Evaluation of an Integrated Telemonitoring Surveillance System in Patients with Coronary Heart Disease.

OBJECTIVES: Cardiovascular diseases are the most frequent cause of death in industrialized countries. Non-adherence with prescribed medication and recommended lifestyle changes significantly increases the risk of major cardiovascular events. The telemonitoring programme MyCor (Myokardinfarkt und Koronarstent Programm in Tirol) is a multi-modal intervention programme to improve lifestyle and medication management of patients with coronary heart disease (CHD). It includes patient education, self-monitoring with goal-setting and feedback, and regular clinical visits. We evaluated the MyCor telemonitoring programme regarding technical feasibility, user acceptance, patient adherence, change in health status, and change in quality of life. METHODS: A 4½-month study was conducted with two telemonitoring phases and one interim phase. The study comprised patient surveys, standardized assessment of quality of life using the MacNew questionnaire at study entry and after 4 and 18 weeks, analysis of adherence to medication and physical activity during the two telemonitoring phases, and analysis of reached goals regarding health conditions during the telemonitoring phases. RESULTS: Twenty-five patients (mean age: 63 years) participated in the study. Patients showed a high acceptance of the MyCor telemonitoring programme. Patients reported feelings of self-control, motivation for lifestyle changes, and improved quality of life. Adherence to daily measurements was high with 86% and 77% in the two telemonitoring phases. Adherence to medication was also high with up to 87% and 80%. Pre-defined goals for physical activity were reached in up to 86% and 73% of days, respectively. Quality of life improved from 5.5 at study entry to 6.3 at the end (p< 0.01; MacNew questionnaire). Reductions in blood pressure and heart rate or an improvement in reaching defined goals could not be observed. CONCLUSIONS: The MyCor telemonitoring programme Tirol for CHD patients has a high rate of acceptance among included patients. Critical evaluation revealed subjective benefits regarding quality of life and health status as well as high adherence rates to medication and lifestyle changes. Achieving long-term adherence and verifying clinical outcomes, however, remains an open issue. Our findings will promote further studies, addressing different strategies for an optimal mix of patient education, telemonitoring, feedback, and clinical follow-ups.

IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951.

The added value of IKZF1 gene deletion (IKZF1(del)) as a stratifying criterion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is still debated. We performed a comprehensive analysis of the impact of IKZF1(del) in a large cohort of children (n=1223) with BCR-ABL1-negative BCP-ALL treated in the EORTC-CLG trial 58951. Patients with IKZF1(del) had a lower 8-year event-free survival (EFS, 67.7% versus 86.5%; hazard ratio (HR)=2.41; 95% confidence interval (CI)=1.75-3.32; P<0.001). Importantly, despite association with high-risk features such as high minimal residual disease, IKZF1(del) remained significantly predictive in multivariate analyses. Analysis by genetic subtype showed that IKZF1(del) increased risk only in the high hyperdiploid ALLs (HR=2.57; 95% CI=1.19-5.55; P=0.013) and in 'B-other' ALLs, that is, lacking classifying genetic lesions (HR=2.22; 95% CI=1.45-3.39; P<0.001), the latter having then a dramatically low 8-year EFS (56.4; 95% CI=44.6-66.7). Among IKZF1(del)-positive patients randomized for vincristine-steroid pulses during maintenance, those receiving pulses had a significantly higher 8-year EFS (93.3; 95% CI=61.3-99.0 versus 42.1; 95% CI=20.4-62.5). Thus, IKZF1(del) retains independent prognostic significance in the context of current risk-adapted protocols, and is associated with a dismal outcome in 'B-other' ALL. Addition of vincristine-steroid pulses during maintenance may specifically benefit to IKZF1(del) patients in preventing relapses.

Specific accumulation of CYP94A1 transcripts after exposure to gaseous benzaldehyde: induction of lauric acid ω-hydroxylase activity in Vicia sativa exposed to atmospheric pollutants.

