Anti-Inflammatory Mechanism Involved in Pomegranate-Mediated Prevention of Breast Cancer: the Role of NF-κB and Nrf2 Signaling Pathways.

Nutrients. 2017 Apr 28;9(5):

Authors: Mandal A, Bhatia D, Bishayee A

Abstract
Pomegranate (Punica granatum L.), a nutrient-rich unique fruit, has been used for centuries for the prevention and treatment of various inflammation-driven diseases. Based on our previous study, a characterized pomegranate emulsion (PE) exhibited a striking inhibition of dimethylbenz(a)anthracene (DMBA)-initiated rat mammary tumorigenesis via antiproliferative and apoptosis-inducing mechanisms. The objective of the present work is to investigate the anti-inflammatory mechanism of action of PE during DMBA rat mammary carcinogenesis by evaluating the expression of cyclooxygenase-2 (COX-2), heat shock protein 90 (HSP90), nuclear factor-κB (NF-κB) and nuclear factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2). Mammary tumor samples were harvested from our previous chemopreventive study in which PE (0.2-5.0 g/kg) was found to reduce mammary tumorigenesis in a dose-dependent manner. The expressions of COX-2, HSP90, NF-κB, inhibitory κBα (IκBα) and Nrf2 were detected by immunohistochemical techniques. PE decreased the expression of COX-2 and HSP90, prevented the degradation of IκBα, hindered the translocation of NF-κB from cytosol to nucleus and increased the expression and nuclear translocation of Nrf2 during DMBA-induced mammary tumorigenesis. These findings, together with our previous results, indicate that PE-mediated prevention of DMBA-evoked mammary carcinogenesis may involve anti-inflammatory mechanisms through concurrent but differential regulation of two interrelated molecular pathways, namely NF-κB and Nrf2 signaling.

PMID: 28452959 [PubMed - indexed for MEDLINE]

Streptococcal pyrogenic exotoxin B inhibits apoptotic cell clearance by macrophages through protein S cleavage.

Sci Rep. 2016 05 16;6:26026

Authors: Chen CL, Wu YY, Lin CF, Kuo CF, Han CL, Wang S, Chuang WJ, Chen CY, Wu JJ, Tsai PJ, Liu CC, Lin YS

Abstract
Clearance of apoptotic cells by macrophages plays an important role in maintaining tissue homeostasis. Previous study indicated that streptococcal pyrogenic exotoxin B (SPE B) reduces phagocytic activity in group A streptococcus (GAS) infection. Here, we demonstrate that SPE B causes an inhibitory effect on protein S-mediated phagocytosis. In the presence of SPE B, serum- and purified protein S-mediated phagocytosis of apoptotic cells were significantly inhibited. The binding abilities of protein S to apoptotic cells were decreased by treatment with SPE B. Bacterial culture supernatants from GAS NZ131 strain also caused a reduction of protein S binding to apoptotic cells, but speB mutant strain did not. SPE B directly cleaved protein S in vitro and in vivo, whereas a lower level of cleavage occurred in mice infected with a speB isogenic mutant strain. SPE B-mediated initial cleavage of protein S caused a disruption of phagocytosis, and also resulted in a loss of binding ability of protein S-associated C4b-binding protein to apoptotic cells. Taken together, these results suggest a novel pathogenic role of SPE B that initiates protein S degradation followed by the inhibition of apoptotic cell clearance by macrophages.

PMID: 27181595 [PubMed - indexed for MEDLINE]

Influence of three-dimensional lung epithelial cells and interspecies interactions on antibiotic efficacy against Mycobacterium abscessus and Pseudomonas aeruginosa.

