35-40 years, as well as an increased risk of various other malignancies. CRC can be prevented by the identification of the high risk population and by the timely implementation of rigid screening programs which will lead to special medico-surgical interventions.

The assumption that the arterial wall behaves like incompressible material simplifies the analysis of arterial wall elasticity. Experimental evidence for the incompressibility assumption has been obtained directly by volume-displacement and radiological methods. Recent developments in ultrasound technology have made it possible to take direct, high-resolution measurements of the internal diameter and wall thickness of an artery and thus calculate the cross-sectional area of the arterial wall. The objective of this study was to determine the cross-sectional area of the arterial wall in vitro at different levels of strain in order to demonstrate the incompressibility assumption.Two different types of fresh, human, medium-sized arteries were studied, the internal mammary artery, and a less elastic and more muscular artery, the radial artery. The internal diameter and wall thickness were measured with an ultrasonic echo-tracking device (NIUS 1; Asulab, Neuchâtel, Switzerland) over 1-min steps of increasing intra-arterial pressure (0, 50, 100, 150 and 175 mmHg).The cross-sectional area of the arterial wall of the radial and internal mammary artery remained unchanged under different levels of strain.Since the artery length remained constant during the pressure increases, the lack of change in the cross-sectional area of the arterial wall suggests that the arterial wall of human medium-sized arteries is essentially incompressible.

Quality of health care is a hot topic, especially with regard to cancer. Although rectal cancer is, in many aspects, a model oncologic entity, there seem to be substantial differences in quality of care between countries, hospitals and physicians. PROCARE, a Belgian multidisciplinary national project to improve outcome in all patients with rectum cancer, identified a set of quality of care indicators covering all aspects of the management of rectal cancer. This set should permit national and international benchmarking, i.e. comparing results from individual hospitals or teams with national and international performances with feedback to participating teams. Such comparison could indicate whether further improvement is possible and/or warranted.

Colorectal cancer is really a public health problem. The authors review the literature about the environmental factors leading to colorectal cancer. Chemoprevention of colorectal cancer is also discussed, particularly by aspirin and non steroidal anti-inflammatory drugs. Development of specific cyclooxygenase-2 inhibitors constitutes a promising research's field. Secondary prevention by coloscopy and polypectomy must lead to a lower rate of colorectal cancer disease and improvement of mortality.

Palpation of the radial pulses is one of the most important techniques in traditional Chinese medicine. Two double-blind randomised trials of the effects of real and sham acupuncture on radial artery hemodynamics were conducted in 19 patients regularly exposed to acupuncture (sensitised subjects), and in 8 healthy subjects devoid of previous exposure (naive subjects), respectively. Radial artery diameter and pulse waveform was measured with a high-resolution echotracking system and aplanation tonometry, respectively, before and during a 20-minute's acupuncture period. In sensitised patients, arterial diameter significantly increased during real acupuncture, compared to the sham group (+7.5 +/- 2.8% vs -2.9 +/- 2.7%, respectively; p0.01). By contrast, in naive subjects, arterial diameter did not change during real or sham acupuncture. In both populations, no significant difference was observed between real and sham acupuncture, concerning the time-course of blood pressure, radial artery distensibility and pressure waveform. Our results demonstrate that real acupuncture can determine an objective vasodilatation of the radial artery in patients regularly exposed to acupuncture, but not in naive subjects.

To identify the socio-demographic, clinical, psycho-behavioural and therapeutic factors explaining uncontrolled blood pressure in a population of hypertensives in ambulatory practice.The DUO-HTA survey is a national, cross-sectional, mirrored, observational study, from a representative sample of 347 general practitioners (MG) and 210 cardiologists, and a population of 2022 hypertensive patients followed by these doctors. The data were collected by means of questionnaires completed by the hypertensives and their doctors.The factors significantly discriminating patients for whom BP was controlled (C) from those patients whose BP was not controlled (NC) were an age less than 65 years, smoking, obesity, alcohol consumption, sedentary lifestyle and multiple anti-hypertensive treatment. On the psycho-behavioural front, the NC patients were more often anxious and irritable, claiming to lead a stressful life and for whom hypertension was often perceived as a "foreign entity" and a source of frustration and multiple deprivations. The factors discriminating the NC doctors from the C doctors were essentially psycho-behavioural, with the NC doctors considering the management of hypertension as being less gratifying, and hypertension as a condition with fluctuating progression, poorly understood and dramatized by patients.The DUO-HTA survey underlines the weight of reciprocal representation systems in hypertension for patients and their doctors, as well as the quality of the doctor-patient relationship in blood pressure control. It prompts the development of sensitisation actions for practitioners centered on improving the doctor-patient relationship.

Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan–Meier survival analysis. Results: A 5′-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5′ risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3′ of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3′ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3′ of SNCA. Several 5′ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584–598.

International audience; Background: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD).Objective: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD.Methods: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests.Results: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls.Conclusion: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.

It remains unclear which blood pressure (BP) characteristics best predict cardiovascular risk in different age groups and between sexes. We leveraged data from the MORGAM (MONICA [Monitoring of Trends and Determinants in Cardiovascular Disease], Risk, Genetics, Archiving and Monograph) Project to investigate determinants of BP characteristics and their prognostic importance, in younger and older (P interaction P P P P =0.03), enhanced continuous net reclassification improvement (0.150 [95% CI, 0.087–0.215]) and improved the prognostic value of the European Society of Cardiology/European Society of Hypertension hypertension definition (categorical net reclassification improvement=0.0255, P =0.005). In conclusion, diastolic BP may provide additional prognostic utility beyond systolic BP, in predicting composite cardiovascular events among younger individuals.

Introduction Masked uncontrolled hypertension (MUCH) carries an increased risk of cardiovascular (CV) complications and can be identified through combined use of office (O) and ambulatory (A) blood pressure (BP) monitoring (M) in treated patients. However, it is still debated whether the information carried by ABPM should be considered for MUCH management. Aim of the MASked-unconTrolled hypERtension management based on OBP or on ambulatory blood pressure measurement (MASTER) Study is to assess the impact on outcome of MUCH management based on OBPM or ABPM. Methods and analysis MASTER is a 4-year prospective, randomised, open-label, blinded-endpoint investigation. A total of 1240 treated hypertensive patients from about 40 secondary care clinical centres worldwide will be included -upon confirming presence of MUCH (repeated on treatment OBP

Several sets of guidelines have been published recently and more are in the works. The very recent American College of Physicians/American Academy of Family Practitioners guidelines were put together by a set of authors and consultants without any expertise in the topic under discussion, that is, hypertension. Although we are not maintaining that all guidelines should be written exclusively by experts, complete lack of expertise among guideline authors is not acceptable. ispartof: Journal Of Hypertension vol:35 issue:8 pages:1564-1566 ispartof: location:Netherlands status: published

International audience; : Document reviewers: Guy De Backer (ESC Review Co-ordinator) (Belgium), Anthony M. Heagerty (ESH Review Co-ordinator) (UK), Stefan Agewall (Norway), Murielle Bochud (Switzerland), Claudio Borghi (Italy), Pierre Boutouyrie (France), Jana Brguljan (Slovenia), Héctor Bueno (Spain), Enrico G. Caiani (Italy), Bo Carlberg (Sweden), Neil Chapman (UK), Renata Cifkova (Czech Republic), John G. F. Cleland (UK), Jean-Philippe Collet (France), Ioan Mircea Coman (Romania), Peter W. de Leeuw (The Netherlands), Victoria Delgado (The Netherlands), Paul Dendale (Belgium), Hans-Christoph Diener (Germany), Maria Dorobantu (Romania), Robert Fagard (Belgium), Csaba Farsang (Hungary), Marc Ferrini (France), Ian M. Graham (Ireland), Guido Grassi (Italy), Hermann Haller (Germany), F. D. Richard Hobbs (UK), Bojan Jelakovic (Croatia), Catriona Jennings (UK), Hugo A. Katus (Germany), Abraham A. Kroon (The Netherlands), Christophe Leclercq (France), Dragan Lovic (Serbia), Empar Lurbe (Spain), Athanasios J. Manolis (Greece), Theresa A. McDonagh (UK), Franz Messerli (Switzerland), Maria Lorenza Muiesan (Italy), Uwe Nixdorff (Germany), Michael Hecht Olsen (Denmark), Gianfranco Parati (Italy), Joep Perk (Sweden), Massimo Francesco Piepoli (Italy), Jorge Polonia (Portugal), Piotr Ponikowski (Poland), Dimitrios J. Richter (Greece), Stefano F. Rimoldi (Switzerland), Marco Roffi (Switzerland), Naveed Sattar (UK), Petar M. Seferovic (Serbia), Iain A. Simpson (UK), Miguel Sousa-Uva (Portugal), Alice V. Stanton (Ireland), Philippe van de Borne (Belgium), Panos Vardas (Greece), Massimo Volpe (Italy), Sven Wassmann (Germany), Stephan Windecker (Switzerland), Jose Luis Zamorano (Spain).The disclosure forms of all experts involved in the development of these Guidelines are available on the ESC website www.escardio.org/guidelines.

