Emerging role of GLP-1 receptor agonists in the treatment of obesity

The prevalence of obesity has increased dramatically in recent decades, both in the US and worldwide. Pharmacotherapy can augment the weight-reducing effects of lifestyle modification and can facilitate long-term weight maintenance. However, there is a paucity of pharmacologic agents approved for the treatment of obesity, and the use of existing weight loss medications is frequently limited by contraindications, drug interactions, adverse effects, limited coverage by third-party payers, and cost. In recent years, there has been an increased understanding and appreciation of the role of gastrointestinal hormones in the control of body weight. One such hormone, GLP-1, also plays an important role in glucose homeostasis. GLP-1 receptor agonists, such as exenatide and liraglutide, have been developed and are already approved for the treatment of type 2 diabetes. There has also been interest in the use of GLP-1 receptor agonists for the treatment of obesity in nondiabetic patients. This review explores the potential utility and limitations of exenatide and liraglutide as therapeutic agents for obesity

Numerical study of the influence of surface reaction probabilities on reactive species in an rf atmospheric pressure plasma containing humidity

International audienceThe quantification and control of reactive species (RS) in atmospheric pressure plasmas (APPs) is of great interest for their technological applications, in particular in biomedicine. Of key importance in simulating the densities of these species are fundamental data on their production and destruction. In particular, data concerning particle-surface reaction probabilities in APPs are scarce, with most of these probabilities measured in low-pressure systems. In this work, the role of surface reaction probabilities, gamma, of reactive neutral species (H, O and OH) on neutral particle densities in a He-H2O radio-frequency micro APP jet (COST-mu APPJ) are investigated using a global model. It is found that the choice of gamma, particularly for low-mass species having large diffusivities, such as H, can change computed species densities significantly. The importance of gamma even at elevated pressures offers potential for tailoring the RS composition of atmospheric pressure microplasmas by choosing different wall materials or plasma geometries

Dynamics of ionization wave splitting and merging of atmospheric-pressure plasmas in branched dielectric tubes and channels

Atmospheric-pressure fast ionization waves (FIWs) generated by nanosecond, high voltage pulses are able to propagate long distances through small diameter dielectric tubes or channels, and so deliver UV fluxes, electric fields, charged and excited species to remote locations. In this paper, the dynamics of FIW splitting and merging in a branched dielectric channel are numerically investigated using a two-dimensional plasma hydrodynamics model with radiation transport, and the results are compared with experiments. The channel consists of a straight inlet section branching 90° into a circular loop which terminates to form a second straight outlet section aligned with the inlet section. The plasma is sustained in neon gas with a trace amount of xenon at atmospheric pressure. The FIW generated at the inlet approaches the first branch point with speeds of ≈10 8 cm s −1 , and produces a streamer at the inlet–loop junction. The induced streamer then splits into two FIW fronts, each propagating in opposite directions through half of the loop channel. The FIWs slow as they traverse the circular sections due to a shorting of the electric field by the other FIW. Approaching the loop–outlet junction, the two FIW fronts nearly come to a halt, induce another streamer which goes through further splitting and finally develops into a new FIW front. The new FIW increases in speed and plasma density propagating in the straight outlet channel. The electrical structure of the FIWs and the induced streamers during the splitting and merging processes are discussed with an emphasis on their mutual influence and their interaction with the channel wall. The FIW propagation pattern is in good agreement with experimental observations. Based on numerical and experimental investigations, a model for the splitting and merging FIWs in the branched loop channel is proposed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98591/1/0022-3727_45_27_275201.pd

Dual-Channel Two-Photon Microscopy Study of Transdermal Transport in Skin Treated with Low-Frequency Ultrasound and a Chemical Enhancer

Visualization of transdermal permeant pathways is necessary to substantiate model-based conclusions drawn using permeability data. The aim of this investigation was to visualize the transdermal delivery of sulforhodamine B (SRB), a fluorescent hydrophilic permeant, and of rhodamine B hexyl ester (RBHE), a fluorescent hydrophobic permeant, using dual-channel two-photon microscopy (TPM) to better understand the transport pathways and the mechanisms of enhancement in skin treated with low-frequency ultrasound (US) and/or a chemical enhancer (sodium lauryl sulfate – SLS) relative to untreated skin (the control). The results demonstrate that (1) both SRB and RBHE penetrate beyond the stratum corneum and into the viable epidermis only in discrete regions (localized transport regions – LTRs) of US treated and of US/SLS-treated skin, (2) a chemical enhancer is required in the coupling medium during US treatment to obtain two significant levels of increased penetration of SRB and RBHE in US-treated skin relative to untreated skin, and (3) transcellular pathways are present in the LTRs of US treated and of US/SLS-treated skin for SRB and RBHE, and in SLS-treated skin for SRB. In summary, the skin is greatly perturbed in the LTRs of US treated and US/SLS-treated skin with chemical enhancers playing a significant role in US-mediated transdermal drug delivery

