Surgical approaches to adenocarcinoma of the gastroesophageal junction: the Siewert II conundrum.

BACKGROUND: The Siewert classification system for gastroesophageal junction adenocarcinoma has provided morphological and topographical information to help guide surgical decision-making. Evidence has shown that Siewert I and III tumors are distinct entities with differing epidemiologic and histologic characteristics and distinct patterns of disease progression, requiring different treatment. Siewert II tumors share some of the characteristics of type I and III lesions, and the surgical approach is not universally agreed upon. Appropriate surgical options include transthoracic esophagogastrectomy, transhiatal esophagectomy, and transabdominal extended total gastrectomy. PURPOSE: A review of the available evidence of the surgical management of Siewert II tumors is presented. CONCLUSIONS: Careful review of the data appear to support the fact that a satisfactory oncologic resection can be achieved via a transabdominal extended total gastrectomy with a slight advantage in terms of perioperative complications, and overall postoperative quality of life. Overall and disease-free survival compares favorably to the transthoracic approach. These results can be achieved with careful selection of patients balancing more than just the Siewert type in the decision-making but considering also preoperative T and N stages, histological type (diffuse type requiring longer margins that are not always achievable via gastrectomy), and the presence of Barrett\u27s esophagus

Event-driven simulation of spiking neurons with stochastic dynamics

We present a new technique, based on a proposed event-based strategy (Mattia & Del Giudice, 2000), for efficiently simulating large networks of simple model neurons. The strategy was based on the fact that interactions among neurons occur by means of events that are well localized in time (the action potentials) and relatively rare. In the interval between two of these events, the state variables associated with a model neuron or a synapse evolved deterministically and in a predictable way. Here, we extend the event-driven simulation strategy to the case in which the dynamics of the state variables in the inter-event intervals are stochastic. This extension captures both the situation in which the simulated neurons are inherently noisy and the case in which they are embedded in a very large network and receive a huge number of random synaptic inputs. We show how to effectively include the impact of large background populations into neuronal dynamics by means of the numerical evaluation of the statistical properties of single-model neurons under random current injection. The new simulation strategy allows the study of networks of interacting neurons with an arbitrary number of external afferents and inherent stochastic dynamics

On the Firing Rate Dependency of the Phase Response Curve of Rat Purkinje Neurons In Vitro

Synchronous spiking during cerebellar tasks has been observed across Purkinje cells: however, little is known about the intrinsic cellular mechanisms responsible for its initiation, cessation and stability. The Phase Response Curve (PRC), a simple input-output characterization of single cells, can provide insights into individual and collective properties of neurons and networks, by quantifying the impact of an infinitesimal depolarizing current pulse on the time of occurrence of subsequent action potentials, while a neuron is firing tonically. Recently, the PRC theory applied to cerebellar Purkinje cells revealed that these behave as phase-independent integrators at low firing rates, and switch to a phase-dependent mode at high rates. Given the implications for computation and information processing in the cerebellum and the possible role of synchrony in the communication with its post-synaptic targets, we further explored the firing rate dependency of the PRC in Purkinje cells. We isolated key factors for the experimental estimation of the PRC and developed a closed-loop approach to reliably compute the PRC across diverse firing rates in the same cell. Our results show unambiguously that the PRC of individual Purkinje cells is firing rate dependent and that it smoothly transitions from phase independent integrator to a phase dependent mode. Using computational models we show that neither channel noise nor a realistic cell morphology are responsible for the rate dependent shift in the phase response curve

Enhanced self-administration of the CB1 receptor agonist WIN55,212-2 in olfactory bulbectomized rats: evaluation of possible serotonergic and dopaminergic underlying mechanisms

Depression has been associated with drug consumption, including heavy or problematic cannabis use. According to an animal model of depression and substance use disorder comorbidity, we combined the olfactory bulbectomy (OBX) model of depression with intravenous drug self-administration procedure to verify whether depressive-like rats displayed altered voluntary intake of the CB1 receptor agonist WIN55,212-2 (WIN, 12.5 μg/kg/infusion). To this aim, olfactory-bulbectomized (OBX) and sham-operated (SHAM) Lister Hooded rats were allowed to self-administer WIN by lever-pressing under a continuous [fixed ratio 1 (FR-1)] schedule of reinforcement in 2 h daily sessions. Data showed that both OBX and SHAM rats developed stable WIN intake; yet, responses in OBX were constantly higher than in SHAM rats soon after the first week of training. In addition, OBX rats took significantly longer to extinguish the drug-seeking behavior after vehicle substitution. Acute pre-treatment with serotonin 5HT1B receptor agonist, CGS-12066B (2.5-10 mg/kg), did not significantly modify WIN intake in OBX and SHAM Lister Hooded rats. Furthermore, acute pre-treatment with CGS-12066B (10 and 15 mg/kg) did not alter responses in parallel groups of OBX and SHAM Sprague Dawley rats self-administering methamphetamine under higher (FR-2) reinforcement schedule with nose-poking as operandum. Finally, dopamine levels in the nucleus accumbens (NAc) of OBX rats did not increase in response to a WIN challenge, as in SHAM rats, indicating a dopaminergic dysfunction in bulbectomized rats. Altogether, our findings suggest that a depressive-like state may alter cannabinoid CB1 receptor agonist-induced brain reward function and that a dopaminergic rather than a 5-HT1B mechanism is likely to underlie enhanced WIN self-administration in OBX rats

Treatments for Ocular Diseases in Pregnancy and Breastfeeding: A Narrative Review.

