Rate and Pulse Based Plasticity Governed by Local Synaptic State Variables

Classically, action-potential-based learning paradigms such as the Bienenstock–Cooper–Munroe (BCM) rule for pulse rates or spike timing-dependent plasticity for pulse pairings have been experimentally demonstrated to evoke long-lasting synaptic weight changes (i.e., plasticity). However, several recent experiments have shown that plasticity also depends on the local dynamics at the synapse, such as membrane voltage, Calcium time course and level, or dendritic spikes. In this paper, we introduce a formulation of the BCM rule which is based on the instantaneous postsynaptic membrane potential as well as the transmission profile of the presynaptic spike. While this rule incorporates only simple local voltage- and current dynamics and is thus neither directly rate nor timing based, it can replicate a range of experiments, such as various rate and spike pairing protocols, combinations of the two, as well as voltage-dependent plasticity. A detailed comparison of current plasticity models with respect to this range of experiments also demonstrates the efficacy of the new plasticity rule. All experiments can be replicated with a limited set of parameters, avoiding the overfitting problem of more involved plasticity rules

Evaluation of LC-MS data for the absolute quantitative analysis of marker proteins

The serum complexity makes the absolute quantitative analysis of medium to low-abundant proteins very challenging. Tens of thousands proteins are present in human serum and dispersed over an extremely wide dynamic range. The reliable identification and quantitation of proteins, which are potential biomarkers of disease, in serum or plasma as matrix still represents one of the most difficult analytical challenges. The difficulties arise from the presence of a few, but highly abundant proteins in serum and from the non-availability of isotope-labeled proteins, which serve to calibrate the method and to account for losses during sample preparation. For the absolute quantitation of serum proteins, we have developed an analytical scheme based on first-dimension separation of the intact proteins by anion-exchange high-performance liquid chromatography (HPLC), followed by proteolytic digestion and second-dimension separation of the tryptic peptides by reversed-phase HPLC in combination with electrospray ionization mass spectrometry (ESI-MS). The potential of mass spectrometric peptide identification in complex mixtures by means of peptide mass fingerprinting (PMF) and peptide fragment fingerprinting (PFF) was evaluated and compared utilizing synthetic mixtures of commercially available proteins and electrospray-ion trap- or electrospray time-of-flight mass spectrometers. While identification of peptides by PFF is fully supported by automated spectrum interpretation and database search routines, reliable identification by PMF still requires substantial efforts of manual calibration and careful data evaluation in order to avoid false positives. Quantitation of the identified peptides, however, is preferentially performed utilizing full-scan mass spectral data typical of PMF. Algorithmic solutions for PMF that incorporate both recalibration and automated feature finding on the basis of peak elution profiles and isotopic patterns are therefore highly desirable in order to speed up the process of data evaluation and calculation of quantitative results. Calibration for quantitative analysis of serum proteins was performed upon addition of known amounts of authentic protein to the serum sample. This was essential for the analysis of human serum samples, for which isotope-labeled protein standards are usually not available. We present the application of multidimensional HPLC-ESI-MS to the absolute quantitative analysis of myoglobin in human serum, a very sensitive biomarker for myocardial infarction. It was possible to determine myoglobin concentrations in human serum down to 100-500 ng/mL. Calibration graphs were linear over at least one order of magnitude and the relative standard deviation of the method ranged from 7-15%

Cardiac Imaging Using Clinical 1.5 T MRI Scanners in a Murine Ischemia/Reperfusion Model

