Stochastic amplitude-modulated stretching of Rabbit flexor digitorum profundus tendons reduces stiffness compared to Cyclic Loading but does not affect Tenocyte Metabolism

Background It has been demonstrated that frequency modulation of loading influences cellular response and metabolism in 3D tissues such as cartilage, bone and intervertebral disc. However, the mechano-sensitivity of cells in linear tissues such as tendons or ligaments might be more sensitive to changes in strain amplitude than frequency. Here, we hypothesized that tenocytes in situ are mechano-responsive to random amplitude modulation of strain. Methods We compared stochastic amplitude-modulated versus sinusoidal cyclic stretching. Rabbit tendon were kept in tissue-culture medium for twelve days and were loaded for 1h/day for six of the total twelve culture days. The tendons were randomly subjected to one of three different loading regimes: i) stochastic (2 – 7% random strain amplitudes), ii) cyclic_RMS (2–4.42% strain) and iii) cyclic_high (2 - 7% strain), all at 1 Hz and for 3,600 cycles, and one unloaded control. Results At the end of the culture period, the stiffness of the “stochastic” group was significantly lower than that of the cyclic_RMS and cyclic_high groups (both, p < 0.0001). Gene expression of eleven anabolic, catabolic and inflammatory genes revealed no significant differences between the loading groups. Conclusions We conclude that, despite an equivalent metabolic response, stochastically stretched tendons suffer most likely from increased mechanical microdamage, relative to cyclically loaded ones, which is relevant for tendon regeneration therapies in clinical practice.

The ω3-polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A(2) and suppress PGE(2) formation in mesangial cells

ω3-polyunsaturated fatty acids (ω3-PUFAs) are known to exert anti-inflammatory effects in various disease models although their direct targets are only poorly characterized.

Outcome and patterns of failure after postoperative intensity modulated radiotherapy for locally advanced or high-risk oral cavity squamous cell carcinoma

Background To determine the outcome and patterns of failure in oral cavity cancer (OCC) patients after postoperative intensity modulated radiotherapy (IMRT) with concomitant systemic therapy. Methods All patients with locally advanced (AJCC stage III/IV) or high-risk OCC (AJCC stage II) who underwent postoperative IMRT at our institution between December 2006 and July 2010 were retrospectively analyzed. The primary endpoint was locoregional recurrence-free survival (LRRFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), acute and late toxicities. Results Overall 53 patients were analyzed. Twenty-three patients (43%) underwent concomitant chemotherapy with cisplatin, two patients with carboplatin (4%) and four patients were treated with the monoclonal antibody cetuximab (8%). At a median follow-up of 2.3 (range, 1.1–4.6) years the 3-year LRRFS, DMFS and OS estimates were 79%, 90%, and 73% respectively. Twelve patients experienced a locoregional recurrence. Eight patients, 5 of which had both a flap reconstruction and extracapsular extension (ECE), showed an unusual multifocal pattern of recurrence. Ten locoregional recurrences occurred marginally or outside of the high-risk target volumes. Acute toxicity grades of 2 (27%) and 3 (66%) and late toxicity grades of 2 (34%) and 3 (11%) were observed. Conclusion LRRFS after postoperative IMRT is satisfying and toxicity is acceptable. The majority of locoregional recurrences occurred marginally or outside of the high-risk target volumes. Improvement of high-risk target volume definition especially in patients with flap reconstruction and ECE might transfer into better locoregional control.

The cannabinoid CB1 receptor antagonists rimonabant (SR141716) and AM251 directly potentiate GABA(A) receptors

Rimonabant (SR141716) and the structurally related AM251 are widely used in pharmacological experiments as selective cannabinoid receptor CB(1) antagonists / inverse agonists. Concentrations of 0.5-10 µM are usually applied in in vitro experiments. We intended to show that these drugs did not act at GABA(A) receptors but found a significant positive allosteric modulation instead.

The antinociceptive triterpene β-amyrin inhibits 2-arachidonoylglycerol (2-AG) hydrolysis without directly targeting cannabinoid receptors

Pharmacological activation of cannabinoid CB(1) and CB(2) receptors is a therapeutic strategy to treat chronic and inflammatory pain. It was recently reported that a mixture of natural triterpenes α- and β-amyrin bound selectively to CB(1) receptors with a subnanomolar K(i) value (133 pM). Orally administered α/β-amyrin inhibited inflammatory and persistent neuropathic pain in mice through both CB(1) and CB(2) receptors. Here, we investigated effects of amyrins on the major components of the endocannabinoid system.

