Burden and Risk Factors for Pseudomonas aeruginosa Community-acquired Pneumonia: a Multinational Point Prevalence Study of Hospitalised Patients.

Eur Respir J. 2018 Jul 05;:

Authors: Restrepo MI, Babu BL, Reyes LF, Chalmers JD, Soni NJ, Sibila O, Faverio P, Cilloniz C, Rodriguez-Cintron W, Aliberti S

Abstract
Pseudomonas aeruginosa is a challenging bacterium to treat due to its intrinsic antibiotic resistance to the most frequently used antibiotics in patients with community-acquired pneumonia (CAP). Data about the global burden and risk factors associated with P. aeruginosa-CAP are limited. We assessed the multinational burden and specific risk factors associated with P. aeruginosa-CAP.We enrolled 3,193 patients in 54 countries with confirmed diagnosis of CAP that underwent microbiological testing at admission. Prevalence was calculated according to the identification of P. aeruginosa Logistic regression analysis was used to identify risk factors for antibiotic-susceptible and antibiotic-resistant P. aeruginosa-CAP.The prevalence of P. aeruginosa and antibiotic-resistant P. aeruginosa-CAP was 4.2% and 2.0%, respectively. The rate of P. aeruginosa CAP in patients with prior infection/colonisation due to P. aeruginosa and at least one of the three independently associated chronic lung diseases [i.e., tracheostomy, bronchiectasis and/or very severe COPD]) was 67%. In contrast, the rate of P. aeruginosa CAP was 2% in patients without prior P. aeruginosa infection/colonisation and none of the selected chronic lung diseases.The multinational prevalence of P. aeruginosa-CAP is low. The risk factors identified in this study may guide healthcare professionals in deciding empirical antibiotic coverage for CAP patients.

PMID: 29976651 [PubMed - as supplied by publisher]

Flos Magnoliae Inhibits Chloride Secretion via ANO1 Inhibition in Calu-3 Cells.

Am J Chin Med. 2018 Jul 05;:1-14

Authors: Kim HJ, Nam YR, Nam JH

Abstract
Flos Magnoliae (FM, Chinese name: Xin-yi) is an oriental medicinal herb commonly used for symptomatic relief from allergic rhinitis, sinusitis, and headache, including in traditional Chinese and Korean medicine formulations. FM inhibits histamine release from mast cells and cytokine secretion from T cells. However, the mechanism of action of FM on the anoctamin-1 (ANO1) ion channel, which is responsible for nasal hypersecretion in allergic rhinitis, has not been elucidated. Therefore, in this study, we investigated the effect of a 30% ethanolic extract of FM (FMEtOH) and its chemical constituents on ANO1 activity. We used high-performance liquid chromatography analysis to identify five major chemical constituents of FMEtOH: vanillic acid, tiliroside, eudesmin, magnolin, and fargesin. Using a conventional whole-cell patch clamp method, we found that FMEtOH (30, 100, and 300[Formula: see text][Formula: see text]g/mL) and its chemical constituent tiliroside inhibited ANO1 activity in ANO1-overexpressing HEK293T cells. In addition, we found that the treatment of the airway epithelial cell line Calu-3 with interleukin 4 significantly increased Ca[Formula: see text] activated Cl[Formula: see text] current (ICaCC), but not cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride current (ICFTR). FMEtOH and tiliroside specifically inhibited ICaCC. Thus, in this study, we identified a novel mechanism underlying the alleviation of allergic rhinitis by FMEtOH. Our results indicate that FMEtOH and its chemical constituent tiliroside are promising and potent agents for the prevention and treatment of allergic rhinitis.

PMID: 29976084 [PubMed - as supplied by publisher]

Evaluation of high resolution computed tomography findings of cystic fibrosis.