To perform cardiac imaging in mice without having to invest in expensive dedicated equipment, we adapted a clinical 1.5 Tesla (T) magnetic resonance imaging (MRI) scanner for use in a murine ischemia/reperfusion model. Phase-sensitive inversion recovery (PSIR) sequence facilitated the determination of infarct sizes in vivo by late gadolinium enhancement. Results were compared to histological infarct areas in mice after ischemia/reperfusion procedure with a good correlation (r = 0.807, P < .001). In addition, fractional area change (FAC) was assessed with single slice cine MRI and was matched to infarct size (r = −0.837) and fractional shortening (FS) measured with echocardiography (r = 0.860); both P < .001. Here, we demonstrate the use of clinical 1.5 MRI scanners as a feasible method for basic phenotyping in mice. These widely available scanners are capable of investigating in vivo infarct dimensions as well as assessment of cardiac functional parameters in mice with reasonable throughput

Displacement of the Greater Tuberosity in Humeral Head Fractures Does Not only Depend on Rotator Cuff Status

It is assumed that dorsocranial displacement of the greater tuberosity in humeral head fractures is caused by rotator cuff traction. The purpose of this study was to investigate the association between rotator cuff status and displacement characteristics of the greater tuberosity in four-part humeral head fractures. Computed tomography scans of 121 patients with Neer type 4 fractures were analyzed. Fatty infiltration of the supra- and infraspinatus muscles was classified according to Goutallier. Position determination of the greater tuberosity fragment was performed in both coronary and axial planes to assess the extent of dorsocranial displacement. Considering non-varus displaced fractures, the extent of the dorsocranial displacement was significantly higher in patients with mostly inconspicuous posterosuperior rotator cuff status compared to advanced fatty degenerated cuffs (cranial displacement: Goutallier 0–1: 6.4 mm ± 4.6 mm vs. Goutallier 2–4: 4.2 mm ± 3.5 mm, p = 0.020; dorsal displacement: Goutallier 0–1: 28.4° ± 32.3° vs. Goutallier 2–4: 13.1° ± 16.1°, p = 0.010). In varus displaced humeral head fractures, no correlation between the displacement of the greater tuberosity and the condition of the posterosuperior rotator cuff could be detected (p ≥ 0.05). The commonly accepted theory of greater tuberosity displacement in humeral head fractures by rotator cuff traction cannot be applied to all fracture types

A Biohybrid Setup for Coupling Biological and Neuromorphic Neural Networks

Developing technologies for coupling neural activity and artificial neural components, is key for advancing neural interfaces and neuroprosthetics. We present a biohybrid experimental setting, where the activity of a biological neural network is coupled to a biomimetic hardware network. The implementation of the hardware network (denoted NeuroSoC) exhibits complex dynamics with a multiplicity of time-scales, emulating 2880 neurons and 12.7 M synapses, designed on a VLSI chip. This network is coupled to a neural network in vitro, where the activities of both the biological and the hardware networks can be recorded, processed, and integrated bidirectionally in real-time. This experimental setup enables an adjustable and well-monitored coupling, while providing access to key functional features of neural networks. We demonstrate the feasibility to functionally couple the two networks and to implement control circuits to modify the biohybrid activity. Overall, we provide an experimental model for neuromorphic-neural interfaces, hopefully to advance the capability to interface with neural activity, and with its irregularities in pathology

The Loop Tenodesis Procedure—From Biomechanics to First Clinical Results

(1) Introduction: Several surgical therapy options for the treatment of pathologies of the long biceps tendon (LHB) have been established. However, tenotomy, as well as established tenodesis techniques, has disadvantages, such as cosmetic deformities, functional impairments and residual shoulder pain. This study presents the first clinical and structural results of the recently introduced loop tenodesis procedure for the LHB, developed to overcome these issues. (2) Methods: 37 patients (11 women, 26 men, mean age 52 years), who underwent loop tenodesis of the LHB were examined six months after surgery. For the clinical evaluation the Constant score, as well as the LHB score, were used, complemented by elbow flexion and supination strength measurements. The integrity of the tenodesis construct was evaluated indirectly by sonographic detection of the LHB in the bicipital groove. (3) Results: Both, the overall Constant score as well as the LHB score showed significant improvements six months postoperatively, as compared to the preoperative value. Fourteen patients (38%) presented an examiner-dependent upper arm deformity, although only five patients (13%) reported subjective cosmetic deformities. Both, flexion and supination strength were preserved compared to the preoperative level. In 35 patients (95%), the tenodesis in the bicipital groove was proofed sonographically. (4) Conclusion: The loop tenodesis of the LHB provides good-to-excellent overall clinical results after a short-term follow-up of six month. The incidence of cosmetic deformities was inferior compared to conventional therapy options (tenotomy and anchor tenodesis)