Application of the Aqueous Porous Pathway Model to Quantify the Effect of Sodium Lauryl Sulfate on Ultrasound-Induced Skin Structural Perturbation

This study investigated the effect of sodium lauryl sulfate (SLS) on skin structural perturbation when utilized simultaneously with low-frequency sonophoresis (LFS). Pig full-thickness skin (FTS) and pig split-thickness skin (STS) treated with LFS/SLS and LFS were analyzed in the context of the aqueous porous pathway model to quantify skin perturbation through changes in skin pore radius and porosity-to-tortuosity ratio (ε/τ). In addition, skin treatment times required to attain specific levels of skin electrical resistivity were analyzed to draw conclusions about the effect of SLS on reproducibility and predictability of skin perturbation. We found that LFS/SLS-treated FTS, LFS/SLS-treated STS, and LFS-treated FTS exhibited similar skin perturbation. However, LFS-treated STS exhibited significantly higher skin perturbation, suggesting greater structural changes to the less robust STS induced by the purely physical enhancement mechanism of LFS. Evaluation of ε/τ values revealed that LFS/SLS-treated FTS and STS have similar transport pathways, whereas LFS-treated FTS and STS have lower ε/τ values. In addition, LFS/SLS treatment times were much shorter than LFS treatment times for both FTS and STS. Moreover, the simultaneous use of SLS and LFS not only results in synergistic enhancement, as reflected in the shorter skin treatment times, but also in more predictable and reproducible skin perturbation.National Institutes of Health (U.S.) (Grant EB-00351)Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies (Grant DAAD-19-02-D-002)National Science Foundation (U.S.). Graduate Research Fellowship Progra

Rotating Component Modal Analysis and Resonance Avoidance - An Update

TutorialRotating disk and blade fatigue failures are usually a low percentage of failures in most machinery types, but other than coupling / shaft end failures remain some of the most problematic for extensive repairs. High-cycle fatigue failures of rotating disks and blades are not common in most machinery types, but when they occur, they require extensive repairs and resolution can be problematic. This paper is an update of the tutorial given at the 2004 Turbomachinery Symposium focusing on high-cycle fatigue failures in steam turbines, centrifugal and axial gas compressors in refineries and process plants. The failure theories and many of the descriptions for cases given in 2004 have been updated to include blade resonance concerns for potential flow as well as vane and blade wake effects. Disk vibratory modes can be of concern in many machines, but of little concern in others as will be explained. In addition, vibratory modes are included where blades are coupled via communication with the main disk. Over the past decade, fluid-structure-interaction computational methods and modal testing have improved and have been applied to failure theories and problem resolution in the given cases. There is also added information on the effects of mistuning blades and disks, some beneficial and some with serious concerns for increased resonant amplification. Finally, knowledge about acoustic pressure pulsation excitation, particularly for centrifugal impellers at rotating blade passing frequency, has been greatly expanded. A review of acoustics calculations for failure prevention, mainly for high-pressure applications is covered here

Low-Frequency Sonophoresis: Application to the Transdermal Delivery of Macromolecules and Hydrophilic Drugs

Importance of the field: Transdermal delivery of macromolecules provides an attractive alternative route of drug administration when compared to oral delivery and hypodermic injection because of its ability to bypass the harsh gastrointestinal tract and deliver therapeutics non-invasively. However, the barrier properties of the skin only allow small, hydrophobic permeants to traverse the skin passively, greatly limiting the number of molecules that can be delivered via this route. The use of low-frequency ultrasound for the transdermal delivery of drugs, referred to as low-frequency sonophoresis (LFS), has been shown to increase skin permeability to a wide range of therapeutic compounds, including both hydrophilic molecules and macromolecules. Recent research has demonstrated the feasibility of delivering proteins, hormones, vaccines, liposomes and other nanoparticles through LFS-treated skin. In vivo studies have also established that LFS can act as a physical immunization adjuvant. LFS technology is already clinically available for use with topical anesthetics, with other technologies currently under investigation. Areas covered in this review: This review provides an overview of mechanisms associated with LFS-mediated transdermal delivery, followed by an in-depth discussion of the current applications of LFS technology for the delivery of hydrophilic drugs and macromolecules, including its use in clinical applications. What the reader will gain: The reader will gain an insight into the field of LFS-mediated transdermal drug delivery, including how the use of this technology can improve on more traditional drug delivery methods. Take home message: Ultrasound technology has the potential to impact many more transdermal delivery platforms in the future due to its unique ability to enhance skin permeability in a controlled manner.National Institutes of Health (U.S.) (Grant EB-00351)Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies (Grant DAAD-19-02-D-002

