Blood pressure normalization in a large population of hypertensive patients treated with perindopril/indapamide combination: results of the OPTIMAX trial.

OBJECTIVE: To determine if the fixed-dose perindopril/indapamide combination (Per/Ind) normalizes blood pressure (BP) in the same fraction of hypertensive patients when treated in everyday practice or in controlled trials. METHODS: In this prospective trial, 17 938 hypertensive patients were treated with Per 2 mg/Ind 0.625 mg for 3-6 months. In Group 1 Per/Ind was initiated in newly diagnosed patients (n = 7032); in Group 2 Per/Ind replaced previous therapy in patients already treated but having either their BP still uncontrolled or experiencing side-effects (n = 7423); in Group 3 Per/Ind was added to previous treatment in patients with persistently high BP (n = 3483). BP was considered normalized when < or = 140/90 mm Hg. A multivariate analysis for predictors of BP normalization was performed. RESULTS: Subjects were on average 62 years old and had a baseline BP of 162.3/93.6 mm Hg. After treatment with Per/Ind, BP normalization was reached in 69.6% of patients in the Initiation group, 67.5% in the Replacement Group, and 67.4% in the Add-on Group (where patients were more frequently at risk, diabetic, or with target organ damage). Mean decreases in systolic BP of 22.8 mm Hg and in diastolic BP of 12.4 mm Hg were recorded. CONCLUSIONS: This trial was established to reflect everyday clinical practice, and a treatment strategy based on the Per/Ind combination, administered as initial, replacement, or add-on therapy, led to normalization rates that were superior to those observed in Europe in routine practice. These results support recent hypertension guidelines which encourage the use of combination therapy in the management of arterial hypertension.

European society of hypertension position paper on ambulatory blood pressure monitoring.

Ambulatory blood pressure monitoring (ABPM) is being used increasingly in both clinical practice and hypertension research. Although there are many guidelines that emphasize the indications for ABPM, there is no comprehensive guideline dealing with all aspects of the technique. It was agreed at a consensus meeting on ABPM in Milan in 2011 that the 34 attendees should prepare a comprehensive position paper on the scientific evidence for ABPM.This position paper considers the historical background, the advantages and limitations of ABPM, the threshold levels for practice, and the cost-effectiveness of the technique. It examines the need for selecting an appropriate device, the accuracy of devices, the additional information and indices that ABPM devices may provide, and the software requirements.At a practical level, the paper details the requirements for using ABPM in clinical practice, editing considerations, the number of measurements required, and the circumstances, such as obesity and arrhythmias, when particular care needs to be taken when using ABPM.The clinical indications for ABPM, among which white-coat phenomena, masked hypertension, and nocturnal hypertension appear to be prominent, are outlined in detail along with special considerations that apply in certain clinical circumstances, such as childhood, the elderly and pregnancy, and in cardiovascular illness, examples being stroke and chronic renal disease, and the place of home measurement of blood pressure in relation to ABPM is appraised.The role of ABPM in research circumstances, such as pharmacological trials and in the prediction of outcome in epidemiological studies is examined and finally the implementation of ABPM in practice is considered in relation to the issue of reimbursement in different countries, the provision of the technique by primary care practices, hospital clinics and pharmacies, and the growing role of registries of ABPM in many countries.