The effects of air pollutants such as aldehydes, ozone, nitrogen dioxide and benzene on fatty acid ω-hydroxylase activity in Vicia sativa microsomes have been investigated. Four days old etiolated V. sativa seedlings were exposed to different concentrations of selected pollutants for varying exposure times. Growing etiolated V. sativa seedlings in air containing the gaseous benzaldehyde (150 nM) led to an 8-fold enhancement of lauric acid ω-hydroxylase activity in microsomes of treated plants compared to controls grown in pure air (96 ± 10 versus 12 ± 2 pmol/min/mg protein, respectively). The induction increased with increasing gas phase concentrations (10-1300 nM) and the maximum of activity was measured after 48 h of exposure. Northern blot analysis revealed that this induction occurred via transcriptional activation of the gene coding for CYP94A1. The absence of CYP94A2 and CYP94A3 transcription activation together with the missing effect on epoxide hydrolases activities indicate the specificity of CYP94A1 induction by benzaldehyde. Exposure to nitrogen dioxide, ozone and formaldehyde also stimulated lauric acid ω-hydroxylases activity while exposure to benzene did not show any effect.

Innovative telemonitoring system for cardiology: from science to routine operation.

OBJECTIVE: Results of the Austrian MOBITEL (MOBIle phone based TELemonitoring for heart failure patients) trial indicate that home-based telemonitoring improves outcome of chronic heart failure (CHF) patients and reduces both frequency and duration of hospitalizations. Based on lessons learned, we assessed the weak points to clear the way for routine operations. METHODS: We analyzed the system with respect to recommendations of the ESC Guidelines and experiences gained throughout the trial to identify potential improvements. The following components have been identified: a patient terminal with highest usability, integrated way to document drug-intake and well-being, and automated event detection for worsening of CHF. As a consequence the system was extended by Near Field Communication (NFC) technology and by an event management tool. RESULTS: Usability evaluation with 30 adults (14f, median 51y. IQR[45-65]) showed that 21 (8f) were able to immediately operate the system after reading a step-by-step manual. Eight (6f) needed one time demonstration and one man (80y) failed to operate the blood pressure meter. Routine operation of the revised system started in March 2009. Within 9 months, 15 patients (4f, median 74y. IQR[71-83], all NYHA-III) transmitted 17,149 items. 43 events were detected because of body weight gain of more then 2kg within 2 days. 49 therapy adjustments were documented. Three patients stopped using the system, two (1f) because of non-compliance and one (m, 82y) because of death. Overall, the rate of adherence to daily data transfer was 78%. CONCLUSION: First results confirm the applicability of the revised telemonitoring system in routine operation.

Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial.

OBJECTIVE: To compare the efficacy and safety of subcutaneous (SC) versus oral administration of methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: MTX-naive patients with active RA (Disease Activity Score in 28 joints >or= 4) were eligible for the study if they had not previously taken biologic agents and had not taken disease-modifying antirheumatic drugs for 2 weeks prior to randomization. Patients were randomly assigned to receive 15 mg/week of MTX either orally (2 7.5-mg tablets plus a dummy prefilled syringe; n=187 patients) or SC (prefilled syringe containing 10 mg/ml plus 2 dummy tablets; n=188 patients) for 24 weeks. At week 16, patients who did not meet the American College of Rheumatology criteria for 20% improvement (ACR20) were switched from 15 mg of oral MTX to 15 mg of SC MTX and from 15 mg of SC MTX to 20 mg of SC MTX for the remaining 8 weeks, still in a blinded manner. The primary outcome was an ACR20 response at 24 weeks. RESULTS: At week 24, significantly more patients treated with SC MTX than with oral MTX showed ACR20 (78% versus 70%) and ACR70 (41% versus 33%) responses. Patients with a disease duration >or= 12 months had even higher ACR20 response rates (89% for SC administration and 63% for oral). In 52 of the ACR20 nonresponders (14%), treatment was switched at week 16. Changing from oral to SC MTX and from 15 mg to 20 mg of SC MTX resulted in 30% and 23% ACR20 response rates, respectively, in these patients. MTX was well tolerated. The rate of adverse events was similar in all groups. CONCLUSION: This 6-month prospective, randomized, controlled trial is the first to examine oral versus SC administration of MTX. We found that SC administration was significantly more effective than oral administration of the same MTX dosage. There was no difference in tolerability.

