Prediction of disease progression, treatment response and dropout in chronic obstructive pulmonary disease (COPD).

Drug development in chronic obstructive pulmonary disease (COPD) has been characterised by unacceptably high failure rates. In addition to the poor sensitivity in forced expiratory volume in one second (FEV1), numerous causes are known to contribute to this phenomenon, which can be clustered into drug-, disease- and design-related factors. Here we present a model-based approach to describe disease progression, treatment response and dropout in clinical trials with COPD patients

Kidney involvement in the Schnitzler syndrome, a rare disease

The Schnitzler syndrome (SS) is a rare and underdiagnosed entity that associates a chronic urticarial rash, monoclonal IgM (or sometimes IgG) gammopathy and signs and symptoms of systemic inflammation. During the past 45 years, the SS has evolved from an elusive little-known disorder to the paradigm of a late-onset acquired auto-inflammatory syndrome. Though there is no definite proof of its precise pathogenesis, it should be considered as an acquired disease involving abnormal stimulation of the innate immune system, which can be reversed by the interleukin-1 receptor antagonist anakinra. It clearly expands our view of this group of rare genetic diseases and makes the concept of auto-inflammation relevant in polygenic acquired diseases as well. Increasing numbers of dermatologists, rheumatologists, allergologists, haematologists and, more recently, nephrologists, recognize the SS. The aim of this review is to focus on kidney involvement in the SS. Although the literature regarding kidney involvement in the SS is very poor it can be severe, as in our own case here reported, leading us to recommend the systematic search for nephropathy markers in the SS

Lattice Resistance and Peierls Stress in Finite-size Atomistic Dislocation Simulations

Atomistic computations of the Peierls stress in fcc metals are relatively scarce. By way of contrast, there are many more atomistic computations for bcc metals, as well as mixed discrete-continuum computations of the Peierls-Nabarro type for fcc metals. One of the reasons for this is the low Peierls stresses in fcc metals. Because atomistic computations of the Peierls stress take place in finite simulation cells, image forces caused by boundaries must either be relaxed or corrected for if system size independent results are to be obtained. One of the approaches that has been developed for treating such boundary forces is by computing them directly and subsequently subtracting their effects, as developed by V. B. Shenoy and R. Phillips [Phil. Mag. A, 76 (1997) 367]. That work was primarily analytic, and limited to screw dislocations and special symmetric geometries. We extend that work to edge and mixed dislocations, and to arbitrary two-dimensional geometries, through a numerical finite element computation. We also describe a method for estimating the boundary forces directly on the basis of atomistic calculations. We apply these methods to the numerical measurement of the Peierls stress and lattice resistance curves for a model aluminum (fcc) system using an embedded-atom potential.Comment: LaTeX 47 pages including 20 figure

Physiologically based pharmacokinetic modeling of tacrolimus for food-drug and CYP3A drug-drug-gene interaction predictions

The immunosuppressant and narrow therapeutic index drug tacrolimus is metabolized mainly via cytochrome P450 (CYP) 3A4 and CYP3A5. For its pharmacokinetics (PK), high inter- and intra-individual variability can be observed. Underlying causes include the effect of food intake on tacrolimus absorption as well as genetic polymorphism in the CYP3A5 gene. Furthermore, tacrolimus is highly susceptible to drug–drug interactions, acting as a victim drug when coadministered with CYP3A perpetrators. This work describes the development of a whole-body physiologically based pharmacokinetic model for tacrolimus as well as its application for investigation and prediction of (i) the impact of food intake on tacrolimus PK (food–drug interactions [FDIs]) and (ii) drug–drug(−gene) interactions (DD[G]Is) involving the CYP3A perpetrator drugs voriconazole, itraconazole, and rifampicin. The model was built in PK-Sim® Version 10 using a total of 37 whole blood concentration–time profiles of tacrolimus (training and test) compiled from 911 healthy individuals covering the administration of tacrolimus as intravenous infusions as well as immediate-release and extended-release capsules. Metabolism was incorporated via CYP3A4 and CYP3A5, with varying activities implemented for different CYP3A5 genotypes and study populations. The good predictive model performance is demonstrated for the examined food effect studies with 6/6 predicted FDI area under the curve determined between first and last concentration measurements (AUClast) and 6/6 predicted FDI maximum whole blood concentration (Cmax) ratios within twofold of the respective observed ratios. In addition, 7/7 predicted DD(G)I AUClast and 6/7 predicted DD(G)I Cmax ratios were within twofold of their observed values. Potential applications of the final model include model-informed drug discovery and development or the support of model-informed precision dosing

mTORC1 Inhibition via Rapamycin Promotes Triacylglycerol Lipolysis and Release of Free Fatty Acids in 3T3â L1 Adipocytes