A new blood-based screening test for colorectal cancer: a pilot study

Background: Colorectal cancer (CRC) can be cured when diagnosed in its early or precancerous (adenoma) stages. Mostly due to poor compliance towards invasive screening procedures, detection rates for adenoma and early CRCs are still low. Available non-invasive screening tests have unfortunately low sensitivity and specificity performances. Therefore, there is a large unmet need calling for a cost-effective, reliable and non-invasive test to screen for early neoplastic and pre-neoplastic lesions. Objective: To develop a routine screening test based on a nucleic acids multi-gene assay performed on peripheral blood mononuclear cells (PBMCs) that can detect early CRCs and adenomas. Methods: 116 patients (mean age: 55 years; range: 18 to 74 years; female/male ration 0.98) were included in this pilot, nonblinded, colonoscopy-controlled study. Colonoscopy revealed 21 patients with CRC, 30 patients with adenoma bigger than 1 cm, 24 patients with inflammatory bowel disease (IBD) and 41 patients had no neoplastic or inflammatory lesions. Blood samples were taken from each patient the day of the colonoscopy and PBMCs were purified. Total RNA was extracted following standard procedures. Multiplex RT-qPCR was applied on 92 different candidate biomarkers. Different univariate and multivariate statistical methods were applied on these candidates, and among them, 57 biomarkers with significant p values (<0.01, Wilcoxon test) were selected, including ADAMTS1, MMP9, CXCL10, CXCR4, VEGFA and CDH1. Two distinct biomarker signatures are used to separate patients without neoplastic lesion from those with cancer (named COLOX 1 test), respectively from those with adenoma (named COLOX 2 test). Result: COLOX 1 and 2 tests have successfully separated patients without neoplastic lesion from those with CRC (sensitivity 70%, specificity 90%, AUC 0.88), respectively from those with adenoma bigger than 1cm (sensitivity 61%, specificity 80%, AUC 0.80). 6/24 patients in the IBD group have a positive COLOX 1 test. Conclusion: These two COLOX tests demonstrated an acceptable sensitivity and a high specificity to detect the presence of CRCs and adenomas bigger than 1 cm. The false positives COLOX 1 test in IBD patients could possibly be due to the chronic inflammatory state. A prospective, multicenter, pivotal study is underway in order to confirm these promising results in a larger cohort.

Endotoxin-induced hypotension in rats is not mediated by prekallikrein activation.

To test whether endotoxin decreases blood pressure acutely in rats by activating the plasma kinin-forming system, plasma kallikrein activity was determined in different experimental settings of endotoxemia. Conscious normotensive rats were infused for 45 min with endotoxin (LPS E. coli 0111:B4) at a dose (0.01 mg/min) which had no effect on blood pressure. Additional rats were infused with the vehicle of endotoxin. Plasma prekallikrein activity was measured at the end of the 45 min infusions. In other rats, a bolus intravenous injection of endotoxin (2 mg) was administered following the 45 min infusion of endotoxin or its vehicle. In these two latter groups of rats, plasma prekallikrein activity was determined 15 min after administration of the bolus dose of endotoxin. In rats pretreated with the endotoxin infusion, the bolus dose of endotoxin had no significant effect on blood pressure, whereas rats infused with the vehicle became and remained hypotensive up to the end of the experiment. There was however no significant difference in plasma prekallikrein activity within the different groups of rats. In another group of rats, dextran sulfate (0.25 mg i.v.), which activates factor XII and thereby the conversion of prekallikrein to kallikrein, induced a short-lasting fall in blood pressure. 15 min after administration of dextran sulfate, plasma prekallikrein activity was almost completely suppressed. These results obtained in unanesthetized rats strongly suggest that the blood pressure fall induced by E. coli endotoxin is not due to activation of prekallikrein and consequently of the kinin-forming system.

Treatment strategies in primary vitreoretinal lymphoma: a 17-center European collaborative study.

IMPORTANCE: The best treatment option for primary vitreoretinal lymphoma (PVRL) without signs of central nervous system lymphoma (CNSL) involvement determined on magnetic resonance imaging or in cerebrospinal fluid is unknown. OBJECTIVE: To evaluate the outcomes of treatment regimens used for PVRL in the prevention of subsequent CNSL. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted at 17 referral ophthalmologic centers in Europe. We reviewed clinical, laboratory, and imaging data on 78 patients with PVRL who did not have CNSL on presentation between January 1, 1991, and December 31, 2012, with a focus on the incidence of CNS manifestations during the follow-up period. INTERVENTIONS: The term extensive treatment was used for various combinations of systemic and intrathecal chemotherapy, whole-brain radiotherapy, and peripheral blood stem cell transplantation. Therapy to prevent CNSL included ocular radiotherapy and/or ocular chemotherapy (group A, 31 patients), extensive systemic treatment (group B, 21 patients), and a combination of ocular and extensive treatment (group C, 23 patients); 3 patients did not receive treatment. A total of 40 patients received systemic chemotherapy. MAIN OUTCOMES AND MEASURES: Development of CNSL following the diagnosis of PVRL relative to the use or nonuse of systemic chemotherapy and other treatment regimens. RESULTS: Overall, CNSL developed in 28 of 78 patients (36%) at a median follow-up of 49 months. Specifically, CNSL developed in 10 of 31 (32%) in group A, 9 of 21 (43%) in group B, and 9 of 23 (39%) in group C. The 5-year cumulative survival rate was lower in patients with CNSL (35% [95% CI, 50% to 86%]) than in patients without CNSL (68% [95% CI, 19% to 51%]; P = .003) and was similar among all treatment groups (P = .10). Adverse systemic effects occurred in 9 of 40 (23%) patients receiving systemic chemotherapy; the most common of these effects was acute renal failure. CONCLUSIONS AND RELEVANCE: In the present series of patients with isolated PVRL, the use of systemic chemotherapy was not proven to prevent CNSL and was associated with more severe adverse effects compared with local treatment.