In the BEAUTY study we investigated whether utilizing non-invasive monitoring of hemodynamic parameters combined with a drug selection algorithm (integrated hemodynamic management-IHM) compared to conventional drug selection may improve home BP in patients with uncontrolled hypertension.Uncontrolled (office systolic blood pressure (SBP) 140 mmHg and ambulatory daytime SBP135 mmHg while taking ≥2 antihypertensive drugs) essential hypertensive patients were referred to 5 European Hypertension Excellence Centers and, if eligible, were randomized into IHM-guided vs conventional treatment adjustment. Home blood pressure (BP) was taken with 2 repeated readings at 1-2 min intervals in the morning and in the evening (before drug intake and eating) during the week preceding the visit at the outpatient clinic after 5 min rest using a validated semi-automatic oscillometric arm cuff device and with a correct cuff bladder placement. Home blood pressure was measured in a sub-group of patients (n = 84) not significantly different from the other patients.Home SBP changed from 152.1+/-15.8 and 149.8+/-11.8 mmHg to 131.0 +/-11.1 and 139.6+/-12.8 mmHg in IHM group (n = 46) and Control group (n = 38), respectively, showing significantly greater reduction in IHM than in Control group (d= -10.9 mmHg, 95% CI -17.77, -4.02), p = 0.002. The reduction remained significant after multiple adjustments, particularly for baseline home SBP, recruiting center, age, sex and BMI (SBPDrug selection algorithm based on non-invasive hemodynamic monitoring induced larger reduction in home BP compared to conventional drug selection in uncontrolled hypertensive patients referred to European Hypertension Excellence Centers. Although the main BEAUTY study was negative, these home BP measurements taken by patients themselves may suggest that the integrated hemodynamic monitoring is useful in patients with uncontrolled hypertension. This finding might depend on specific features of home BP measurements which could make it recommended BP measurement method for drug trials.

Objective The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications. Methods Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function. Results Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants. Interpretation Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139-153.

OBJECTIVE:: To evaluate perindopril 3.5mg/amlodipine 2.5mg once daily, a novel fixed-dose combination adapted for first-step treatment in patients with hypertension. This fixed dose had to be equivalent to amlodipine 5mg in terms of blood pressure efficacy, but with an expected better tolerability profile. We selected two drugs with complementary modes of action, with doses chosen so that each drug would contribute similarly to the overall blood pressure-lowering effect METHODS:: An international, randomized, double-blind, placebo-controlled study with six equal parallel treatment arms and an 8-week randomized treatment period, whose design, clinical significance and non-inferiority criteria were in accordance with European guidelines. RESULTS:: In all, 1581 patients with mild-to-moderate uncomplicated hypertension (mean age 51.7 years) were randomized and 94.7% completed the study. The combination was statistically and clinically superior to placebo (between-group differences: SBP: -7.22mmHg, DBP: -4.12mmHg, P

Background The recent finding that aortic pulse wave velocity ( aPWV ) is increased in patients with inflammatory bowel disease may explain why the cardiovascular risk is increased despite the low prevalence of traditional cardiovascular risk factors. We aimed to test whether inflammation is associated with aortic stiffening in this setting after adjustment for major confounders and to perform subgroup analyses. Methods and Results A systematic literature search for aPWV in inflammatory bowel disease was performed using PubMed, Scopus, Web of Science, and Google Scholar databases (last accessed May 7, 2017). Inclusion criterion was peer‐reviewed publications on clinical studies reporting original data. This study followed the Preferred Reporting Items for Systematic Review and Meta‐Analyses of individual participant data 2015 guidelines. Data were provided for 4 cohorts in 3 countries (151 participants with ulcerative colitis, 159 with Crohn's disease, and 227 control patients). Using aPWV , cohort‐specific z scores were calculated after log e ‐transform and combined in meta‐analysis to form pooled effects using a random‐effects model. Compared with controls, aPWV was increased in patients with Crohn's disease (mean difference 0.78 z score; 95% confidence interval, 0.56–1.00 z score [ P z score; 95% confidence interval, 0.52–0.97 z score [ P aPWV was associated with disease duration (years, β=0.05 z score; 95% confidence interval, 0.02–0.08 z score [ P z score; 95% confidence interval, 0.02–0.11 z score [ P =0.002]) but not with markers of acute inflammation (C‐reactive protein and erythrocyte sedimentation rate), cardiovascular risk factors, and therapy. Conclusions The increased aPWV reported in patients with inflammatory bowel disease is associated with inflammation. Clinical Trial Registration URL : http://www.crd.york.ac.uk . Unique identifier: PROSPERO 2016: CRD 42016053070.