Signaling by mTOR complex 1 (mTORC1) promotes anabolic cellular processes in response to growth factors, nutrients, and hormonal cues. Numerous clinical trials employing the mTORC1 inhibitor rapamycin (aka sirolimus) to immunoâ suppress patients following organ transplantation have documented the development of hypertriglyceridemia and elevated serum free fatty acids (FFA). We therefore investigated the cellular role of mTORC1 in control of triacylglycerol (TAG) metabolism using cultured murine 3T3â L1 adipocytes. We found that treatment of adipocytes with rapamycin reduced insulinâ stimulated TAG storage ~50%. To determine whether rapamycin reduces TAG storage by upregulating lipolytic rate, we treated adipocytes in the absence and presence of rapamycin and isoproterenol, a β2â adrenergic agonist that activates the cAMP/protein kinase A (PKA) pathway to promote lipolysis. We found that rapamycin augmented isoproterenolâ induced lipolysis without altering cAMP levels. Rapamycin enhanced the isoproterenolâ stimulated phosphorylation of hormone sensitive lipase (HSL) on Serâ 563 (a PKA site), but had no effect on the phosphorylation of HSL S565 (an AMPK site). Additionally, rapamycin did not affect the isoproterenolâ mediated phosphorylation of perilipin, a protein that coats the lipid droplet to initiate lipolysis upon phosphorylation by PKA. These data demonstrate that inhibition of mTORC1 signaling synergizes with the βâ adrenergicâ cAMP/PKA pathway to augment phosphorylation of HSL to promote hormoneâ induced lipolysis. Moreover, they reveal a novel metabolic function for mTORC1; mTORC1 signaling suppresses lipolysis, thus augmenting TAG storage.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141428/1/lipd1089.pd

Evaluation of gut modulatory and bronchodilator activities of Amaranthus spinosus Linn.

Background The aqueous-methanolic extract of Amaranthus spinosus (A. spinosus Linn.,) whole plant, was studied for its laxative, spasmolytic and bronchodilator activities to validate some of its medicinal uses. Methods The crude extract of A. spinosus was studied in-vivo for bronchodilator and laxative activities and in-vitro using isolated tissue preparations which were mounted in tissue baths assembly containing physiological salt solutions, maintained at 37°C and aerated with carbogen, to assess the spasmolytic effect and to find out the possible underlying mechanisms. Results In the in-vivo experiments in mice, the administration of A. spinosus increased fecal output at doses of 100 and 300 mg/kg showing laxative activity. It also inhibited carbachol-induced bronchospasm in anesthetized rats at 1, 3, 10 and 30 mg/kg indicative of bronchodilator activity. When tested on isolated gut preparations, the plant extract showed a concentration-dependent (0.01-10.0 mg/ml) spasmogenic effect in spontaneously contracting rabbit jejunum and guinea-pig ileum. The spasmogenic effect was partially blocked in tissues pretreated with atropine (0.1 μM). When tested on K+ (80 mM)-induced sustained contractions in isolated rabbit jejunum, the plant extract caused complete relaxation and also produced a shift in the Ca++ concentration-response curves (CRCs) towards right, similar to diltiazem. In rabbit trachea, the plant extract completely inhibited K+ (80 mM) and carbachol (CCh, 1 μM)-induced contractions at 1 mg/ml but pretreatment of tissue with propranolol (1 μM), caused around 10 fold shift in the inhibitory CRCs of the plant extract constructed against CCh-induced contraction. The plant extract (up to 0.3 mg/ml) also increased both force and rate of spontaneous contractions of isolated guinea-pig atria, followed by relaxation at higher concentration (1.0-5.0 mg/ml). The cardio-stimulant effect was abolished in the presence of propranolol, similar to that of isoprenaline. Activity-directed fractionation revealed that the spasmolytic component(s) was separated in the organic fraction, whereas the spasmogenic component was concentrated in the aqueous fraction. Conclusion These results indicate that A. spinosus possesses laxative activity partially mediated through cholinergic action. The spasmolytic effect was mediated through calcium channel blocking (CCB), while bronchodilator activity through a combination of β-adrenergic and CCB pathways, which may explain the traditional uses of A. spinosus in gut and airways disorders