Pathog Dis. 2018 Apr 10;:

Authors: Rodríguez-Sevilla G, Rigauts C, Vandeplassche E, Ostyn L, Mahíllo-Fernández I, Esteban J, Peremarch CP, Coenye T, Crabbé A

Abstract
Mycobacterium abscessus lung infection is a major health problem for cystic fibrosis (CF) patients. Understanding the in vivo factors that influence the outcome of therapy may help addressing the poor correlation between in vitro and in vivo antibiotic efficacy. We evaluated the influence of interspecies interactions and lung epithelial cells on antibiotic efficacy. Therefore, single and dual species biofilms of M. abscessus and a major CF pathogen (Pseudomonas aeruginosa) were cultured on a plastic surface or on in vivo-like three-dimensional (3-D) lung epithelial cells, and the activity of antibiotics (colistin, amikacin, clarithromycin, ceftazidime) in inhibiting biofilm formation was evaluated. Using the most physiologically relevant model (dual species biofilms on 3-D cells), we observed that treatment with antibiotics during biofilm development inhibited P. aeruginosa but not M. abscessus biofilms, resulting in a competitive advantage for the latter. Clarithromycin efficacy against P. aeruginosa was inhibited by 3-D lung cells. In addition, biofilm induction of M. abscessus was observed by certain antibiotics on plastic but not on 3-D cells. P. aeruginosa influenced the efficacy of certain antibiotics against M. abscessus, but not vice versa. In conclusion, these results suggest a role of host cells and interspecies interactions in bacterial responses to antimicrobials.

PMID: 29648588 [PubMed - as supplied by publisher]

Histopathology in Chronic Rhinosinusitis Varies With Sinus Culture.

Am J Rhinol Allergy. 2018 Mar;32(2):112-118

Authors: Heilingoetter AL, Tajudeen B, Kuhar HN, Gattuso P, Ghai R, Mahdavinia M, Batra PS

Abstract
Background Structured histopathology reporting facilitates better understanding of the underlying pathophysiologic mechanisms of chronic rhinosinusitis. The microbiology of chronic rhinosinusitis has been studied extensively; however, distinct histopathologic changes associated with bacteria isolated in chronic rhinosinusitis are largely unknown. Objective The goal of this study is to better understand the relationship between culturable bacteria and histopathology in chronic rhinosinusitis. Methods A structured histopathology report was utilized to analyze sinus tissue removed during functional endoscopic sinus surgery in a group of patients with chronic rhinosinusitis refractory to medical therapy. Patients with cystic fibrosis or ciliary dysfunction were excluded. Histology variables included eosinophil count per high-power field, neutrophil infiltrate, basement membrane thickening, subepithelial edema, hyperplastic/papillary changes, mucosal ulceration, squamous metaplasia, fibrosis, fungal elements, Charcot-Leyden crystals, and eosinophil aggregates. Baseline Lund-Mackay score and Sinonasal Outcome Test 22 score were also collected. The association of culture data with the aforementioned variables was assessed. Results A total of 59 chronic rhinosinusitis patients who underwent functional endoscopic sinus surgery were included. Chronic rhinosinusitis patients with Pseudomonas aeruginosa had significantly increased neutrophil infiltrate (71.4% vs. 26.9%, p = 0.048), subepithelial edema (28.6% vs. 3.8%, p = 0.047), and a trend toward increased fungal elements (28.6% vs. 5.8%, p = 0.071). Chronic rhinosinusitis patients with Staphylococcus aureus had significantly more hyperplastic changes (20% vs. 2.3%, p = 0.050) and a trend toward increased squamous metaplasia (33.3% vs. 14.2%, p = 0.069). Conclusion Distinct histopathologic changes were noted based on sinus culture data for S. aureus and P. aeruginosa. These findings may have important implications on the extent of surgical management and prognosis after surgery.

PMID: 29644905 [PubMed - in process]

Mucin gel assembly is controlled by a collective action of non-mucin proteins, disulfide bridges, Ca2+-mediated links, and hydrogen bonding.

