Body composition, muscle strength, functional capacity, and physical disability risk in liver transplanted familial amyloidotic polyneuropathy patients

Abstract: Background: Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disease leading to sensory and motor polyneuropathies, and functional limitations. Liver transplantation is the only treatment for FAP, requiring medication that negatively affects bone and muscle metabolism. The aim of this study was to compare body composition, levels of specific strength, level of physical disability risk, and functional capacity of transplanted FAP patients (FAPTx) with a group of healthy individuals (CON). Methods: A group of patients with 48 FAPTx (28 men, 20 women) was compared with 24 CON individuals (14 men, 10 women). Body composition was assessed by dual-energy X-ray absorptiometry, and total skeletal muscle mass (TBSMM) and skeletal muscle index (SMI) were calculated. Handgrip strength was measured for both hands as was isometric strength of quadriceps. Muscle quality (MQ) was ascertained by the ratio of strength to muscle mass. Functional capacity was assessed by the six-minute walk test. Results: Patients with FAPTx had significantly lower functional capacity, weight, body mass index, total fat mass, TBSMM, SMI, lean mass, muscle strength, MQ, and bone mineral density. Conclusion: Patients with FAPTx appear to be at particularly high risk of functional disability, suggesting an important role for an early and appropriately designed rehabilitation program

Spore-forming bacteria as pharmaceutical factories

Many Bacilli form dormant structures, spores, which routinely survive physical, chemical and biological challenge. How do spores encapsulate their contents, and could it be possible to mimic or adapt them to make better drug products? Key spore component 2,6-dipicolinic acid (DPA) is necessary for protein stability, but investigation of its role is confounded with that of water content. Tests replacing DPA with chemical analogues were not successful, but led to the novel approach of doping spores with extra DPA. Various Bacillus species, in the main B. subtilis and B. thuringiensis, have been engineered to produce, for the first time, fragments of a humanized monoclonal antibody: kindly provided by Medimmune. It is possible to produce antibodies inside the spore core. This work proposes for the first time that such therapeutic spores might lack an outer coat, and demonstrates that antibody production continues. It is understood they continue to resist most challenges including wet heat, which damages proteins, yet they become susceptible to lysozyme. Such spores, further developed to lyse in presence of intestinal, though not gastric fluid, may have use in oral delivery. Cry1Ac of B. thuringiensis offers an alternative; large protein crystals are produced during sporulation. Here, various fluorescent fusions that maintain fluorescence over months were developed and investigated in detail. For the first time, fluorescent antibody crystals were produced. In addition to drug delivery, these fusions offer a novel approach to crystallization of intransigent proteins, for structural studies. This work shows that it might be feasible to use spores as pharmaceutical formulations. A number of challenges remain: from fabrication, through limits of current good manufacturing practice, to engineering biology to protect the environment and commercial interests. Bacterial spores have for the past century and a half been known for their dormancy, and it’s about time engineers took advantage.Medimmune (now AZ's biologics division) part funded the studentship and lab costs. Reference MA-417339

Private or Public Right? Who Should Adjudicate Patentability Disputes and Is the Current Scheme Really Constitutional?

