Epigenetic changes are a hallmark of short- and long-term transcriptional regulation, and hence instrumental in the control of cellular identity and plasticity. Epigenetic mechanisms leading to ...changes in chromatin structure, accessibility for recruitment of transcriptional complexes, and interaction of enhancers and promoters all contribute to acute and chronic adaptations of cells, tissues and organs to internal and external perturbations. Similarly, the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is activated by stimuli that alter the cellular energetic demand, and subsequently controls complex transcriptional networks responsible for cellular plasticity. It thus is of no surprise that PGC-1α is under the control of epigenetic mechanisms, and constitutes a mediator of epigenetic changes in various tissues and contexts. In this review, we summarize the current knowledge of the link between epigenetics and PGC-1α in health and disease.
We describe the performance of our latest generations of sensitive wide-band high-resolution digital fast Fourier transform spectrometer (FFTS). Their design, optimized for a wide range of radio ...astronomical applications, is presented. Developed for operation with the GREAT far infrared heterodyne spectrometer on-board SOFIA, the eXtended bandwidth FFTS (XFFTS) offers a high instantaneous bandwidth of 2.5 GHz with 88.5 kHz spectral resolution and has been in routine operation during SOFIA’s Basic Science since July 2011. We discuss the advanced field programmable gate array (FPGA) signal processing pipeline, with an optimized multi-tap polyphase filter bank algorithm that provides a nearly loss-less time-to-frequency data conversion with significantly reduced frequency scallop and fast sidelobe fall-off. Our digital spectrometers have been proven to be extremely reliable and robust, even under the harsh environmental conditions of an airborne observatory, with Allan-variance stability times of several 1000 s. An enhancement of the present 2.5 GHz XFFTS will duplicate the number of spectral channels (64k), offering spectroscopy with even better resolution during Cycle 1 observations.
Abstract Background Compliance with immunosuppressive therapy plays a major role in the long-term success of liver transplantation. Thus, the development of strategies to promote compliance of liver ...transplant patients and its evaluation over time are of particular interest. Objective The main objective of this study was to compare medication compliance rates among liver transplant patients over time after transplantation where switched from a twice- to once-daily tacrolimus-based regimen. Methods Sixty-five liver transplant patients being administered tacrolimus-based therapy were classified into three subgroups with regard to time posttransplantation. Medication compliance with tacrolimus-based therapy was measured using an electronic medication event monitoring system over a 12-month period: for 6 months tacrolimus was administered twice-daily and for 6 months, once-daily. Dosing, taking, and timing compliance as well as drug holidays were compared intra-individually between twice- and once-daily intake and among the three subgroups. In addition, patient compliance and quality of life were evaluated using questionnaires. Results A per protocol analysis of electronically obtained data showed 63 patients to be eligible. The resulting dosing, taking, and timing compliance rates of the patients were higher during the once-daily dosing period. No significant differences in compliance rates with tacrolimus therapy were observed among three subgroups independent of the dosing regimen. More patients failed the correct timing of the evening compared to the morning dose. Missing doses occurred particularly during weekends. Compliance variables measured by questionnaires (Morisky score, self-report, Medication Experience Scale for Immunosuppressants (MESI) score) and the Hospital Anxiety and Depression Scale score were similar in the two dosing periods. The short-form health survey (SF-36) score was higher with once-daily intake. Conclusion The high measured compliance rates did not vary significantly dependent upon the time after transplantation. Nevertheless, compliance rates were greater using once-daily tacrolimus dosing.
Context
The antiproliferative mechanism of mycophenolate acid (MPA) suggests a beneficial effect in patients with Graves’ orbitopathy (GO).
Objective
To systematically analyze for the first time ...adverse events (AEs) during MPA treatment in GO.
Design
Prospective longitudinal study.
Setting
Academic tertiary referral center with a joint thyroid-eye clinic.
Patients
Fifty-three consecutive, unselected patients with clinically active and moderate-to-severe GO.
Methods
MPA 0.720 g was given once daily for 24-weeks in GO patients. AEs were documented and coded according to the standardized medical dictionary for regulatory activities (MedDRA). AE were followed up and seriousness as defined by ICH-guideline E6 was documented. All AEs were analyzed regarding a possible underlying cause and if not, graded as side effect (SE).
Results
Fifty GO patients (93 %) had Graves’ disease, 37 (70 %) and 29 (54.7 %) were female and smoker, respectively. Thirty-six patients (68 %) reported at least one AE. A total of 88 AEs were documented, most frequent AEs were insomnia (
N
= 6), fatigue (
N
= 5) and optic neuropathy (
N
= 5), while other AEs occurred in up to three patients (5.6 %), only. In 12 (23 %) patients, at least one SE occurred. All 17 reported SE, i.e. mild infections and gastrointestinal intolerance were within the known safety profile of MPA. No patient dropped MPA medication because of drug-induced SE. Most AEs showed a recovered (76 %) or recovering (16 %) outcome. Seven (13 %) patients were hospitalized, five (62 %) due to optic neuropathy, none of these events was graded as SE.
Conclusions
MedDRA-coded data documented the good tolerance of a moderate MPA dose in GO patients.