Sci Rep. 2018 Apr 11;8(1):5802

Authors: Meldrum OW, Yakubov GE, Bonilla MR, Deshmukh O, McGuckin MA, Gidley MJ

Abstract
Mucus is characterized by multiple levels of assembly at different length scales which result in a unique set of rheological (flow) and mechanical properties. These physical properties determine its biological function as a highly selective barrier for transport of water and nutrients, while blocking penetration of pathogens and foreign particles. Altered integrity of the mucus layer in the small intestine has been associated with a number of gastrointestinal tract pathologies such as Crohn's disease and cystic fibrosis. In this work, we uncover an intricate hierarchy of intestinal mucin (Muc2) assembly and show how complex rheological properties emerge from synergistic interactions between mucin glycoproteins, non-mucin proteins, and Ca2+. Using a novel method of mucus purification, we demonstrate the mechanism of assembly of Muc2 oligomers into viscoelastic microscale domains formed via hydrogen bonding and Ca2+-mediated links, which require the joint presence of Ca2+ ions and non-mucin proteins. These microscale domains aggregate to form a heterogeneous yield stress gel-like fluid, the macroscopic rheological properties of which are virtually identical to that of native intestinal mucus. Through proteomic analysis, we short-list potential protein candidates implicated in mucin assembly, thus paving the way for identifying the molecules responsible for the physiologically critical biophysical properties of mucus.

PMID: 29643478 [PubMed - in process]

Deep Learning of Genomic Variation and Regulatory Network Data.

Hum Mol Genet. 2018 Apr 10;:

Authors: Telenti A, Lippert C, Chang PC, DePristo M

Abstract
The human genome is now investigated through high throughput functional assays, and through the generation of population genomic data. These advances support the identification of functional genetic variants and the prediction of traits (eg. deleterious variants and disease). This review summarizes lessons learned from the large-scale analyses of genome and exome datasets, modeling of population data and machine learning strategies to solve complex genomic sequence regions. The review also portrays the rapid adoption of artificial intelligence/deep neural networks in genomics; in particular, deep learning approaches are well suited to model the complex dependencies in the regulatory landscape of the genome, and to provide predictors for genetic variant calling and interpretation.

PMID: 29648622 [PubMed - as supplied by publisher]

COQ2 variants in Parkinson's disease and multiple system atrophy.

J Neural Transm (Vienna). 2018 Apr 11;:

Authors: Mikasa M, Kanai K, Li Y, Yoshino H, Mogushi K, Hayashida A, Ikeda A, Kawajiri S, Okuma Y, Kashihara K, Sato T, Kondo H, Funayama M, Nishioka K, Hattori N

Abstract
Coenzyme Q2, polyprenyltransferase (COQ2) variants have been reported to be associated with multiple system atrophy (MSA). However, the relationship between COQ2 variants and familial Parkinson's disease (PD) remains unclear. We investigated the frequency of COQ2 variants and clinical symptoms among familial PD and MSA. We screened COQ2 using the Sanger method in 123 patients with familial PD, 52 patients with sporadic PD, and 39 patients with clinically diagnosed MSA. Clinical information was collected from medical records for the patients with COQ2 variants. Allele frequencies of detected rare non-synonymous variants were compared by public database of the Exome Aggregation Consortium (ExAC) and Japanese genetic variation database, using Fisher's exact test. We detected two probands with rare variants in COQ2, the p.P157S from Family A, whose patient was clinically diagnosed as having juvenile PD, and the p.H15 N/p.G331S from Family B, whose patients shared common symptoms of PD. Furthermore, in an association study comparing these familial PD and MSA cases with a public variant database, eight non synonymous variants were detected in COQ2. Three of these were very rare variants, namely, p.P157S, p.L261Qfs*4, and p.G331S, and one variant, p.G21S, was found to show a significant association with familial PD. COQ2 variants rarely may associate with the disease onset of familial PD. Our findings contribute to an understanding of COQ2 variants in neurodegenerative disorders.

PMID: 29644397 [PubMed - as supplied by publisher]

Somatic activating mutations in MAP2K1 cause melorheostosis.

Nat Commun. 2018 Apr 11;9(1):1390

Authors: Kang H, Jha S, Deng Z, Fratzl-Zelman N, Cabral WA, Ivovic A, Meylan F, Hanson EP, Lange E, Katz J, Roschger P, Klaushofer K, Cowen EW, Siegel RM, Marini JC, Bhattacharyya T