Korean J Intern Med. 2018 Jul 06;:

Authors: Sasihuseyinoglu AS, Altıntaş DU, Soyupak S, Dogruel D, Yılmaz M, Serbes M, Duyuler G

Abstract
Background/Aims: Morphological changes due to lung disease in patients with cystic fibrosis (CF) were evaluated using high resolution computed tomography (HRCT), and the HRCT scores obtained using the Bhalla scoring system were correlated with those obtained using clinical and laboratory indicators.
Methods: Medical records of 28 children with CF who underwent chest CT in Department of Pediatric Allergy and Immunology, Cukurova University Balcali Hospital between March 2011 and January 2016 were retrospectively reviewed. Demographic data and physical examination, respiratory cultures, pulmonary function tests, and chest HRCT findings were evaluated. Patients were divided into the following two groups according to their forced expiratory volume in the first second (FEV1) values: normal FEV1 (≥ 80% of predicted values) and low FEV1 (< 80% of predicted values). Deep throat or sputum cultures were evaluated for the presence of Pseudomonas aeruginosa (PsA) and other bacteria. HRCT scans were scored using the Bhalla scoring system.
Results: No significant correlation was found between the Bhalla scores and sex, age group, or height percentiles. Significant relationships were found between the Bhalla score and weight (p = 0.036) and body mass index (BMI) (p = 0.032) percentiles below the third percentile, bacterial growth in the sputum/ deep throat cultures (p = 0.009), and presence of PsA (p = 0.004). Moreover, a significant correlation was found between the Bhalla score and FEV1 (r = -0.315, p = 0.0272), forced vital capacity (FVC; r = -0.381, p = 0.0178), forced expiratory flow between 25% and 75% of FVC (r = -0.229, p = 0.0431), and BMI (r = -3.368, p = 0.050).
Conclusions: Chest HRCT is an important diagnostic tool for the pulmonary evaluation of children with CF.

PMID: 29976036 [PubMed - as supplied by publisher]

Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function.

Am J Hum Genet. 2018 Jul 05;103(1):100-114

Authors: Xu Z, Lo WS, Beck DB, Schuch LA, Oláhová M, Kopajtich R, Chong YE, Alston CL, Seidl E, Zhai L, Lau CF, Timchak D, LeDuc CA, Borczuk AC, Teich AF, Juusola J, Sofeso C, Müller C, Pierre G, Hilliard T, Turnpenny PD, Wagner M, Kappler M, Brasch F, Bouffard JP, Nangle LA, Yang XL, Zhang M, Taylor RW, Prokisch H, Griese M, Chung WK, Schimmel P

Abstract
The tRNA synthetases catalyze the first step of protein synthesis and have increasingly been studied for their nuclear and extra-cellular ex-translational activities. Human genetic conditions such as Charcot-Marie-Tooth have been attributed to dominant gain-of-function mutations in some tRNA synthetases. Unlike dominantly inherited gain-of-function mutations, recessive loss-of-function mutations can potentially elucidate ex-translational activities. We present here five individuals from four families with a multi-system disease associated with bi-allelic mutations in FARSB that encodes the beta chain of the alpha2beta2 phenylalanine-tRNA synthetase (FARS). Collectively, the mutant alleles encompass a 5'-splice junction non-coding variant (SJV) and six missense variants, one of which is shared by unrelated individuals. The clinical condition is characterized by interstitial lung disease, cerebral aneurysms and brain calcifications, and cirrhosis. For the SJV, we confirmed exon skipping leading to a frameshift associated with noncatalytic activity. While the bi-allelic combination of the SJV with a p.Arg305Gln missense mutation in two individuals led to severe disease, cells from neither the asymptomatic heterozygous carriers nor the compound heterozygous affected individual had any defect in protein synthesis. These results support a disease mechanism independent of tRNA synthetase activities in protein translation and suggest that this FARS activity is essential for normal function in multiple organs.

PMID: 29979980 [PubMed - in process]

Knobloch syndrome caused by homozygous frameshift mutation of the COL18A1 gene in a Chinese pedigree.

Int J Ophthalmol. 2018;11(6):918-922

Authors: Zhang LS, Li HB, Zeng J, Yang Y, Ding C

Abstract
AIM: To explore the clinical feature and genetic etiology of a Chinese Knobloch syndrome family.
METHODS: Ocular examinations and magnetic resonance imagings (MRIs) were performed on the family. Whole exome sequencing was conducted on the two patients. Sanger sequencing was utilized to validate the presence of variation in the family as well as in 100 normal controls. Real-time quantitative polymerase chain reaction (PCR) was used to detect the expression level of COL18A1 in peripheral blood lymphocytes of the patients and normal carriers.
RESULTS: The affected subjects presented with vision loss, exotropia, cataracts, retinal detachment, and other complications. A homozygous c.4759_4760delCT (p.Leu1587ValfsX72) mutation (rs398122391) in COL18A1 was identified in the two patients, cosegregating with the phenotypes, and did not be detected in 100 normal controls. This mutation caused significant decreased expression of COL18A1 mRNA in the patients.
CONCLUSION: The findings strongly indicate that this mutation is the disease-causing mutation. Moreover, this is the first Knobloch syndrome pedigree reported in the Chinese population.