Consensus protocol for EEG and amplitude-integrated EEG assessment and monitoring in neonates

The aim of this work is to establish inclusive guidelines on electroencephalography (EEG) applicable to all neonatal intensive care units (NICUs). Guidelines on ideal EEG monitoring for neonates are available, but there are significant barriers to their implementation in many centres around the world. These include barriers due to limited resources regarding the availability of equipment and technical and interpretive round-the-clock personnel. On the other hand, despite its limitations, amplitude-integrated EEG (aEEG) (previously called Cerebral Function Monitor [CFM]) is a common alternative used in NICUs. The Italian Neonatal Seizure Collaborative Network (INNESCO), working with all national scientific societies interested in the field of neonatal clinical neurophysiology, performed a systematic literature review and promoted interdisciplinary discussions among experts (neonatologists, paediatric neurologists, neurophysiologists, technicians) between 2017 and 2020 with the aim of elaborating shared recommendations. A consensus statement on videoEEG (vEEG) and aEEG for the principal neonatal indications was established. The authors propose a flexible frame of recommendations based on the complementary use of vEEG and aEEG applicable to the various neonatal units with different levels of complexity according to local resources and specific patient features. Suggestions for promoting cooperation between neonatologists, paediatric neurologists, and neurophysiologists, organisational restructuring, and teleneurophysiology implementation are provided

A sequence-based genetic linkage map as a reference for Brassica rapa pseudochromosome assembly

<p>Abstract</p> <p>Background</p> <p><it>Brassica rapa </it>is an economically important crop and a model plant for studies concerning polyploidization and the evolution of extreme morphology. The multinational <it>B. rapa </it>Genome Sequencing Project (BrGSP) was launched in 2003. In 2008, next generation sequencing technology was used to sequence the <it>B. rapa </it>genome. Several maps concerning <it>B. rapa </it>pseudochromosome assembly have been published but their coverage of the genome is incomplete, anchoring approximately 73.6% of the scaffolds on to chromosomes. Therefore, a new genetic map to aid pseudochromosome assembly is required.</p> <p>Results</p> <p>This study concerns the construction of a reference genetic linkage map for <it>Brassica rapa</it>, forming the backbone for anchoring sequence scaffolds of the <it>B. rapa </it>genome resulting from recent sequencing efforts. One hundred and nineteen doubled haploid (DH) lines derived from microspore cultures of an F1 cross between a Chinese cabbage (<it>B. rapa </it>ssp. <it>pekinensis</it>) DH line (Z16) and a rapid cycling inbred line (L144) were used to construct the linkage map. PCR-based insertion/deletion (InDel) markers were developed by re-sequencing the two parental lines. The map comprises a total of 507 markers including 415 InDels and 92 SSRs. Alignment and orientation using SSR markers in common with existing <it>B. rapa </it>linkage maps allowed ten linkage groups to be identified, designated A01-A10. The total length of the linkage map was 1234.2 cM, with an average distance of 2.43 cM between adjacent marker loci. The lengths of linkage groups ranged from 71.5 cM to 188.5 cM for A08 and A09, respectively. Using the developed linkage map, 152 scaffolds were anchored on to the chromosomes, encompassing more than 82.9% of the <it>B. rapa </it>genome. Taken together with the previously available linkage maps, 183 scaffolds were anchored on to the chromosomes and the total coverage of the genome was 88.9%.</p> <p>Conclusions</p> <p>The development of this linkage map is vital for the integration of genome sequences and genetic information, and provides a useful resource for the international <it>Brassica </it>research community.</p

EBSD characterization of cryogenically rolled type 321 austenitic stainless steel

Electron backscatter diffraction was applied to investigate microstructure evolution during cryogenic rolling of type 321 metastable austenitic stainless steel. As expected, rolling promoted deformation-induced martensitic transformation which developed preferentially in deformation bands. Because a large fraction of the imposed strain was accommodated by deformation banding, grain refinement in the parent austenite phase was minimal. The martensitic transformation was found to follow a general orientation relationship, {111}γ||{0001}ε||{110}α′ and 〈110〉γ||〈11-20〉ε||〈111〉α′, and was characterized by noticeable variant selection