Saturable metabolism of continuous high-dose ifosfamide with mesna and GM-CSF: a pharmacokinetic study in advanced sarcoma patients. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide mesna +/- GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas. PATIENTS AND METHODS: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed. RESULTS: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosuppression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%). CONCLUSION: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studies.

Safety and accuracy of robot-assisted versus fluoroscopy-guided pedicle screw insertion for degenerative diseases of the lumbar spine: a matched cohort comparison.

Object Recent years have been marked by efforts to improve the quality and safety of pedicle screw placement in spinal instrumentation. The aim of the present study is to compare the accuracy of the SpineAssist robot system with conventional fluoroscopy-guided pedicle screw placement. Methods Ninety-five patients suffering from degenerative disease and requiring elective lumbar instrumentation were included in the study. The robot cohort (Group I; 55 patients, 244 screws) consisted of an initial open robot-assisted subgroup (Subgroup IA; 17 patients, 83 screws) and a percutaneous cohort (Subgroup IB, 38 patients, 161 screws). In these groups, pedicle screws were placed under robotic guidance and lateral fluoroscopic control. In the fluoroscopy-guided cohort (Group II; 40 patients, 163 screws) screws were inserted using anatomical landmarks and lateral fluoroscopic guidance. The primary outcome measure was accuracy of screw placement on the Gertzbein-Robbins scale (Grade A to E and R [revised]). Secondary parameters were duration of surgery, blood loss, cumulative morphine, and length of stay. Results In the robot group (Group I), a perfect trajectory (A) was observed in 204 screws (83.6%). The remaining screws were graded B (n = 19 [7.8%]), C (n = 9 [3.7%]), D (n = 4 [1.6%]), E (n = 2 [0.8%]), and R (n = 6 [2.5%]). In the fluoroscopy-guided group (Group II), a completely intrapedicular course graded A was found in 79.8% (n = 130). The remaining screws were graded B (n = 12 [7.4%]), C (n = 10 [6.1%]), D (n = 6 [3.7%]), and E (n = 5 [3.1%]). The comparison of "clinically acceptable" (that is, A and B screws) was neither different between groups (I vs II [p = 0.19]) nor subgroups (Subgroup IA vs IB [p = 0.81]; Subgroup IA vs Group II [p = 0.53]; Subgroup IB vs Group II [p = 0.20]). Blood loss was lower in the robot-assisted group than in the fluoroscopy-guided group, while duration of surgery, length of stay, and cumulative morphine dose were not statistically different. Conclusions Robot-guided pedicle screw placement is a safe and useful tool for assisting spine surgeons in degenerative spine cases. Nonetheless, technical difficulties remain and fluoroscopy backup is advocated.

Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations.

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

Acetaminophen increases blood pressure in patients with coronary artery disease.