Abstract
Melorheostosis is a sporadic disease of uncertain etiology characterized by asymmetric bone overgrowth and functional impairment. Using whole exome sequencing, we identify somatic mosaic MAP2K1 mutations in affected, but not unaffected, bone of eight unrelated patients with melorheostosis. The activating mutations (Q56P, K57E and K57N) cluster tightly in the MEK1 negative regulatory domain. Affected bone displays a mosaic pattern of increased p-ERK1/2 in osteoblast immunohistochemistry. Osteoblasts cultured from affected bone comprise two populations with distinct p-ERK1/2 levels by flow cytometry, enhanced ERK1/2 activation, and increased cell proliferation. However, these MAP2K1 mutations inhibit BMP2-mediated osteoblast mineralization and differentiation in vitro, underlying the markedly increased osteoid detected in affected bone histology. Mosaicism is also detected in the skin overlying bone lesions in four of five patients tested. Our data show that the MAP2K1 oncogene is important in human bone formation and implicate MEK1 inhibition as a potential treatment avenue for melorheostosis.

PMID: 29643386 [PubMed - in process]

A curated gene list for reporting results of newborn genomic sequencing.

Genet Med. 2017 Jul;19(7):809-818

Authors: Ceyhan-Birsoy O, Machini K, Lebo MS, Yu TW, Agrawal PB, Parad RB, Holm IA, McGuire A, Green RC, Beggs AH, Rehm HL

Abstract
PURPOSE: Genomic sequencing (GS) for newborns may enable detection of conditions for which early knowledge can improve health outcomes. One of the major challenges hindering its broader application is the time it takes to assess the clinical relevance of detected variants and the genes they impact so that disease risk is reported appropriately.
METHODS: To facilitate rapid interpretation of GS results in newborns, we curated a catalog of genes with putative pediatric relevance for their validity based on the ClinGen clinical validity classification framework criteria, age of onset, penetrance, and mode of inheritance through systematic evaluation of published evidence. Based on these attributes, we classified genes to guide the return of results in the BabySeq Project, a randomized, controlled trial exploring the use of newborn GS (nGS), and used our curated list for the first 15 newborns sequenced in this project.
RESULTS: Here, we present our curated list for 1,514 gene-disease associations. Overall, 954 genes met our criteria for return in nGS. This reference list eliminated manual assessment for 41% of rare variants identified in 15 newborns.
CONCLUSION: Our list provides a resource that can assist in guiding the interpretive scope of clinical GS for newborns and potentially other populations.Genet Med advance online publication 12 January 2017.

PMID: 28079900 [PubMed - indexed for MEDLINE]

Slow infusion of low{\hyphen}dose ketamine reduces bothersome side effects compared to IV push: a double{\hyphen}blind, double dummy, randomized controlled trial.

Acad Emerg Med. 2018 Apr 12;:

Authors: Clattenburg EJ, Hailozian C, Haro D, Yoo T, Flores S, Louie D, Herring AA

Abstract
STUDY OBJECTIVE: We compared the analgesic efficacy and incidence of side effects when low{\hyphen}dose (0.3 mg{\sol}kg) ketamine (LDK) is administered as a slow infusion (SI) over 15 minutes versus an intravenous push (IVP) over one minute.
METHODS: This was a prospective, randomized, double blind, double dummy, placebo{\hyphen}controlled trial of adult ED patients presenting with moderate to severe pain (numerical rating score ≥ 5). Patients received ketamine 0.3mg{\sol}kg administered either as a SI or IVP. Our primary outcome was the proportion of patients experiencing any psychoperceptual side effect over 60 minutes. A secondary outcome was incidence of moderate or greater psychoperceptual side effects. Additional outcomes included reduction in pain NRS scores at 60 minutes and percent maximum summed pain intensity difference ({\percnt}SPID).
RESULTS: Fifty{\hyphen}nine participants completed the study. 86.2{\percnt} of the IVP arm and 70.0{\percnt} of the SI arm experienced any side effect (difference 16.2{\percnt}, 95{\percnt}CI {\hyphen}5.4 - 37.8). We found a large reduction in moderate or greater psychoperceptual side effects with SI administration-75.9{\percnt} reported moderate or greater side effects versus 43.4{\percnt} in the SI arm (difference 32.5{\percnt}, 95{\percnt}CI 7.9 - 57.1). Additionally, the IVP arm experienced more hallucinations (n{\equal}8, 27.6{\percnt}) than the SI arm (SI n{\equal}2, 6.7{\percnt}; difference 20.9{\percnt}, 95{\percnt}CI 1.8 - 43.4). We found no significant differences in analgesic efficacy. At 60 minutes, the mean {\percnt}SPID in the IVP and SI arms was 39.9{\percnt} and 33.5{\percnt}, respectively, with a difference of 6.5{\percnt} (95{\percnt}CI {\hyphen}5.8 - 18.7).
CONCLUSION: Most patients who are administered LDK experience a psychoperceptual side effect regardless of administration via SI or IVP. However, patients receiving LDK as a SI reported significantly fewer moderate or greater psychoperceptual side effects and hallucinations with equivalent analgesia. This article is protected by copyright. All rights reserved.

