Systemic Sclerosis–Associated Interstitial Lung Disease: How to Incorporate Two Food and Drug Administration–Approved Therapies in Clinical Practice

Systemic sclerosis (SSc; scleroderma) has the highest individual mortality of all rheumatic diseases and interstitial lung disease (ILD) is among the leading causes of SSc-related death. Two drugs are now approved by the Food & Drug Administration (FDA) and indicated for slowing the rate of decline in pulmonary function in patients with SSc-ILD: nintedanib (a tyrosine kinase inhibitor) and tocilizumab (the first biologic agent targeting the interleukin-6 pathway in SSc). In addition, two generic drugs with cytotoxic and immunoregulatory activity, mycophenolate mofetil and cyclophosphamide, have shown comparable efficacy in a Phase II trial but are not FDA-approved for SSc-ILD. In light of the heterogeneity of the disease, the optimal therapeutic strategy in the management of patients with SSc-ILD is still to be determined. The objectives of this review are two-fold: (1) review the body of research focused on the diagnosis and treatment of SSc-ILD; and (2) propose a practical approach for diagnosis, stratification, management, and therapeutic decision-making in this clinical context. This review presents a practical classification of SSc patients in terms of disease severity (subclinical vs. clinical ILD) and associated risk of progression (low vs. high risk). The pharmacological and non-pharmacological options as first and second-line therapy, as well as potential combination approaches, are discussed in light of the recent approval of tocilizumab for SSc-ILD

Clinical Applications of Pediatric Pulmonary Function Testing: Lung Function in Recurrent Wheezing and Asthma

Pulmonary function testing remains the gold standard for the diagnosis and management of wheezing disorders in older children and adults. Although wheezing disorders are among the most common clinical problems in pediatrics, most young children and toddlers cannot perform most of the currently clinically available pulmonary function tests. In this article, we review the different types of pulmonary function tests available and discuss the applicability and utility in the different age groups with specific reference to suitability in the diagnosis and management of wheezing disorders.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90475/1/ped-2E2010-2E0060.pd

An evaluation of enteral nutrition practices and nutritional provision in children during the entire length of stay in critical care

<b>Background</b> Provision of optimal nutrition in children in critical care is often challenging. This study evaluated exclusive enteral nutrition (EN) provision practices and explored predictors of energy intake and delay of EN advancement in critically ill children.<p></p> <b>Methods</b> Data on intake and EN practices were collected on a daily basis and compared against predefined targets and dietary reference values in a paediatric intensive care unit. Factors associated with intake and advancement of EN were explored.<p></p> <b>Results</b> Data were collected from 130 patients and 887 nutritional support days (NSDs). Delay to initiate EN was longer in patients from both the General Surgical and congenital heart defect (CHD) Surgical groups [Median (IQR); CHD Surgical group: 20.3 (16.4) vs General Surgical group: 11.4 (53.5) vs Medical group: 6.5 (10.9) hours; p <= 0.001]. Daily fasting time per patient was significantly longer in patients from the General Surgical and CHD Surgical groups than those from the Medical group [% of 24 h, Median (IQR); CHD Surgical group: 24.0 (29.2) vs General Surgical group: 41.7 (66.7) vs Medical group: 9.4 (21.9); p <= 0.001]. A lower proportion of fluids was delivered as EN per patient (45% vs 73%) or per NSD (56% vs 73%) in those from the CHD Surgical group compared with those with medical conditions. Protein and energy requirements were achieved in 38% and 33% of the NSDs. In a substantial proportion of NSDs, minimum micronutrient recommendations were not met particularly in those patients from the CHD Surgical group. A higher delivery of fluid requirements (p < 0.05) and a greater proportion of these delivered as EN (p < 0.001) were associated with median energy intake during stay and delay of EN advancement. Fasting (31%), fluid restriction (39%) for clinical reasons, procedures requiring feed cessation and establishing EN (22%) were the most common reasons why target energy requirements were not met.<p></p> <b>Conclusions</b> Provision of optimal EN support remains challenging and varies during hospitalisation and among patients. Delivery of EN should be prioritized over other "non-nutritional" fluids whenever this is possible.<p></p&gt

An expedited screening platform for the discovery of anti-ageing compounds in vitro and in vivo.