Pregnancy is a medical condition in which the physiological changes in the maternal body and the potential impact on the developing fetus require a cautious approach in terms of drug administration. Individual treatment, a thorough assessment of the extent of the disease, and a broad knowledge of the therapeutic options and different routes of administration of ophthalmic drugs are essential to ensure the best possible results while minimizing risks. Although there are currently several routes of administration of drugs for the treatment of eye diseases, even with topical administration, there is a certain amount of systemic absorption that must be taken into account. Despite continuous developments and advances in ophthalmic drugs, no updated data are available on their safety profile in these contexts. The purpose of this review is both to summarize the current information on the safety of ophthalmic treatments during pregnancy and lactation and to provide a practical guide to the ophthalmologist for the treatment of eye diseases while minimizing harm to the developing fetus and addressing maternal health needs

Plasticity and Adaptation in Neuromorphic Biohybrid Systems

Neuromorphic systems take inspiration from the principles of biological information processing to form hardware platforms that enable the large-scale implementation of neural networks. The recent years have seen both advances in the theoretical aspects of spiking neural networks for their use in classification and control tasks and a progress in electrophysiological methods that is pushing the frontiers of intelligent neural interfacing and signal processing technologies. At the forefront of these new technologies, artificial and biological neural networks are tightly coupled, offering a novel \u201cbiohybrid\u201d experimental framework for engineers and neurophysiologists. Indeed, biohybrid systems can constitute a new class of neuroprostheses opening important perspectives in the treatment of neurological disorders. Moreover, the use of biologically plausible learning rules allows forming an overall fault-tolerant system of co-developing subsystems. To identify opportunities and challenges in neuromorphic biohybrid systems, we discuss the field from the perspectives of neurobiology, computational neuroscience, and neuromorphic engineering. \ua9 2020 The Author(s

Edoxaban vs. warfarin in patients with atrial fibrillation on amiodarone: a subgroup analysis of the ENGAGE AF-TIMI 48 trial

Background In the ENGAGE AF-TIMI 48 trial, the higher-dose edoxaban (HDE) regimen had a similar incidence of ischaemic stroke compared with warfarin, whereas a higher incidence was observed with the lower-dose regimen (LDE). Amiodarone increases edoxaban plasma levels via P-glycoprotein inhibition. The current pre-specified exploratory analysis was performed to determine the effect of amiodarone on the relative efficacy and safety profile of edoxaban. Methods and results At randomization, 2492 patients (11.8%) were receiving amiodarone. The primary efficacy endpoint of stroke or systemic embolic event was significantly lower with LDE compared with warfarin in amiodarone treated patients vs. patients not on amiodarone (hazard ratio [HR] 0.60, 95% confidence intervals [CIs] 0.36-0.99 and HR 1.20, 95% CI 1.03-1.40, respectively; P interaction <0.01). In patients randomized to HDE, no such interaction for efficacy was observed (HR 0.73, 95% CI 0.46-1.17 vs. HR 0.89, 95% CI 0.75-1.05, P interaction = 0.446). Major bleeding was similar in patients on LDE (HR 0.35, 95% CI 0.21-0.59 vs. HR 0.53, 95% CI 0.46-0.61, P interaction = 0.131) and HDE (HR 0.94, 95% CI 0.65-1.38 vs. HR 0.79, 95% CI 0.69-0.90, P interaction = 0.392) when compared with warfarin, independent of amiodarone use. Conclusions Patients randomized to the LDE treated with amiodarone at the time of randomization demonstrated a significant reduction in ischaemic events vs. warfarin when compared with those not on amiodarone, while preserving a favourable bleeding profile. In contrast, amiodarone had no effect on the relative efficacy and safety of HD

Medical Student and Resident Foley Catheterization training program to decrease Post-Operative Catheter Associated Urinary Tract Infections

Objective: Determine whether a more comprehensive medical student urinary catherer training curriculum can be successful in decreasing post-operative CAUTI rates in general and vascular surgery patient populations. Primary target: Reduce post-operative UTI rates by 0.5% over 6 months Secondary targets: Achieve 100% medical student confidence in Foley catheter placement, understanding indications and contraindications to urinary catheterization. Improve objective performance of urinary catheterization skills as determined by objective clinical skills exam (OSCE) scores.https://jdc.jefferson.edu/patientsafetyposters/1000/thumbnail.jp

Dissecting the Interactions between Chlorin e6 and Human Serum Albumin

Chlorin e6 (Ce6) is among the most used sensitizers in photodynamic (PDT) and sonodynamic (SDT) therapy; its low solubility in water, however, hampers its clinical exploitation. Ce6 has a strong tendency to aggregate in physiological environments, reducing its performance as a photo/sono-sensitizer, as well as yielding poor pharmacokinetic and pharmacodynamic properties. The interaction of Ce6 with human serum albumin (HSA) (i) governs its biodistribution and (ii) can be used to improve its water solubility by encapsulation. Here, using ensemble docking and microsecond molecular dynamics simulations, we identified the two Ce6 binding pockets in HSA, i.e., the Sudlow I site and the heme binding pocket, providing an atomistic description of the binding. Comparing the photophysical and photosensitizing properties of Ce6@HSA with respect to the same properties regarding the free Ce6, it was observed that (i) a red-shift occurred in both the absorption and emission spectra, (ii) a maintaining of the fluorescence quantum yield and an increase of the excited state lifetime was detected, and (iii) a switch from the type II to the type I mechanism in a reactive oxygen species (ROS) production, upon irradiation, took place

Modulation of coordinated activity across cortical layers by plasticity of inhibitory synapses

Louren\ue7o et al. demonstrate that burst firing of layer 5 pyramidal neurons (PNs) induces long-term potentiation of inhibition (LTPi). LTPi strongly affects PN input/output spikes, prevents transfer of information across cortical layers, and affects phase locking of PN firing to cognition-relevant rhythmic activity