Mobile phone-based surveillance of cardiac patients at home.

We tested the reliability, acceptability and feasibility of a home-monitoring system for cardiac patients. Each participant was equipped with a mobile phone, an automatic blood pressure device and a digital weight scale. In total, 20 patients (14 patients with chronic heart failure, six patients with hypertension; mean age 50 years, standard deviation [SD] 14) were monitored for 90 days each. They were asked to measure their blood pressure, pulse and body weight every day, and to transfer the data together with the dosage of medication to the telemonitoring server using wireless Internet technology in the mobile phone. The physician in charge received email alerts when reported data fell outside pre-defined limits. The patients' compliance with the system was high. During a cumulative monitoring period of 1,735 days, there were 2,040 data transfer sessions, a mean of 102 per patient (SD 43). The mean percentage of successful data transfers was 83% (SD 22). The stability of the telemonitoring system was 98%, meaning that patient data transfer was almost always possible. The accessibility of the secure web server for physicians was above 99%. The web-based home-monitoring system was reliable and easy to handle for both patients and health care professionals. It may be a useful tool for patients with heart failure as well as hypertensive patients.

Initial experiences with a telemedicine framework for remote pacemaker follow-up.

According to international guidelines implanted cardiac pacemakers (PM) have to be checked periodically to ensure that they are working correctly. To spare a significant number of patients the burden of traveling to specialized PM clinics a telemedicine framework has been developed prototypically. A mobile, personal digital assistant (PDA) based PM follow-up unit provides the caregiver at the point-of-care with the necessary infrastructure to perform a basic PM follow-up examination remotely. In case of detected malfunction of the PM the patient is ordered to the hospital for further examination. The system has been evaluated in a clinical pilot trial on 44 patients with a total of 23 different PM models from 8 different manufacturers. The initial results indicate the potential of the concept to work as an efficient, manufacturer independent screening method with the ultimate goal to increase the safety, quality and efficiency of PM therapy.

HPLC assay in plasma and preliminary pharmacokinetic study of a quinazolinone derivative with spasmolytic effect.

An analytical method for analysis of 3-(o-bromo)-phenyl-2-(2',3'-dihydroxypropylthio)-4(3H)-quinazolinone from rat plasma using HPLC with reversed phase C18 and liquid-liquid extraction was developed. This method was used for a pharmacokinetic study in rat.

Correlation between changes in stroke volume and the paced intracardiac electrogram.

AIM: The aim of this study was to examine the relation between cardiac haemodynamics and parameters extracted from the intracardiac electrogram obtained during pacing, i.e. ventricular evoked response. METHODS AND RESULTS: In the course of routinely scheduled right heart catheterization, intracardiac electrograms and cardiac haemodynamics were monitored simultaneously in ten heart transplant patients (two females, aged 48 +/- 12 (18-59) years), using pacemaker telemetry and Swan-Ganz thermodilution techniques. Different haemodynamic states were induced by pacemaker programming (pacing rate changes) and table tilting (postural changes). Forty different haemodynamic states were assessed, with an average of three (2.4) haemodynamic variations in each patient. Linear regression analysis between relative stroke volume changes and relative changes in the R wave slew rate as extracted from the evoked responses revealed a strong, inverse, and highly significant correlation (r= - 0.93, P<0.0001) between those parameters. Similar results were obtained for pacing rate and postural variations alone, respectively. CONCLUSIONS: The strong correlation between changes in stroke volume and R slew rate indicates that paced intracardiac electrograms reflect changes in the size and geometry of the heart. Telemetrically recorded intracardiac electrograms may thus be used non-invasively to assess key aspects of cardiac haemodynamics.