Transport Pathways and Enhancement Mechanisms within Localized and Non-Localized Transport Regions in Skin Treated with Low-Frequency Sonophoresis and Sodium Lauryl Sulfate

Recent advances in transdermal drug delivery utilizing low-frequency sonophoresis (LFS) and sodium lauryl sulfate (SLS) have revealed that skin permeability enhancement is not homogenous across the skin surface. Instead, highly perturbed skin regions, known as localized transport regions (LTRs), exist. Despite these findings, little research has been conducted to identify intrinsic properties and formation mechanisms of LTRs and the surrounding less-perturbed non-LTRs. By independently analyzing LTR, non-LTR, and total skin samples treated at multiple LFS frequencies, we found that the pore radii (r[subscript pore]) within non-LTRs are frequency-independent, ranging from 18.2 to 18.5 Å, but significantly larger than r[subscript pore] of native skin samples (13.6 Å). Conversely, r[subscript pore] within LTRs increase significantly with decreasing frequency from 161 to 276 Å and to ∞ (>300 Å) for LFS/SLS-treated skin at 60, 40, and 20 kHz, respectively. Our findings suggest that different mechanisms contribute to skin permeability enhancement within each skin region. We propose that the enhancement mechanism within LTRs is the frequency-dependent process of cavitation-induced microjet collapse at the skin surface, whereas the increased r[subscript pore] values in non-LTRs are likely due to SLS perturbation, with enhanced penetration of SLS into the skin resulting from the frequency-independent process of microstreaming

In-House Digital Workflow for the Management of Acute Mandible Fractures

Computer-aided design and additive manufacturing are revolutionizing oral and maxillofacial surgery. Current methods use virtual surgical planning sessions and custom plate milling via third-party vendors, which is costly and time-consuming, negating the effectiveness in acute facial trauma. This technical note describes a state-of-the-art in-house expedited digital workflow for computer-aided virtual fracture reduction, 3-dimensional printing, and preoperative reconstruction plate adaptation for the management of an acute mandible fracture. This process uses the computed tomographic scan a patient receives in the emergency department or clinic. The DICOM (Digital Imaging and Communications in Medicine) data are transferred into US Food and Drug Administration–approved software, in which the fracture is segmented and virtually reduced based on condylar position, midline symmetries, and occlusion if present. The reduced mandible is then printed, which serves as a template for preoperative reconstruction plate adaptation. This method facilitates a virtually reduced fractured mandible, 3-dimensionally printed model, and ideally adapted plates ready for sterilization before surgery within 2 hours after DICOM upload

Simulation of Sweep-Jet Flow Control, Single Jet and Full Vertical Tail

This work is a simulation technology demonstrator, of sweep jet flow control used to suppress boundary layer separation and increase the maximum achievable load coefficients. A sweep jet is a discrete Coanda jet that oscillates in the plane parallel to an aerodynamic surface. It injects mass and momentum in the approximate streamwise direction. It also generates turbulent eddies at the oscillation frequency, which are typically large relative to the scales of boundary layer turbulence, and which augment mixing across the boundary layer to attack flow separation. Simulations of a fluidic oscillator, the sweep jet emerging from a nozzle downstream of the oscillator, and an array of sweep jets which suppresses boundary layer separation are performed. Simulation results are compared to data from a dedicated validation experiment of a single oscillator and its sweep jet, and from a wind tunnel test of a full-scale Boeing 757 vertical tail augmented with an array of sweep jets. A critical step in the work is the development of realistic time-dependent sweep jet inflow boundary conditions, derived from the results of the single-oscillator simulations, which create the sweep jets in the full-tail simulations. Simulations were performed using the computational fluid dynamics (CFD) solver Overow, with high-order spatial discretization and a range of turbulence modeling. Good results were obtained for all flows simulated, when suitable turbulence modeling was used