ifo Konjunkturprognose 2011: Aufschwung setzt sich verlangsamt fort

Am 14. Dezember 2010 stellte das ifo Institut im Rahmen seines vorweihnachtlichen Pressegesprächs seine Prognose für die Jahre 2010 und 2011 vor. Die deutsche Wirtschaft hat ihren vor mehr als einem Jahr begonnenen Aufholprozess mit hoher Dynamik fortgesetzt. Nachdem die Impulse dafür zunächst aus dem Ausland gekommen waren, gewann die Binnenwirtschaft in den vergangenen drei Quartalen mehr und mehr an Bedeutung. Besonders wichtig war dafür der Investitionsanreiz, der aus einem historisch niedrigen Zinsniveau resultierte. Die gesamtwirtschaftliche Produktion, getrieben vom kräftig expandierenden industriellen Kern, dürfte im Jahresendquartal 2010 saison- und kalenderbereinigt leicht beschleunigt um 0,8% zugenommen haben. Im Jahresdurchschnitt 2010 expandiert das reale Bruttoinlandsprodukt damit um 3,7%. Im kommenden Jahr bleiben die Konjunkturampeln in Deutschland auf Grün, das Bruttoinlandsprodukt dürfte - bei einem 67%-Unsicherheitsintervall von 1,4 bis 3,4% - um 2,4% steigen. Entscheidend hierfür wird voraussichtlich die Entwicklung der heimischen Nachfrage sein. Bei alledem ist zu erwarten, dass sich die Beschäftigungssituation weiter verbessert. Nachdem die Unternehmen des verarbeitenden Gewerbes in diesem Jahr überwiegend Leiharbeiter eingestellt haben, dürften im kommenden Jahr auch die Stammbelegschaften ausgeweitet werden. Auch werden wohl wieder vermehrt sozialversicherungspflichtige Vollzeitstellen geschaffen. Die Arbeitslosenquote dürfte auf 7,0% sinken. Im Gefolge des Aufschwungs werden die Verbraucherpreise etwas anziehen, mit voraussichtlich 1,7% wird die Inflationsrate aber unter dem Preisziel der EZB bleiben. Das staatliche Budgetdefizit, das im laufenden Jahr in Relation zum nominalen Bruttoinlandsprodukt 3,5% beträgt, wird im nächsten Jahr aufgrund der anhaltend guten Konjunktur, der Konsolidierungsmaßnahmen im Rahmen des Zukunftspakets und der Sparmaßnahmen in der gesetzlichen Krankenversicherung auf 2,3% sinken

Predictive preoperative clinical score for patients with liver-only oligometastatic colorectal cancer

BACKGROUND: Resection of liver metastases from colorectal cancer (CRC) in the oligometastatic stage improves survival and is a potentially curative treatment. Thus, predictive scores that reliably identify those patients who especially benefit from surgery are essential. PATIENTS AND METHODS: In this multicenter analysis, 512 patients had undergone surgery for liver metastases from CRC. We investigated distinct cancer-specific risk factors that are routinely available in clinical practice and developed a predictive preoperative score using a training cohort (TC), which was thereafter tested in a validation cohort (VC). RESULTS: Inflammatory response to the tumor, a right-sided primary tumor, multiple liver metastases, and node-positive primary tumor were significant adverse variables for overall survival (OS). Patients were stratified in five groups according to the cumulative score given by the presence of these risk factors. Median OS for patients without risk factors was 133.8 months [95% confidence interval (CI) 81.2-not reached (nr)] in the TC and was not reached in the VC. OS decreased significantly for each subsequent group with increasing number of risk factors. Median OS was significantly shorter (P < 0.0001) for patients presenting all four risk factors: 14.3 months (95% CI 10.5 months-nr) in the TC and 16.6 months (95% CI 14.6 months-nr) in the VC. CONCLUSIONS: Including easily obtainable variables, this preoperative score identifies oligometastatic CRC patients with prolonged survival rates that may be cured, and harbors potential to be implemented in daily clinical practice

