Code-specific learning rules improve action selection by populations of spiking neurons

Population coding is widely regarded as a key mechanism for achieving reliable behavioral decisions. We previously introduced reinforcement learning for population-based decision making by spiking neurons. Here we generalize population reinforcement learning to spike-based plasticity rules that take account of the postsynaptic neural code. We consider spike/no-spike, spike count and spike latency codes. The multi-valued and continuous-valued features in the postsynaptic code allow for a generalization of binary decision making to multi-valued decision making and continuous-valued action selection. We show that code-specific learning rules speed up learning both for the discrete classification and the continuous regression tasks. The suggested learning rules also speed up with increasing population size as opposed to standard reinforcement learning rules. Continuous action selection is further shown to explain realistic learning speeds in the Morris water maze. Finally, we introduce the concept of action perturbation as opposed to the classical weight- or node-perturbation as an exploration mechanism underlying reinforcement learning. Exploration in the action space greatly increases the speed of learning as compared to exploration in the neuron or weight space.

Spatial-temporal clustering of companion animal enteric syndrome: detection and investigation through the use of electronic medical records from participating private practices

SUMMARY There is interest in the potential of companion animal surveillance to provide data to improve pet health and to provide early warning of environmental hazards to people. We implemented a companion animal surveillance system in Calgary, Alberta and the surrounding communities. Informatics technologies automatically extracted electronic medical records from participating veterinary practices and identified cases of enteric syndrome in the warehoused records. The data were analysed using time-series analyses and a retrospective space-time permutation scan statistic. We identified a seasonal pattern of reports of occurrences of enteric syndromes in companion animals and four statistically significant clusters of enteric syndrome cases. The cases within each cluster were examined and information about the animals involved (species, age, sex), their vaccination history, possible exposure or risk behaviour history, information about disease severity, and the aetiological diagnosis was collected. We then assessed whether the cases within the cluster were unusual and if they represented an animal or public health threat. There was often insufficient information recorded in the medical record to characterize the clusters by aetiology or exposures. Space-time analysis of companion animal enteric syndrome cases found evidence of clustering. Collection of more epidemiologically relevant data would enhance the utility of practice-based companion animal surveillance.

Direct observation of molecular arrays in the organized smooth endoplasmic reticulum.

BACKGROUND Tubules and sheets of endoplasmic reticulum perform different functions and undergo inter-conversion during different stages of the cell cycle. Tubules are stabilized by curvature inducing resident proteins, but little is known about the mechanisms of endoplasmic reticulum sheet stabilization. Tethering of endoplasmic reticulum membranes to the cytoskeleton or to each other has been proposed as a plausible way of sheet stabilization. RESULTS Here, using fluorescence microscopy we show that the previously proposed mechanisms, such as membrane tethering via GFP-dimerization or coiled coil protein aggregation do not explain the formation of the calnexin-induced organized smooth endoplasmic reticulum membrane stacks. We also show that the LINC complex proteins known to serve a tethering function in the nuclear envelope are excluded from endoplasmic reticulum stacks. Finally, using cryo-electron microscopy of vitreous sections methodology that preserves cellular architecture in a hydrated, native-like state, we show that the sheet stacks are highly regular and may contain ordered arrays of macromolecular complexes. Some of these complexes decorate the cytosolic surface of the membranes, whereas others appear to span the width of the cytosolic or luminal space between the stacked sheets. CONCLUSION Our results provide evidence in favour of the hypothesis of endoplasmic reticulum sheet stabilization by intermembrane tethering.

Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis

OBJECTIVE: To determine the effect of glucosamine, chondroitin, or the two in combination on joint pain and on radiological progression of disease in osteoarthritis of the hip or knee. Design Network meta-analysis. Direct comparisons within trials were combined with indirect evidence from other trials by using a Bayesian model that allowed the synthesis of multiple time points. MAIN OUTCOME MEASURE: Pain intensity. Secondary outcome was change in minimal width of joint space. The minimal clinically important difference between preparations and placebo was prespecified at -0.9 cm on a 10 cm visual analogue scale. DATA SOURCES: Electronic databases and conference proceedings from inception to June 2009, expert contact, relevant websites. Eligibility criteria for selecting studies Large scale randomised controlled trials in more than 200 patients with osteoarthritis of the knee or hip that compared glucosamine, chondroitin, or their combination with placebo or head to head. Results 10 trials in 3803 patients were included. On a 10 cm visual analogue scale the overall difference in pain intensity compared with placebo was -0.4 cm (95% credible interval -0.7 to -0.1 cm) for glucosamine, -0.3 cm (-0.7 to 0.0 cm) for chondroitin, and -0.5 cm (-0.9 to 0.0 cm) for the combination. For none of the estimates did the 95% credible intervals cross the boundary of the minimal clinically important difference. Industry independent trials showed smaller effects than commercially funded trials (P=0.02 for interaction). The differences in changes in minimal width of joint space were all minute, with 95% credible intervals overlapping zero. Conclusions Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space. Health authorities and health insurers should not cover the costs of these preparations, and new prescriptions to patients who have not received treatment should be discouraged.

Screening the Structural Space of Bicyclo-DNA: Synthesis and Properties of Bicyclo-DNA Functionalized at C(6’)

The synthesis of a novel bicyclo-thymidine nucleoside bearing an ester functionality at C(6') (bc(alpha-alk)-nucleosides) is reported. This nucleoside was incorporated into oligodeoxynucleotides via solid phase phosphoramidite chemistry, and the ester moiety was post-synthetically converted to an amide or a carboxy group, or was left unchanged. Thermal melting data (T-m) with complementary DNA and RNA were collected and compared to natural DNA and to bc- and bc(ox)-DNA. It was found that single incorporations of bc(alpha-alk)-nucleosides in DNA duplexes were destabilizing by 0.5 to 2.5 degrees C/mod, whereas two consecutive bc(alpha-alk)-residues were less destabilizing, and in some cases even stabilizing by 0.5 degrees C/mod. In duplexes with complementary RNA, isolated bc(alpha-alk)-residues destabilized the duplex by -1.0 to -4.0 degrees C/mod, depending on the chemical nature of the substituent, whereas two consecutive modifications were only destabilizing by 0.3-1.0 degrees C/mod. The pairing selectivity was similar to that of unmodified or bc-DNA.

Placement of coiled catheters into the paravertebral space

There are conflicting results with regard to the use of catheter-based techniques for continuous paravertebral block. Local anaesthetic spread within the paravertebral space is limited and the clinical effect is often variable. Discrepancies between needle tip position and final catheter position can also be problematic. The aim of this proof-of-concept study was to assess the reliability of placing a newly developed coiled catheter in human cadavers. Sixty Tuohy needles and coiled catheters were placed under ultrasound guidance, three on each side of the thoracic vertebral column in 10 human cadavers. Computed tomography was used to assess needle tip and catheter tip locations. No catheter was misplaced into the epidural, pleural or prevertebral spaces. The mean (SD) distance between catheter tips and needle tips was 8.2 (4.9) mm. The median (IQR [range]) caudo-cephalad spread of contrast dye injectate through a subset of 20 catheters was 4 (4-5[3-8]) thoracic segments. All catheters were removed without incident. Precise paravertebral catheter placement can be achieved using ultrasound-guided placement of a coiled catheter.

Eosinophils in the gastrointestinal tract: friends or foes?