BACKGROUND: Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan. METHODS: Using Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture. RESULTS: We developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo. CONCLUSIONS: Our method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors

Cavalier King Charles Spaniels with Chiari-like malformation and Syringomyelia have increased variability of spatio-temporal gait characteristics

Abstract Background Chiari-like malformation in the Cavalier King Charles Spaniel is a herniation of the cerebellum and brainstem into or through the foramen magnum. This condition predisposes to Syringomyelia; fluid filled syrinxes within the spinal cord. The resulting pathology in spinal cord and cerebellum create neuropathic pain and changes in gait. This study aims to quantify the changes in gait for Cavalier King Charles Spaniel with Chiari-like malformation and Syringomyelia. Methods We compared Cavalier King Charles Spaniel with Chiari-like malformation with (n = 9) and without (n = 8) Syringomyelia to Border Terriers (n = 8). Two video cameras and manual tracking was used to quantify gait parameters. Results and conclusions We found a significant increase in coefficient of variation for the spatio-temporal characteristics and ipsilateral distance between paws and a wider base of support in the thoracic limbs but not in the pelvic limbs for Cavalier King Charles Spaniels compared with the border terrier

Cytomolecular identification of individual wheat-wheat chromosome arm associations in wheat-rye hybrids

Chromosome pairing in the meiotic metaphase I of wheatrye hybrids has been characterized by sequential genomic and fluorescent in situ hybridization allowing not only the discrimination of wheat and rye chromosomes, but also the identification of the individual wheat and rye chromosome arms involved in the chromosome associations. The majority of associations (93.8%) were observed between the wheat chromosomes. The largest number of wheat-wheat chromosome associations (53%) was detected between the A and D genomes, while the frequency of B-D and A-B associations was significantly lower (32 and 8%, respectively). Among the A-D chromosome associations, pairing between the 3AL and 3DL arms was observed with the highest frequency, while the most frequent of all the chromosome associations (0.113/ cell) was found to be the 3DS-3BS. Differences in the pairing frequency of the individual chromosome arms of wheat-rye hybrids have been discussed in relation to the homoeologous relationships between the constituent genomes of hexaploid wheat

Phenomenological Consequences of sub-leading Terms in See-Saw Formulas

Several aspects of next-to-leading (NLO) order corrections to see-saw formulas are discussed and phenomenologically relevant situations are identified. We generalize the formalism to calculate the NLO terms developed for the type I see-saw to variants like the inverse, double or linear see-saw, i.e., to cases in which more than two mass scales are present. In the standard type I case with very heavy fermion singlets the sub-leading terms are negligible. However, effects in the percent regime are possible when sub-matrices of the complete neutral fermion mass matrix obey a moderate hierarchy, e.g. weak scale and TeV scale. Examples are cancellations of large terms leading to small neutrino masses, or inverse see-saw scenarios. We furthermore identify situations in which no NLO corrections to certain observables arise, namely for mu-tau symmetry and cases with a vanishing neutrino mass. Finally, we emphasize that the unavoidable unitarity violation in see-saw scenarios with extra fermions can be calculated with the formalism in a straightforward manner.Comment: 22 pages, matches published versio

A multidimensional systems biology analysis of cellular senescence in aging and disease.

BACKGROUND: Cellular senescence, a permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of aging and has been linked to aging-related diseases. Many genes play a role in cellular senescence, yet a comprehensive understanding of its pathways is still lacking. RESULTS: We develop CellAge (http://genomics.senescence.info/cells), a manually curated database of 279 human genes driving cellular senescence, and perform various integrative analyses. Genes inducing cellular senescence tend to be overexpressed with age in human tissues and are significantly overrepresented in anti-longevity and tumor-suppressor genes, while genes inhibiting cellular senescence overlap with pro-longevity and oncogenes. Furthermore, cellular senescence genes are strongly conserved in mammals but not in invertebrates. We also build cellular senescence protein-protein interaction and co-expression networks. Clusters in the networks are enriched for cell cycle and immunological processes. Network topological parameters also reveal novel potential cellular senescence regulators. Using siRNAs, we observe that all 26 candidates tested induce at least one marker of senescence with 13 genes (C9orf40, CDC25A, CDCA4, CKAP2, GTF3C4, HAUS4, IMMT, MCM7, MTHFD2, MYBL2, NEK2, NIPA2, and TCEB3) decreasing cell number, activating p16/p21, and undergoing morphological changes that resemble cellular senescence. CONCLUSIONS: Overall, our work provides a benchmark resource for researchers to study cellular senescence, and our systems biology analyses reveal new insights and gene regulators of cellular senescence