Function of RARalpha during the maturation of neutrophils.

The retinoic acid receptor alpha gene is the target of chromosomal rearrangements in all cases of acute promyelocytic leukemia (APL). This recurrent involvement of RARalpha in the pathogenesis of APL is likely to reflect an important role played by this receptor during the differentiation of immature myeloid cells to neutrophils. RARalpha is a negative regulator of promyelocyte differentiation when not complexed with RA, and stimulates this differentiation when bound to RA. Since RARs are dispensable for the generation of mature neutrophils, their role thus appears to be to modulatory, rather than obligatory, for the control of neutrophil differentiation. In vitro, retinoic acid is also a potent inducer of neutrophil cell fate, suggesting that it might play a role in the commitment of pluripotent hematopoietic progenitors to the neutrophil lineage. Thus, the APL translocations target an important regulator of myeloid cell differentiation.

Selective ablation of retinoid X receptor alpha in hepatocytes impairs their lifespan and regenerative capacity.

Retinoid X receptors (RXRs) are involved in a number of signaling pathways as heterodimeric partners of numerous nuclear receptors. Hepatocytes express high levels of the RXRalpha isotype, as well as several of its putative heterodimeric partners. Germ-line disruption (knockout) of RXRalpha has been shown to be lethal in utero, thus precluding analysis of its function at later life stages. Hepatocyte-specific disruption of RXRalpha during liver organogenesis has recently revealed that the presence of hepatocytes is not mandatory for the mouse, at least under normal mouse facility conditions, even though a number of metabolic events are impaired [Wan, Y.-J., et al. (2000) Mol. Cell. Biol. 20, 4436-4444]. However, it is unknown whether RXRalpha plays a role in the control of hepatocyte proliferation and lifespan. Here, we report a detailed analysis of the liver of mice in which RXRalpha was selectively ablated in adult hepatocytes by using the tamoxifen-inducible chimeric Cre recombinase system. Our results show that the lifespan of adult hepatocytes lacking RXRalpha is shorter than that of their wild-type counterparts, whereas proliferative hepatocytes of regenerating liver exhibit an even shorter lifespan. These lifespan shortenings are accompanied by increased polyploidy and multinuclearity. We conclude that RXRalpha plays important cell-autonomous function(s) in the mechanism(s) involved in the lifespan of hepatocytes and liver regeneration.

Positive and negative regulation of granulopoiesis by endogenous RARalpha.

Acute promyelocytic leukemia (APL) is always associated with chromosomal translocations that disrupt the retinoic acid receptor alpha (RARalpha) gene. Whether these translocations relate to a role for endogenous RARalpha in normal granulopoiesis remains uncertain because most studies addressing this question have used non-physiological overexpression systems. Granulocyte differentiation in cells derived from RARalpha-deficient (RARalpha(-/-)) mice was studied and evaluated in the context of agonist-bound and ligand-free RARalpha. Our results demonstrate that RARalpha is dispensable for granulopoiesis, as RARalpha(-/-) mice have a normal granulocyte population despite an impaired ability to respond to retinoids. However, although it is not absolutely required, RARalpha can bidirectionally modulate granulopoiesis. RARalpha stimulates differentiation in response to exogenous retinoic acid. Furthermore, endogenous retinoids control granulopoiesis in vivo, as either vitamin A-deficient mice or animals treated with an RAR antagonist accumulate more immature granulocytes in their bone marrow. Conversely, RARalpha acts to limit differentiation in the absence of ligand because granulocyte precursors from RARalpha(-/-) mice differentiate earlier in culture. Thus, the block in granulopoiesis exerted by RARalpha fusion proteins expressed in APL cells may correspond to an amplification of a normal function of unliganded RARalpha.