PMID: 29645317 [PubMed - as supplied by publisher]

[Pharmacological treatment of osteoarthritis-related pain].

Schmerz. 2018 Apr 11;:

Authors: Nees TA, Schiltenwolf M

Abstract
Joint pain due to osteoarthritis (OA) is often severe and disabling and affects a large proportion of the aging population impairing daily living and quality of life. Numerous pharmacological treatment approaches are available. Including major OA guidelines this review presents the current evidence of pharmacological therapies in OA-related pain and covers topical, oral and intraarticular treatment approaches. In patients with mild OA topical nonsteroidal antiinflammatory drugs (NSAIDs) can be recommended. Topical capsaicin can be used when other treatments are ineffective or contraindicated. In patients with moderate to severe OA oral NSAIDs are suggested at the lowest effective dose for the shortest possible duration to control symptoms. Importantly, drug-related side effects and gastrointestinal, cardiovascular and renal comorbidities need to be taken into account. In patients with multiple-joint OA and high risk of NSAID-induced adverse events duloxetine can be considered. The evidence of metamizole, symptomatic slow-acting drugs in osteoarthritis and other nutritional supplements in the treatment of OA pain is uncertain and the use of opioids is not routinely recommended. In patients suffering from severe OA-related pain intraarticular injections with glucocorticoids can be suggested to achieve short-term pain relief. Evidence for interventional approaches using hyaluronic acid or platelet-rich plasma is uncertain. Yet, the efficacy of pharmacological therapies in OA-related pain is often inconsistent and severe adverse events might occur. Thus, critical use of the different treatment options considering patient-related comorbidities and nonpharmacological therapies is of major importance.

PMID: 29644468 [PubMed - as supplied by publisher]

Beneficial Effects of Bioactive Compounds in Mulberry Fruits against Cisplatin-Induced Nephrotoxicity.

Int J Mol Sci. 2018 Apr 09;19(4):

Authors: Lee D, Yu JS, Lee SR, Hwang GS, Kang KS, Park JG, Kim HY, Kim KH, Yamabe N

Abstract
Mulberry, the fruit of white mulberry tree (Morus alba L., Moraceae), is commonly used in traditional Chinese medicines as a sedative, tonic, laxative, and emetic. In our continuing research of the bioactive metabolites from mulberry, chemical analysis of the fruits led to the isolation of five compounds, 1-5. The compounds were identified as butyl pyroglutamate (1), quercetin 3-O-β-d-glucoside (2), kaempferol 3-O-β-d-rutinoside (3), rutin (4), and 2-phenylethyl d-rutinoside (5) by spectroscopic data analysis, comparing their nuclear magnetic resonance (NMR) data with those in published literature, and liquid chromatography-mass spectrometry analysis. The isolated compounds 1-5 were evaluated for their effects on anticancer drug-induced side effects by cell-based assays. Compound 1 exerted the highest protective effect against cisplatin-induced kidney cell damage. This effect was found to be mediated through the attenuation of phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, p38, mitogen-activated protein kinase, and caspase-3 in cisplatin-induced kidney cell damage.

PMID: 29642519 [PubMed - in process]

Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury.