“The patent bargain is the foundation upon which the patent system is built: in exchange for protections for an invention, the inventor agrees to make public their inventions so that others may build upon it.” The patent bargain creates a presumption of protection for the inventors, yet categorizing the patent a public right or a private right has diminished expectations for inventors and confusion for the masses. On October 11, 2016, the Supreme Court denied two petitions for writ of certiorari that challenged the constitutionality of Patent Trial and Review Board proceedings on the basis of the patent owner’s Seventh Amendment right to a jury trial and Article III separation of powers. The latter of those cases is the cornerstone for which this comment rests. In Cooper v. Lee, Petitioner J. Carl Cooper asked the United States Supreme Court to review a section of the Leahy-Smith America Invents Act that established “inter partes review,” (IPR) a procedure for administrative review of a patent. Making a number of constitutional challenges, Cooper asserts that inter partes review empowers an executive agency tribunal to assert judicial power cancelling a private property right. Moreover, Cooper stresses that patent disputes among private parties are disputes that have been known in the common law courts of 1789, afforded a trial, and cannot be adjudicated by an advisory opinion.6 After a tumultuous trip through the legal system in an attempt to finally determine the constitutionality of the IPR system, the high court has again left us pondering the issue of patent adjudication. With its denial of the petitioner’s writ for certiorari, the Court has again refused to declare whether patent rights are a private or public right. What does this mean for patent owners going forward? The waters are murky, but we will continue to see the adjudication of patent disputes by a non-Article III tribunal. This Comment examines a key question for patent administrative law: whether the grant of a patent is a public right, (i.e. a right that is primarily a concern of the public and can only be conferred by the government) thus subject to revocation by an administrative agency? In analyzing this concern, this Comment will address three subjects. First, this Comment will explore how section 311 of the Patent Act established the process of inter-partes proceedings and section 321 established the post-grant review of patents. Second, this Comment will outline the case law challenging the constitutionality of section 311 and section 321. Third, this Comment will examine the competing perspectives of whether a patent is a public or private right. This Comment has important implications for whether section 311 and section 321 are constitutional exercises of congressional power. Finally, this Comment will attempt to foreshadow how the outcome of current case law will affect the patent bargain and adjudication scheme

The effect of hypoxia and work intensity on insulin resistance in type 2 diabetes

Context:Hypoxia and muscle contraction stimulate glucose transport in vitro. We have previously demonstrated that exercise and hypoxia have an additive effect on insulin sensitivity in type 2 diabetics.Objectives:Our objective was to examine the effects of three different hypoxic/exercise (Hy Ex) trials on glucose metabolism and insulin resistance in the 48 h after acute hypoxia in type 2 diabetics.Design, Participants, and Interventions:Eight male type 2 diabetics completed 60 min of hypoxic [mean (sem) O(2) = ∼14.7 (0.2)%] exercise at 90% of lactate threshold [Hy Ex(60); 49 (1) W]. Patients completed an additional two hypoxic trials of equal work, lasting 40 min [Hy Ex(40); 70 (1) W] and 20 min [Hy Ex(20); 140 (12) W].Main Outcome Measures:Glucose rate of appearance and rate of disappearance were determined using the one-compartment minimal model. Homeostasis models of insulin resistance (HOMA(IR)), fasting insulin resistance index and β-cell function (HOMA(β-cell)) were calculated at 24 and 48 h after trials.Results:Peak glucose rate of appearance was highest during Hy Ex(20) [8.89 (0.56) mg/kg · min, P < 0.05]. HOMA(IR) and fasting insulin resistance index were improved in the 24 and 48 h after Hy Ex(60) and Hy Ex(40) (P < 0.05). HOMA(IR) decreased 24 h after Hy Ex(20) (P < 0.05) and returned to baseline values at 48 h.Conclusions:Moderate-intensity exercise in hypoxia (Hy Ex(60) and Hy Ex(40)) stimulates acute- and moderate-term improvements in insulin sensitivity that were less apparent in Hy Ex(20). Results suggest that exercise duration and not total work completed has a greater influence on acute and moderate-term glucose control in type 2 diabetics

Local Rules and Procedures of the United States Court of Appeals for the Federal Circuit

The Federal Courts Improvement Act of 1982 abolished the United States Court of Claims and the United States Court of Customs and Patent Appeals and created the United States Court of Appeals for the Federal Circuit (CAFC) and the United States Claims Court. The Act provided for an advisory committee to be appointed by the CAFC in order to study the proposed rules of practice and internal operating procedures of the court. The recommendations of the advisory committee were given considerable weight when the court promulgated the Rules of the United States Court of Appeals for the Federal Circuit (CAFC Rules), and a procedural handbook effective October 1, 1982. The rules are intended to supplement the Federal Rules of Appellate Procedure and to reflect the court\u27s nationwide and varied jurisdiction, as well as a commitment to the expeditious determination of cases brought before it. This Article walks through the more pertinent rules which help to illustrate how the court will operate, as well as clarify earlier points of confusion

Rapid-Onset Anti-Stress Effects of a Kappa-Opioid Receptor Antagonist, LY2795050, against Immobility in an Open Space Swim Paradigm in Male and Female Mice