Eosinophils play an important role in the mucosal immune system of the gastrointestinal tract under resting and under inflammatory conditions. Under steady-state conditions, the mucosa of the digestive tract is the only organ harboring a substantial number of eosinophils, which, if need be, get activated and exert several effector and immunoregulatory functions. The precise function of these late-phase inflammatory cells is not yet completely understood. Nevertheless, it has recently been demonstrated that lipopolysaccharides from gram-negative bacteria activate eosinophils to rapidly release mitochondrial DNA in the extracellular space. Released mitochondrial DNA and eosinophil granule proteins form extracellular structures able to bind and inactivate bacteria. These findings suggest a novel mechanism of eosinophil-mediated innate immune responses that might be important in maintaining the intestinal barrier function. Moreover, eosinophils also play a crucial role in several inflammatory conditions, such as intestinal infections, immune-mediated inflammations and hypersensitivity reactions. Under chronic inflammatory conditions, the ability of the eosinophils to induce repair can lead to pathological sequelae in the tissue, such as esophageal remodeling in eosinophilic esophagitis. It is established that the uncontrolled eosinophilic inflammation induces fibrosis, esophageal wall thickening and strictures leading to damage that results in a loss of esophageal function. One potential mechanism of this remodeling is so-called 'epithelial mesenchymal transition', which is triggered by eosinophils and is potentially reversible under successful anti-eosinophil treatment. Therefore, eosinophils may act either as friends or as foes, depending on the microenvironment.

Effect of added dead space on sleep disordered breathing at high altitude

Sleep disordered breathing with central apnea or hypopnea frequently occurs at high altitude and is thought to be caused by a decrease in blood CO(2) level. The aim of this study was to assess the effects of added respiratory dead space on sleep disordered breathing.

An Instrument Design for Space-Based Optical Observation of Space Debris

Currently, observations of space debris are primarily performed with ground-based sensors. These sensors have a detection limit at some centimetres diameter for objects in Low Earth Orbit (LEO) and at about two decimetres diameter for objects in Geostationary Orbit (GEO). The few space-based debris observations stem mainly from in-situ measurements and from the analysis of returned spacecraft surfaces. Both provide information about mostly sub-millimetre-sized debris particles. As a consequence the population of centimetre- and millimetre-sized debris objects remains poorly understood. The development, validation and improvement of debris reference models drive the need for measurements covering the whole diameter range. In 2003 the European Space Agency (ESA) initiated a study entitled “Space-Based Optical Observation of Space Debris”. The first tasks of the study were to define user requirements and to develop an observation strategy for a space-based instrument capable of observing uncatalogued millimetre-sized debris objects. Only passive optical observations were considered, focussing on mission concepts for the LEO, and GEO regions respectively. Starting from the requirements and the observation strategy, an instrument system architecture and an associated operations concept have been elaborated. The instrument system architecture covers the telescope, camera and onboard processing electronics. The proposed telescope is a folded Schmidt design, characterised by a 20 cm aperture and a large field of view of 6°. The camera design is based on the use of either a frame-transfer charge coupled device (CCD), or on a cooled hybrid sensor with fast read-out. A four megapixel sensor is foreseen. For the onboard processing, a scalable architecture has been selected. Performance simulations have been executed for the system as designed, focussing on the orbit determination of observed debris particles, and on the analysis of the object detection algorithms. In this paper we present some of the main results of the study. A short overview of the user requirements and observation strategy is given. The architectural design of the instrument is discussed, and the main tradeoffs are outlined. An insight into the results of the performance simulations is provided.

Versatility of the abductor hallucis muscle as a conjoined or distally-based flap