BACKGROUND: Because traditional nonsteroidal antiinflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, particularly in patients at increased cardiovascular risk. Hence, the aim of this study was to evaluate the safety of acetaminophen in patients with coronary artery disease. METHODS AND RESULTS: The 33 patients with coronary artery disease included in this randomized, double-blind, placebo-controlled, crossover study received acetaminophen (1 g TID) on top of standard cardiovascular therapy for 2 weeks. Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin system, inflammation, and oxidative stress were determined at baseline and after each treatment period. Treatment with acetaminophen resulted in a significant increase in mean systolic (from 122.4±11.9 to 125.3±12.0 mm Hg P=0.02 versus placebo) and diastolic (from 73.2±6.9 to 75.4±7.9 mm Hg P=0.02 versus placebo) ambulatory blood pressures. On the other hand, heart rate, endothelial function, early endothelial progenitor cells, and platelet function did not change. CONCLUSIONS: This study demonstrates for the first time that acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease. Thus, the use of acetaminophen should be evaluated as rigorously as traditional nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors, particularly in patients at increased cardiovascular risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00534651.

Is adjuvant chemotherapy of benefit for postmenopausal women who receive endocrine treatment for highly endocrine-responsive, node-positive breast cancer? International Breast Cancer Study Group Trials VII and 12-93.

To compare the efficacy of chemoendocrine treatment with that of endocrine treatment (ET) alone for postmenopausal women with highly endocrine responsive breast cancer. In the International Breast Cancer Study Group (IBCSG) Trials VII and 12-93, postmenopausal women with node-positive, estrogen receptor (ER)-positive or ER-negative, operable breast cancer were randomized to receive either chemotherapy or endocrine therapy or combined chemoendocrine treatment. Results were analyzed overall in the cohort of 893 patients with endocrine-responsive disease, and according to prospectively defined categories of ER, age and nodal status. STEPP analyses assessed chemotherapy effect. The median follow-up was 13 years. Adding chemotherapy reduced the relative risk of a disease-free survival event by 19% (P = 0.02) compared with ET alone. STEPP analyses showed little effect of chemotherapy for tumors with high levels of ER expression (P = 0.07), or for the cohort with one positive node (P = 0.03). Chemotherapy significantly improves disease-free survival for postmenopausal women with endocrine-responsive breast cancer, but the magnitude of the effect is substantially attenuated if ER levels are high.

Target blood pressure attainment with antihypertensive therapy in Swiss primary care.

Introduction: The control of high blood pressure (BP) remains insufficient in developed as well as in developing countries. We conducted a cross-sectional survey to investigate the management of hypertension and the achievement of target BPs in a large population of hypertensive patients treated by Swiss primary care physicians. Methods. Data from 4594 hypertensive patients were collected and assessed for demographic data, mode of treatment and BP achievements for the overall population and for high-risk patients such as diabetics and patients with impaired renal function (CKD patients). Furthermore, we analysed the achieved BP in patients receiving single pill combinations or dual free combinations for the three most commonly prescribed substances. Results. In this large patient population, 84% of patients were receiving an antihypertensive treatment of which 54% showed BP control (< 140/90 mmHg or < 130/80 mmHg for diabetics and patients with CKD). Considering the higher BP target in the elderly, 60.6% of treated patients were on target. In contrast, 28.8% of treated diabetics and 29.7% of patients with impaired renal function met BP goals. Diuretics and blockers of the renin-angiotensin system were the most commonly prescribed substances. High-risk patients and patients at advanced age (≥ 80 years) received dual free combination more frequently than younger patients. The use of diuretics was particularly high because of the prescription of single pill formulations. Differences in the pattern of drug prescription were found according to the linguistic areas. Conclusion. The control of hypertension in the Swiss hypertensive population is relatively high but still insufficient particularly among high cardiovascular risk patients such as diabetics and patients with impaired renal function. A further improvement of BP control could perhaps be achieved with a greater use of single pill combinations particularly in patients with complicated hypertension.

Geneva cocktail for cytochrome p450 and P-glycoprotein activity assessment using dried blood spots.

The suitability of the capillary dried blood spot (DBS) sampling method was assessed for simultaneous phenotyping of cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) using a cocktail approach. Ten volunteers received an oral cocktail capsule containing low doses of the probes bupropion (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and fexofenadine (P-gp) with coffee/Coke (CYP1A2) on four occasions. They received the cocktail alone (session 1), and with the CYP inhibitors fluvoxamine and voriconazole (session 2) and quinidine (session 3). In session 4, subjects received the cocktail after a 7-day pretreatment with the inducer rifampicin. The concentrations of probes/metabolites were determined in DBS and plasma using a single liquid chromatography-tandem mass spectrometry method. The pharmacokinetic profiles of the drugs were comparable in DBS and plasma. Important modulation of CYP and P-gp activities was observed in the presence of inhibitors and the inducer. Minimally invasive one- and three-point (at 2, 3, and 6 h) DBS-sampling methods were found to reliably reflect CYP and P-gp activities at each session.