Daily organ tracking in intensity-modulated radiotherapy of prostate cancer using an electronic portal imaging device with a dose saving acquisition mode

BACKGROUND AND PURPOSE: Daily use of conventional electronic portal imaging devices (EPID) for organ tracking is limited due to the relatively high dose required for high quality image acquisition. We studied the use of a novel dose saving acquisition mode (RadMode) allowing to take images with one monitor unit per image in prostate cancer patients undergoing intensity-modulated radiotherapy (IMRT) and tracking of implanted fiducial gold markers. PATIENTS AND METHODS: Twenty five patients underwent implantation of three fiducial gold markers prior to the planning CT. Before each treatment of a course of 37 fractions, orthogonal localization images from the antero-posterior and from the lateral direction were acquired. Portal images of both the setup procedure and the five IMRT treatment beams were analyzed. RESULTS: On average, four localization images were needed for a correct patient setup, resulting in four monitor units extra dose per fraction. The mean extra dose delivered to the patient was thereby increased by 1.2%. The procedure was precise enough to reduce the mean displacements prior to treatment to < o =0.3 mm. CONCLUSIONS: The use of a new dose saving acquisition mode enables to perform daily EPID-based prostate tracking with a cumulative extra dose of below 1 Gy. This concept is efficiently used in IMRT-treated patients, where separation of setup beams from treatment beams is mandatory.

Affective and linguistic processing of speech prosody: DC potential studies

Speech melody or prosody subserves linguistic, emotional, and pragmatic functions in speech communication. Prosodic perception is based on the decoding of acoustic cues with a predominant function of frequency-related information perceived as speaker's pitch. Evaluation of prosodic meaning is a cognitive function implemented in cortical and subcortical networks that generate continuously updated affective or linguistic speaker impressions. Various brain-imaging methods allow delineation of neural structures involved in prosody processing. In contrast to functional magnetic resonance imaging techniques, DC (direct current, slow) components of the EEG directly measure cortical activation without temporal delay. Activation patterns obtained with this method are highly task specific and intraindividually reproducible. Studies presented here investigated the topography of prosodic stimulus processing in dependence on acoustic stimulus structure and linguistic or affective task demands, respectively. Data obtained from measuring DC potentials demonstrated that the right hemisphere has a predominant role in processing emotions from the tone of voice, irrespective of emotional valence. However, right hemisphere involvement is modulated by diverse speech and language-related conditions that are associated with a left hemisphere participation in prosody processing. The degree of left hemisphere involvement depends on several factors such as (i) articulatory demands on the perceiver of prosody (possibly, also the poser), (ii) a relative left hemisphere specialization in processing temporal cues mediating prosodic meaning, and (iii) the propensity of prosody to act on the segment level in order to modulate word or sentence meaning. The specific role of top-down effects in terms of either linguistically or affectively oriented attention on lateralization of stimulus processing is not clear and requires further investigations.

Contractile performance of adult ventricular rat cardiomyocytes is not directly jeopardized by NO/cGMP-dependent induction of pro-apoptotic pathways

The activation of NO/cGMP pathways can induce pro-apoptotic pathways in cardiomyocytes although only a small number of cardiomyocytes fulfill the criteria of apoptosis. The same pathways reduce the contractile performance of cardiomyocytes. In the present study, we tested the hypothesis that exposure of cells to NO/cGMP for 24 h decrease their contractile performance due to an activation of pro-apoptotic pathways. Experiments were performed on freshly isolated and cultured adult ventricular rat cardiomyocytes. Cells were incubated with 8-bromo-cyclo-GMP (100 nmol/L-1 micromol/L), the NO donor SNAP (1 nmol/L-100 micromol/L), or the guanylyl cyclase activator YC-1 (3 micromol/L). Cell shortening, contraction and relaxation velocities, and diastolic cell lengths were determined at beating frequencies of 0.5, 1, and 2 Hz 24 h later. The activation of pro-apoptotic pathways was determined by staining of cardiomyocytes with an antibody directed against active caspase-3 and quantification of the number of apoptotic cells (annexin staining). Caspase-3 activation and an increase in the number of apoptotic cells was observed, but only at the highest concentrations tested (8-bromo-cyclo-GMP: 1-10 mmol/L; SNAP: 1-100 micromol/L). At these concentrations, none of the drugs decreased the mean cell shortening of cardiomyocytes. However, at concentrations lower than those required for induction of apoptotic cell death, the diastolic cell lengths and sarcomere lengths increased but cell shortening decreased. In conclusion, low concentrations of either NO or cGMP cause a desensitization of myofibrils, as indicated by elongated cell shapes, increased sarcomere lengths and reduced load-free cell shortening. High concentrations of NO/cGMP induce caspase-3 activation and increase the number of cells fulfilling the criteria of apoptotic cell death but did not impair cell function. Therefore, induction of apoptotic cell death per se seems not to contribute to the loss of contractile efficiency on the cellular level.