The kappa-opioid receptor (KOR) / dynorphin system is implicated with behavioral and neurobiological effects of stress exposure (including heavy exposure to drugs of abuse) in translational animal models. Thus some KOR-antagonists can decrease the aversive, depressant-like and anxiety-like effects caused by stress exposure. The first generation of selective KOR-antagonists have slow onsets (hours) and extremely long durations of action (days-weeks), in vivo. A new generation of KOR antagonists with rapid onset and shorter duration of action can potentially decrease the effects of stress exposure in translational models, and may be of interest for medication development. This study examined the rapid onset anti-stress effects of one of the shorter acting novel KOR-antagonists (LY2795050, (3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide)) in a single-session open space swim (OSS) stress paradigm (15 min duration), in adult male and female C57BL/6 J mice. LY2795050 (0.32 mg/kg, i.p.) had rapid onset (within 15 min) and short duration (\u3c 3 h) of KOR-antagonist effects, based on its blockade of the locomotor depressant effects of the KOR-agonist U50,488 (10 mg/kg). LY2795050 (0.32 mg/kg), when administered only 1 min prior to the OSS stress paradigm, decreased immobility in males, but not females. With a slightly longer pretreatment time (15 min), this dose of LY2795050 decreased immobility in both males and females. A 10-fold smaller dose of LY2795050 (0.032 mg/kg) was inactive in the OSS, showing dose-dependence of this anti-stress effect. Overall, these studies show that a novel KOR-antagonist can produce very rapid onset anti-immobility effects in this model of acute stress exposure

Aerosol direct radiative effects over the northwest Atlantic, northwest Pacific, and North Indian Oceans: estimates based on in-situ chemical and optical measurements and chemical transport modeling

International audienceThe largest uncertainty in the radiative forcing of climate change over the industrial era is that due to aerosols, a substantial fraction of which is the uncertainty associated with scattering and absorption of shortwave (solar) radiation by anthropogenic aerosols in cloud-free conditions (IPCC, 2001). Quantifying and reducing the uncertainty in aerosol influences on climate is critical to understanding climate change over the industrial period and to improving predictions of future climate change for assumed emission scenarios. Measurements of aerosol properties during major field campaigns in several regions of the globe during the past decade are contributing to an enhanced understanding of atmospheric aerosols and their effects on light scattering and climate. The present study, which focuses on three regions downwind of major urban/population centers (North Indian Ocean (NIO) during INDOEX, the Northwest Pacific Ocean (NWP) during ACE-Asia, and the Northwest Atlantic Ocean (NWA) during ICARTT), incorporates understanding gained from field observations of aerosol distributions and properties into calculations of perturbations in radiative fluxes due to these aerosols. This study evaluates the current state of observations and of two chemical transport models (STEM and MOZART). Measurements of burdens, extinction optical depth (AOD), and direct radiative effect of aerosols (DRE ? change in radiative flux due to total aerosols) are used as measurement-model check points to assess uncertainties. In-situ measured and remotely sensed aerosol properties for each region (mixing state, mass scattering efficiency, single scattering albedo, and angular scattering properties and their dependences on relative humidity) are used as input parameters to two radiative transfer models (GFDL and University of Michigan) to constrain estimates of aerosol radiative effects, with uncertainties in each step propagated through the analysis. Constraining the radiative transfer calculations by observational inputs increases the clear-sky, 24-h averaged AOD (34±8%), top of atmosphere (TOA) DRE (32±12%), and TOA direct climate forcing of aerosols (DCF ? change in radiative flux due to anthropogenic aerosols) (37±7%) relative to values obtained with "a priori" parameterizations of aerosol loadings and properties (GFDL RTM). The resulting constrained TOA DCF is ?3.3±0.47, ?14±2.6, ?6.4±2.1 Wm?2 for the NIO, NWP, and NWA, respectively. Constraining the radiative transfer calculations by observational inputs reduces the uncertainty range in the DCF in these regions relative to global IPCC (2001) estimates by a factor of approximately 2. Such comparisons with observations and resultant reductions in uncertainties are essential for improving and developing confidence in climate model calculations incorporating aerosol forcing