Soft tissue coverage of the medial ankle and foot remains a difficult, challenging, and often frustrating problem to patients as well as surgeons. To our knowledge, the abductor hallucis muscle flap is not frequently used and only a few well documented cases were found in literature. The purpose of this paper is to report and to present the long-term results of a series of four patients who underwent reconstruction of foot and ankle defects with the abductor hallucis muscle flap.In two cases, the abductor hallucis muscle flap was transposed in combination with a medialis pedis flap to cover a medial ankle defect, whereas in another case it was combined with a medial plantar flap. In this latter case, the muscle flap served to fill up a calcaneal dead space after osteomyelitis debridement, whereas the cutaneous flap was used to replace debrided skin at the heel. The abductor hallucis flap was used as a distally-based turnover flap to cover a large forefoot defect in a fourth case. Follow-up period ranged between 18 and 64 months (mean 43.3). In the early postoperative period, two flaps healed completely In two patients marginal flap necrosis occurred which was subsequently skin grafted. No donor-site complication occurred in any of the patients. In all cases, protective sensation of the skin was satisfactory as early as 6 months. In two cases mild hyperkeratosis at the skin graft border to the sole skin (non-weight bearing area of medial plantar and medialis pedis flap donor site) was present, but probably related to poor foot care. All patients were fully mobile as early as 3 months after treatment. In the long-term follow-up (43.3 months), all flaps provided with durable coverage. Functional gait deficit due to consumtion of the abductor hallucis muscle was not apparent.Our long-term results demonstrated that the abductor hallucis muscle flap is a versatile, and reliable flap suitable for the reconstruction of foot and ankle defects. Utilizing the abductor hallucis muscle as a pedicled flap (distally or proximally-based) with or without conjoined regional fasciocutaneous flaps offers a successful and durable alternative to microsurgical tree flaps for small to moderate defects over the calcaneus region, medial ankle, medial foot, and forefoot with exposed bone, tendon, or joint.

Die operative Behandlung der Azetabulum-T-Fraktur über eine chirurgische Hüftluxation oder einen Stoppa-Zugang. [Operative treatment of T-type fractures of the acetabulum via surgical hip dislocation or Stoppa approach]

OBJECTIVE: Anatomic reduction and stable fixation by means of tissue- preserving surgical approaches. INDICATIONS Displaced acetabular fractures. Surgical hip dislocation approach with larger displacement of the posterior column in comparison to the anterior column, transtectal fractures, additional intraarticular fragments, marginal impaction. Stoppa approach with larger displacement of the anterior column in comparison to the posterior column. A combined approach might be necessary with difficult reduction. CONTRAINDICATIONS Fractures > 15 days (then ilioinguinal or extended iliofemoral approaches). Suprapubic catheters and abdominal problems (e.g., previous laparotomy due to visceral injuries) with Stoppa approach (then switch to classic ilioinguinal approach). SURGICAL TECHNIQUE: Surgical hip dislocation: lateral decubitus position. Straight lateral incision centered over the greater trochanter. Entering of the Gibson interval. Digastric trochanteric osteotomy with protection of the medial circumflex femoral artery. Opening of the interval between the piriformis and the gluteus minimus muscle. Z-shaped capsulotomy. Dislocation of the femoral head. Reduction and fixation of the posterior column with plate and screws. Fixation of the anterior column with a lag screw in direction of the superior pubic ramus. Stoppa approach: supine position. Incision according to Pfannenstiel. Longitudinal splitting of the anterior portion of the rectus sheet and the rectus abdominis muscle. Blunt dissection of the space of Retzius. Ligation of the corona mortis, if present. Blunt dissection of the quadrilateral plate and the anterior column. Reduction of the anterior column and fixation with a reconstruction plate. Fixation of the posterior column with lag screws. If necessary, the first window of the ilioinguinal approach can be used for reduction and fixation of the posterior column. POSTOPERATIVE MANAGEMENT: During hospital stay, intensive mobilization of the hip joint using a continuous passive motion machine with a maximum flexion of 90 degrees . No active abduction and passive adduction over the body's midline, if a surgical dislocation was performed. Maximum weight bearing 10-15 kg for 8 weeks. Then, first clinical and radiographic follow-up. Deep venous thrombosis prophylaxis for 8 weeks postoperatively. RESULTS: 17 patients with a mean follow-up of 3.2 years. Ten patients were operated via surgical hip dislocation, two patients with a Stoppa approach, and five using a combined or alternative approach. Anatomic reduction was achieved in ten of the twelve patients (83%) without primary total hip arthroplasty. Mean operation time 3.3 h for surgical hip dislocation and 4.2 h for the Stoppa approach. Complications comprised one delayed trochanteric union, one heterotopic ossification, and one loss of reduction. There were no cases of avascular necrosis. In two patients, a total hip arthroplasty was performed due to the development of secondary hip osteoarthritis.