PPA1 Deficiency Causes a Deranged Galactose Metabolism Recognizable in Neonatal Screening

Two siblings showed increased galactose and galactose-related metabolites in neonatal screening. Diagnostic workup did not reveal abnormalities in any of the known disease-causing enzymes involved in galactose metabolism. Using whole-exome sequencing, we identified a homozygous missense variant in PPA1 encoding the cytosolic pyrophosphatase 1 (PPA1), c.557C>T (p.Thr186Ile). The enzyme activity of PPA1 was determined using a colorimetric assay, and the protein content was visualized via western blotting in skin fibroblasts from one of the affected individuals. The galactolytic activity of the affected fibroblasts was determined by measuring extracellular acidification with a Seahorse XFe96 analyzer. PPA1 activity decreased to 22% of that of controls in the cytosolic fraction of homogenates from patient fibroblasts. PPA1 protein content decreased by 50% according to western blot analysis, indicating a reduced stability of the variant protein. The extracellular acidification rate was reduced in patient fibroblasts when galactose was used as a substrate. Untargeted metabolomics of blood samples revealed an elevation of other metabolites related to pyrophosphate metabolism. Besides hyperbilirubinemia in the neonatal period in one child, both children were clinically unremarkable at the ages of 3 and 14 years, respectively. We hypothesize that the observed metabolic derangement is a possible mild manifestation of PPA1 deficiency. Unresolved abnormalities in galactosemia screening might result in the identification of more individuals with PPA1 deficiency, a newly discovered inborn metabolic disorder (IMD)

Partial Anterior Cruciate Ligament Ruptures: Advantages by Intraligament Autologous Conditioned Plasma Injection and Healing Response Technique—Midterm Outcome Evaluation

The historical treatment options for partial anterior cruciate ligament (ACL) ruptures were conservative therapy or ACL reconstruction by injured bundle or entire ACL replacement. In awareness of the regenerative potential of biologic agents such as mesenchymal stem cells or platelet rich plasma (PRP), the healing response technique was developed to preserve the injured ACL with belter outcomes lhan ihe conservative therapy. Further improvement of this technique seems to be obtained by the additional application of PRP products. Thus, the aim of this study was to evaluate the midterm outcome after intraligament autologous conditioned plasma (ACP) by a clinical, scoring, and functional performance assessment. 42 patients were evaluated in this study. The failure rate was 9.5%. Outcome evaluation showed good to excellent results. The scores were IKDC subjective 83.2 (SD 14.5), Lysholm 85.5 (SD 15.5), Tegner 4.7 (SD 1.7), and Cincinnati 85.4 (SD 15.5) afler a mean follow-up of 33 months. Clinical examination showed stable Lachman tesl, negative pivot shift phenomenon, and a significant reduction in AP-laxity compared to preoperative status (rolimeter preoperative: 1.9 (SD1.4); postoperative 0.6 (SD1.8), p=0.001) in all patients. Functional performance testing showed no significant differences between the injured and healthy side. Return to sport was achieved after a mean of 5.8 months (SD 3.6) in 71.1% of the included patients. In summary, this new treatment option revealed in midterm follow-up promising results to treat partial ACL lesions with a reduced need for conversion to ACL reconstruction and with a high percentage of return to preinjury sport activity