Invader immunology: invasion history alters immune system function in cane toads (Rhinella marina) in tropical Australia.

Because an individual's investment into the immune system may modify its dispersal rate, immune function may evolve rapidly in an invader. We collected cane toads (Rhinella marina) from sites spanning their 75-year invasion history in Australia, bred them, and raised their progeny in standard conditions. Evolved shifts in immune function should manifest as differences in immune responses among the progeny of parents collected in different locations. Parental location did not affect the offspring's cell-mediated immune response or stress response, but blood from the offspring of invasion-front toads had more neutrophils, and was more effective at phagocytosis and killing bacteria. These latter measures of immune function are negatively correlated with rate of dispersal in free-ranging toads. Our results suggest that the invasion of tropical Australia by cane toads has resulted in rapid genetically based compensatory shifts in the aspects of immune responses that are most compromised by the rigours of long-distance dispersal.

Involvement of the kallikrein-kinin system in the antihypertensive effect of the angiotensin converting enzyme inhibitors.

1. Studies were performed in normal subjects and in rats to assess the effect of angiotensin converting enzyme (ACE) inhibition on the kallikrein-kinin system. As ACE is identical to kininase II, one of the enzymes physiologically involved in bradykinin degradation, bradykinin may be expected to accumulate during ACE inhibition. 2. A competitive antagonist of bradykinin was used to explore in unanaesthetized rats the contribution of circulating bradykinin to blood pressure control under ACE inhibition. 3. No evidence was found for a role of this vasodilating peptide in the blood pressure lowering effect of acute ACE inhibition. 4. The plasma activity of carboxypeptidase N (= kininase I), another pathway of bradykinin degradation, remained intact during a 1 week course of treatment with an ACE inhibitor in normal subjects. This therefore indicates that bradykinin formed during ACE inhibition can still be metabolized.

Added prognostic value of myocardial blood flow quantitation in rubidium-82 positron emission tomography imaging.

AIMS: We studied the respective added value of the quantitative myocardial blood flow (MBF) and the myocardial flow reserve (MFR) as assessed with (82)Rb positron emission tomography (PET)/CT in predicting major adverse cardiovascular events (MACEs) in patients with suspected myocardial ischaemia. METHODS AND RESULTS: Myocardial perfusion images were analysed semi-quantitatively (SDS, summed difference score) and quantitatively (MBF, MFR) in 351 patients. Follow-up was completed in 335 patients and annualized MACE (cardiac death, myocardial infarction, revascularization, or hospitalization for congestive heart failure or de novo stable angor) rates were analysed with the Kaplan-Meier method in 318 patients after excluding 17 patients with early revascularizations (<60 days). Independent predictors of MACEs were identified by multivariate analysis. During a median follow-up of 624 days (inter-quartile range 540-697), 35 MACEs occurred. An annualized MACE rate was higher in patients with ischaemia (SDS >2) (n = 105) than those without [14% (95% CI = 9.1-22%) vs. 4.5% (2.7-7.4%), P < 0.0001]. The lowest MFR tertile group (MFR <1.8) had the highest MACE rate [16% (11-25%) vs. 2.9% (1.2-7.0%) and 4.3% (2.1-9.0%), P < 0.0001]. Similarly, the lowest stress MBF tertile group (MBF <1.8 mL/min/g) had the highest MACE rate [14% (9.2-22%) vs. 7.3% (4.2-13%) and 1.8% (0.6-5.5%), P = 0.0005]. Quantitation with stress MBF or MFR had a significant independent prognostic power in addition to semi-quantitative findings. The largest added value was conferred by combining stress MBF to SDS. This holds true even for patients without ischaemia. CONCLUSION: Perfusion findings in (82)Rb PET/CT are strong MACE outcome predictors. MBF quantification has an added value allowing further risk stratification in patients with normal and abnormal perfusion images.