Doxycycline for osteoarthritis of the knee or hip

BACKGROUND: Osteoarthritis is a chronic joint disease that involves degeneration of articular cartilage. Pre-clinical data suggest that doxycycline might act as a disease-modifying agent for the treatment of osteoarthritis, with the potential to slow cartilage degeneration. OBJECTIVES: To examine the effects of doxycycline compared with placebo or no intervention on pain and function in patients with osteoarthritis of the hip or knee. SEARCH STRATEGY: We searched CENTRAL ( The Cochrane Library 2008, issue 3), MEDLINE, EMBASE and CINAHL up to 28 July 2008, checked conference proceedings, reference lists, and contacted authors. SELECTION CRITERIA: We included studies if they were randomised or quasi-randomised controlled trials that compared doxycycline at any dosage and any formulation with placebo or no intervention in patients with osteoarthritis of the knee or hip. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate. We contacted investigators to obtain missing outcome information. We calculated differences in means at follow-up between experimental and control groups for continuous outcomes and risk ratios for binary outcomes. MAIN RESULTS: We found one randomised controlled trial that compared doxycycline with placebo in 431 obese women. After 30 months of treatment, clinical outcomes were similar between the two treatment groups, with a mean difference of -0.20 cm (95% confidence interval (CI) -0.77 to 0.37 cm) on a visual analogue scale from 0 to 10 cm for pain and -1.10 units (95% CI -3.86 to 1.66) for function on the WOMAC disability subscale, which ranges from 17 to 85. These differences correspond to clinically irrelevant effect sizes of -0.08 and -0.09 standard deviation units for pain and function, respectively. The difference in changes in minimum joint space narrowing was in favour of doxycycline (-0.15 mm, 95% CI -0.28 to -0.02 mm), which corresponds to a small effect size of -0.23 standard deviation units. More patients withdrew from the doxycycline group compared with placebo due to adverse events (risk ratio 1.69, 95% CI 1.03 to 2.75). AUTHORS' CONCLUSIONS: The symptomatic benefit of doxycycline is minimal to non-existent. The small benefit in terms of joint space narrowing is of questionable clinical relevance and outweighed by safety problems. Doxycycline should not be recommended for the treatment of osteoarthritis of the knee or hip.

Paraseptal accessory pathway in Wolff-Parkinson- White-Syndrom: ablation from the right, from the left or within the coronary sinus/middle cardiac vein?

AIMS In 1999 the consensus statement "living anatomy of the atrioventricular junctions" was published. With that new nomenclature the former posteroseptal accessory pathway (APs) are termed paraseptal APs. The aim of this study was to identify ECG features of manifest APs located in this complex paraseptal space. METHODS AND RESULTS ECG characteristics of all patients who underwent radiofrequency ablation of an AP during a 3 year period were analyzed. Of the 239 patients with one or more APs, 30 patients had a paraseptal AP with preexcitation. Compared to APs within the coronary sinus (CS) or the middle cardiac vein (MCV) the right sided paraseptal APs significantly more often showed an isoelectric delta wave in lead II and/or a negative delta wave in aVR. The left sided paraseptal APs presented a negative delta wave in II significantly more often compared to the right sided APs. CONCLUSIONS According to the site of radiofrequency ablation, paraseptal APs are classified into 4 subgroups: paraseptal right, paraseptal left, inside the CS or inside the MCV. Subtle differences in preexcitation patterns of the delta wave as well as of the QRS complex exist. However, the definitive localization of APs remains reserved to the periinterventional intracardiac electrogram analysis.