Non-invasive graft monitoring after heart transplantation: rationale to reduce the number of endomyocardial biopsies.

The endomyocardial biopsy is invasive, reduces quality of life and cannot be repeated daily. Initial studies on noninvasive cardiac graft monitoring have been presented recently. During the heart transplant procedure, we implanted wideband telemetric pacemakers and fractally coated, epimyocardial electrodes. On biopsy days and during each follow-up, intramyocardial electrogram sequences were obtained. The maximum T-slew rate from the ventricular evoked response (VER) was automatically calculated and compared to the biopsy results (n = 331, ISHLT grading). The VER T-slew rate was significantly lower during rejection grade 2 or higher. The negative predictive value to exclude rejection was 98%. Using a single threshold diagnosis model, 74% of the biopsies could have been avoided. Noninvasive cardiac graft monitoring can reduce the need for surveillance biopsies and may offer a tool to optimize immunosuppressive therapy after heart transplantation.

Non-invasive cardiac allograft monitoring: the graz experience.

Based on previous reports by our group, initial studies on non-invasive cardiac graft monitoring have been presented recently. In this study we define new parameters to monitor rejection and infection after heart transplantation (HTX) the ventricular evoked response (VER) T-slew rate parameter is defined as the maximum negative slope in the descending part of the repolarization phase of the VER. We calculated the VER duration parameter in milliseconds and defined it as the time between the pacemaker spike and the cross-over of the baseline, with the slope line used to calculate the VER T-slew rate. During the HTX procedure, we implant wide-band telemetric pacemakers and fractally coated, epimyocardial electrodes (Physios CTM 01 and ELC 54-UP, Biotronik; Berlin, Germany). During each follow-up and on biopsy days, intramyocardial electrogram sequences were obtained and sent via the Internet to the central data-processing unit in Graz. We scored the infection status of the patients before data acquisition. The VER parameters were automatically calculated and send back within a few minutes. We prospectivly compared 1,613 follow-ups from 42 patients with biopsy (International Society of Heart and Lung Transplantation grading) and infection classification. The VER duration parameter did not change during rejection; however, we found an increase during clinically apparent infection. The VER T-slew rate parameter was lower during rejection grade 2 or higher, as well as during clinically apparent infection. The negative predictive value to rule out rejection was 99%. Our results indicate that rejection and infection cause different, reproducible effects on the electrical activity of the transplanted heart. Non-invasive cardiac graft monitoring may reduce the need for surveillance biopsies and may offer a tool to optimize immunosuppressive therapy after HTX.

RXRalpha overexpression in cardiomyocytes causes dilated cardiomyopathy but fails to rescue myocardial hypoplasia in RXRalpha-null fetuses.

Retinoid X receptor alpha-null (RXRalpha-null) mutants exhibit hypoplasia of their ventricular myocardium and die at the fetal stage. In the present study, we wished to determine whether transgenic re-expression of RXRalpha in mutant cardiac myocytes could rescue these defects. Two transgenic mouse lines specifically overexpressing an RXRalpha protein in cardiomyocytes were generated, using the cardiac alpha-myosin heavy chain (alpha-MHC) promoter. Breeding the high copy number transgenic line onto an RXRalpha-null genetic background did not prevent the myocardial hypoplasia and fetal lethality associated with the RXRalpha(-/-) genotype, even though the transgene was expressed in the ventricles as early as 10. 5 days post-coitum. These data suggest that the RXRalpha function involved in myocardial growth may correspond to a non-cell-autonomous requirement forsignal orchestrating the growth and differentiation of myocytes. Interestingly, the adult transgenic mice developed a dilated cardiomyopathy, associated with myofibrillar abnormalities and specific deficiencies in respiratory chain complexes I and II, thus providing an additional model for this genetically complex disease.