Context. We present the technology and first scientific results of a new generation of very flexible and sensitive spectrometers, well-suited for the needs of spectral-line radio and (sub)millimeter ...astronomy: Fast Fourier Transform Spectrometers (FFTS), which are in operation at the Atacama Pathfinder EXperiment (APEX) telescope. Aims. The FFTS for APEX is a novel high-resolution $2\times 1$ GHz bandwidth digital spectrometer backend. Due to its high frequency resolution, and the demonstrated capability of operating at high altitude, the FFTS became the facility spectrometer for spectral line observations at APEX. Methods. The FFTS is based on one of the currently most powerful digitizer/analyzer boards available from Acqiris, Switzerland. The board incorporates two 1 Gsamples/s analog-to-digital converters (ADCs) with 8-bit resolution which feed an on-board complex field programmable gate array (FPGA) chip. The enormous processing power by today's FPGAs allow for a complete real-time FFT signal processing pipeline to decompose a 1 GHz band into 16 384 spectral channels in just one chip. Results. Since May 2005 an MPIfR FFTS has been extensively used in all regular spectroscopic science observations. The performance at APEX was demonstrated to be very reliable and as good as measured in the first laboratory tests which finally led to the request to provide a second, facility type FFTS for APEX. The unit was delivered and commissioned in March this year. Conclusions. Using a commercially available digitizer board, it was possible to develop a complete FFTS in only a few months. Successful observations at APEX demonstrate that this new generation of FPGA-based spectrometers easily matching and superseding the performance of older technology spectrometers and can built up much more easily. Furthermore, the by now available class of new high-speed ADCs and the continuous increase of FPGA processing power makes it very likely that FFTS can be pushed to broader bandwidth and even more spectral channels in the near future.
Happiness and other emotions spread between people in direct contact, but it is unclear whether massive online social networks also contribute to this spread. Here, we elaborate a novel method for ...measuring the contagion of emotional expression. With data from millions of Facebook users, we show that rainfall directly influences the emotional content of their status messages, and it also affects the status messages of friends in other cities who are not experiencing rainfall. For every one person affected directly, rainfall alters the emotional expression of about one to two other people, suggesting that online social networks may magnify the intensity of global emotional synchrony.
Human behaviour is thought to spread through face-to-face social networks, but it is difficult to identify social influence effects in observational studies, and it is unknown whether online social ...networks operate in the same way. Here we report results from a randomized controlled trial of political mobilization messages delivered to 61 million Facebook users during the 2010 US congressional elections. The results show that the messages directly influenced political self-expression, information seeking and real-world voting behaviour of millions of people. Furthermore, the messages not only influenced the users who received them but also the users' friends, and friends of friends. The effect of social transmission on real-world voting was greater than the direct effect of the messages themselves, and nearly all the transmission occurred between 'close friends' who were more likely to have a face-to-face relationship. These results suggest that strong ties are instrumental for spreading both online and real-world behaviour in human social networks.
Context
Safety of intravenous (IV) steroid pulses in patients with Graves’ orbitopathy (GO) is still controversial while steroid dose and treatment application have not been finalized. Frequency, ...severity and characterization of adverse events (AE) were prospectively analyzed.
Setting
Academic referral orbital center with a joint thyroid-eye clinic.
Patients
Eighty consecutive and unselected patients with active and severe GO.
Methods
During an established treatment with IV methylprednisolone (cumulative dose 4.5 g) occurring AE were prospectively coded according to the standardized and recognized medical dictionary for regulatory activities (MedDRA). Outcome and severity of AE were documented. AEs judged as at least possibly related to drug treatment were graded as side effect (SE). AEs matching a seriousness criteria as defined by the ICH guideline E6 (good clinical practice) were graded as serious.
Results
A total of 38.75 % (31/80) of the treated GO patients reported at least one AE while 18 patients (22.5 %) reported at least one SE. All SE were within the safety profile of IV methylprednisolone; 31/32 SE (96.87 %) were mild-moderate and reversible and only 1/80 patient (1.25 %) stopped steroid treatment due to exacerbation of her depression. Most AE were accessory symptoms of the underlying disease and a few only were directly related to IV steroids. Most AEs (90.6 %) were graded as mild. Only six patients (7.5 %) were hospitalized, three of them due to a dysthyroid optic neuropathy.
Conclusions
Prospective and standardized evaluation with MedDRA and the ICH guideline demonstrated the good pharmacological tolerance and low morbidity of this moderate steroid regimen.
Summary
Angiogenesis is the process by which new blood vessels are created from pre‐existing vessels. It is essential for the growth and development of normal cells and tissues during embryonic and ...neonatal development and of tumour cells. Solid tumours rely on having an extensive network of blood vessels for growth and survival. The key mediator of angiogenesis, vascular endothelial growth factor‐A (VEGF‐A), is critical for the growth of tumours and their subsequent metastasis and is known to initiate angiogenesis. Bevacizumab is a humanized immunoglobulin G monoclonal antibody that binds to VEGF with high specificity, thereby blocking VEGF‐mediated signalling pathways and thus angiogenesis. Clinical trials have shown that bevacizumab is effective in prolonging survival in patients with metastatic colorectal cancer (CRC) when combined with standard chemotherapy. Consequently, bevacizumab has been approved in combination with 5‐fluorouracil‐based chemotherapy for first‐line treatment of patients with metastatic CRC. Bevacizumab is generally well tolerated in most patients and does not exacerbate the adverse events associated with conventional chemotherapy. Bevacizumab‐related side effects are generally manageable; however, monitoring for hypertension, gastrointestinal perforation, bleeding, proteinuria and thromboembolism is advised, especially in patients with predisposing factors. In addition to demonstrated survival benefits, the convenient dosing schedule and lack of interactions should ensure the successful integration of this novel agent into clinical practice.
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