Arch Toxicol. 2017 Aug;91(8):2849-2863

Authors: Proctor WR, Foster AJ, Vogt J, Summers C, Middleton B, Pilling MA, Shienson D, Kijanska M, Ströbel S, Kelm JM, Morgan P, Messner S, Williams D

Abstract
Drug-induced liver injury (DILI) continues to be a major source of clinical attrition, precautionary warnings, and post-market withdrawal of drugs. Accordingly, there is a need for more predictive tools to assess hepatotoxicity risk in drug discovery. Three-dimensional (3D) spheroid hepatic cultures have emerged as promising tools to assess mechanisms of hepatotoxicity, as they demonstrate enhanced liver phenotype, metabolic activity, and stability in culture not attainable with conventional two-dimensional hepatic models. Increased sensitivity of these models to drug-induced cytotoxicity has been demonstrated with relatively small panels of hepatotoxicants. However, a comprehensive evaluation of these models is lacking. Here, the predictive value of 3D human liver microtissues (hLiMT) to identify known hepatotoxicants using a panel of 110 drugs with and without clinical DILI has been assessed in comparison to plated two-dimensional primary human hepatocytes (PHH). Compounds were treated long-term (14 days) in hLiMT and acutely (2 days) in PHH to assess drug-induced cytotoxicity over an 8-point concentration range to generate IC50 values. Regardless of comparing IC50 values or exposure-corrected margin of safety values, hLiMT demonstrated increased sensitivity in identifying known hepatotoxicants than PHH, while specificity was consistent across both assays. In addition, hLiMT out performed PHH in correctly classifying hepatotoxicants from different pharmacological classes of molecules. The hLiMT demonstrated sufficient capability to warrant exploratory liver injury biomarker investigation (miR-122, HMGB1, α-GST) in the cell-culture media. Taken together, this study represents the most comprehensive evaluation of 3D spheroid hepatic cultures up to now and supports their utility for hepatotoxicity risk assessment in drug discovery.

PMID: 28612260 [PubMed - indexed for MEDLINE]

Editorial.

Rev Med Brux. 2016;37(6):459

Authors: Berghmans T

PMID: 28525172 [PubMed - indexed for MEDLINE]

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Erythromelalgia: a cutaneous manifestation of neuropathy?

An Bras Dermatol. 2018 Jan-Feb;93(1):86-94

Authors: Leroux MB

Abstract
The low prevalence of erythromelalgia, classified as an orphan disease, poses diagnostic and therapeutic difficulties. The aim of this review is to be an update of the specialized bibliography. Erythromelalgia is an infrequent episodic acrosyndrome affecting mainly both lower limbs symmetrically with the classic triad of erythema, warmth and burning pain. Primary erythromelalgia is an autosomal dominant inherited disorder, while secondary is associated with myeloproliferative diseases, among others. In its etiopathogenesis, there are neural and vascular abnormalities that can be combined. The diagnosis is based on exhaustive clinical history and physical examination. Complications are due to changes in the skin barrier function, ischemia and compromise of cutaneous nerves. Because of the complexity of its pathogenesis, erythromelalgia should always be included in the differential diagnosis of conditions that cause chronic pain and/or peripheral edema. The prevention of crisis is based on a strict control of triggers and promotion of preventive measures. Since there is no specific and effective treatment, control should focus on the underlying disease. However, there are numerous topical and systemic therapies that patients can benefit from.

PMID: 29641704 [PubMed - in process]

Cancer drug funding decisions in Scotland: impact of new end-of-life, orphan and ultra-orphan processes.

BMC Health Serv Res. 2017 Aug 30;17(1):613

Authors: Morrell L, Wordsworth S, Fu H, Rees S, Barker R

Abstract
BACKGROUND: The Scottish Medicines Consortium evaluates new drugs for use in the National Health Service in Scotland. Reforms in 2014 to their evaluation process aimed to increase patient access to new drugs for end-of-life or rare conditions; the changes include additional steps in the process to gain further information from patients and clinicians, and for revised commercial agreements. This study examines the extent of any impact of the reforms on funding decisions.
METHOD: Data on the Scottish Medicines Consortium's funding decisions during 24 months post-reform were extracted from published Advice, for descriptive statistics and thematic analysis. Comparison data were extracted for the 24 months pre-reform. Data on decisions for England by the National Institute for Clinical and Health Excellence for the same drugs were extracted from published Technology Appraisals.
RESULTS: The new process was used by 90% (53/59) of cancer submissions. It is triggered if the initial advice is not to recommend, and this risk-of-rejection level is higher than in the pre-period. Thirty-eight cancer drugs obtained some level of funding through the new process, but there was no significant difference in the distribution of decision types compared to the pre-reform period. Thematic analysis of patient and clinician input showed no clear relationship between issues raised and funding decision. Differences between SMC's and NICE's definitions of End-of-Life did not fully explain differences in funding decisions.
CONCLUSIONS: The Scottish Medicines Consortium's reforms have allowed funding of up to 38 cancer drugs that might previously have been rejected. However, the contribution of specific elements of the reforms to the final decision is unclear. The process could be improved by increased transparency in how the non-quantitative inputs influence decisions. Some disparities in funding decisions between England and Scotland are likely to remain despite recent process convergence.

PMID: 28854927 [PubMed - indexed for MEDLINE]

ANCA-associated vasculitis in childhood: recent advances.

Ital J Pediatr. 2017 May 05;43(1):46

Authors: Calatroni M, Oliva E, Gianfreda D, Gregorini G, Allinovi M, Ramirez GA, Bozzolo EP, Monti S, Bracaglia C, Marucci G, Bodria M, Sinico RA, Pieruzzi F, Moroni G, Pastore S, Emmi G, Esposito P, Catanoso M, Barbano G, Bonanni A, Vaglio A

Abstract
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are rare systemic diseases that usually occur in adulthood. They comprise granulomatosis with polyangiitis (GPA, Wegener's), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). Their clinical presentation is often heterogeneous, with frequent involvement of the respiratory tract, the kidney, the skin and the joints. ANCA-associated vasculitis is rare in childhood but North-American and European cohort studies performed during the last decade have clarified their phenotype, patterns of renal involvement and their prognostic implications, and outcome. Herein, we review the main clinical and therapeutic aspects of childhood-onset ANCA-associated vasculitis, and provide preliminary data on demographic characteristics and organ manifestations of an Italian multicentre cohort.

PMID: 28476172 [PubMed - indexed for MEDLINE]

SHORT syndrome in a two-year-old girl - case report.

Ital J Pediatr. 2017 May 04;43(1):44

Authors: Klatka M, Rysz I, Kozyra K, Polak A, Kołłątaj W

Abstract
BACKGROUND: SHORT syndrome is a rare genetic congenital defects condition. The frequency of the disease still remains unknown.
CASE PRESENTATION: We report the two-year-four-month old female with SHORT syndrome who present growth retardation and dysmorphic features (triangular-shaped face, prominent forehead, ocular depression, lipodystrophy at the lumbar region and around elbows), consistent with the phenotype described for this syndrome. The molecular analysis showed the presence of heterozygous variant c.1956dupT (p.Lys653*) in exon 15 of PIK3R1.
CONCLUSIONS: The frequency of the disease still remains unknown; solely several dozen cases have been described worldwide.

PMID: 28472977 [PubMed - indexed for MEDLINE]

Using Full Genomic Information to Predict Disease: Breaking Down the Barriers Between Complex and Mendelian Diseases.

Annu Rev Genomics Hum Genet. 2018 Apr 11;:

Authors: Jordan DM, Do R

Abstract
While sequence-based genetic tests have long been available for specific loci, especially for Mendelian disease, the rapidly falling costs of genome-wide genotyping arrays, whole-exome sequencing, and whole-genome sequencing are moving us toward a future where full genomic information might inform the prognosis and treatment of a variety of diseases, including complex disease. Similarly, the availability of large populations with full genomic information has enabled new insights about the etiology and genetic architecture of complex disease. Insights from the latest generation of genomic studies suggest that our categorization of diseases as complex may conceal a wide spectrum of genetic architectures and causal mechanisms that ranges from Mendelian forms of complex disease to complex regulatory structures underlying Mendelian disease. Here, we review these insights, along with advances in the prediction of disease risk and outcomes from full genomic information. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 19 is August 31, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID: 29641912 [PubMed - as supplied by publisher]