PMID: 29977801 [PubMed]

Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency.

Eur J Hum Genet. 2018 Jul 05;:

Authors: Srivastava A, Srivastava KR, Hebbar M, Galada C, Kadavigrere R, Su F, Cao X, Chinnaiyan AM, Girisha KM, Shukla A, Bielas SL

Abstract
Medical genomics research performed in diverse population facilitates a better understanding of the genetic basis of developmental disorders, with regional implications for community genetics. Autosomal recessive mitochondrial complex I deficiency (MCID) accounts for a constellation of clinical features, including encephalopathies, myopathies, and Leigh Syndrome. Using whole-exome sequencing, we identified biallelic missense variants in NDUFV1 that encodes the 51-kD subunit of complex I (NADH dehydrogenase) NDUFV1. Mapping the variants on published crystal structures of mitochondrial complex I demonstrate that the novel c.1118T > C (p.(Phe373Ser)) variant is predicted to diminish the affinity of the active pocket of NDUFV1 for FMN that correlates to an early onset of debilitating MCID symptoms. The c.1156C > T (p.(Arg386Cys)) variant is predicted to alter electron shuttling required for energy production and correlate to a disease onset in childhood. NDUFV1 c.1156C > T (p.(Arg386Cys)) represents a founder variant in South Asian populations that have value in prioritizing this variant in a population-specific manner for genetic diagnostic evaluation. In conclusion, our results demonstrate the advantage of analyzing population-specific sequences to understand the disease pathophysiology and prevalence of inherited risk variants in the underrepresented populations.

PMID: 29976978 [PubMed - as supplied by publisher]

Next generation sequencing identifies novel disease-associated BEST1 mutations in Bestrophinopathy patients.

Sci Rep. 2018 Jul 05;8(1):10176

Authors: Nguyen TT, Poornachandra B, Verma A, Mehta RA, Phalke S, Battu R, Ramprasad VL, Peterson AS, Ghosh A, Seshagiri S

Abstract
Bestinopathies are a spectrum of retinal disorders associated with mutations in BEST1 including autosomal recessive bestrophinopathy (ARB) and autosomal dominant Best vitelliform macular dystrophy (BVMD). We applied whole-exome sequencing on four unrelated Indian families comprising eight affected and twelve unaffected individuals. We identified five mutations in BEST1, including p.Tyr131Cys in family A, p.Arg150Pro in family B, p.Arg47His and p.Val216Ile in family C and p.Thr91Ile in family D. Among these, p.Tyr131Cys, p.Arg150Pro and p.Val216Ile have not been previously reported. Further, the inheritance pattern of BEST1 mutations in the families confirmed the diagnosis of ARB in probands in families A, B and C, while the inheritance of heterozygous BEST1 mutation in family D (p.Thr91Ile) was suggestive of BVMD. Interestingly, the ARB families A and B carry homozygous mutations while family C was a compound heterozygote with a mutation in an alternate BEST1 transcript isoform, highlighting a role for alternate BEST1 transcripts in bestrophinopathy. In the BVMD family D, the heterozygous BEST1 mutation found in the proband was also found in the asymptomatic parent, suggesting an incomplete penetrance and/or the presence of additional genetic modifiers. Our report expands the list of pathogenic BEST1 genotypes and the associated clinical diagnosis.

PMID: 29976937 [PubMed - in process]

Remnant-Like Particle Cholesterol, Low-Density Lipoprotein Triglycerides, and Incident Cardiovascular Disease.

J Am Coll Cardiol. 2018 Jul 10;72(2):156-169

Authors: Saeed A, Feofanova EV, Yu B, Sun W, Virani SS, Nambi V, Coresh J, Guild CS, Boerwinkle E, Ballantyne CM, Hoogeveen RC

Abstract
BACKGROUND: Hypertriglyceridemia is associated with increased remnant-like particle cholesterol (RLP-C) and triglycerides in low-density lipoprotein (LDL-TG). Recent studies have focused on atherogenicity of RLP-C, with few data on LDL-TG.
OBJECTIVES: The aim of this study was to examine associations of RLP-C and LDL-TG with incident cardiovascular disease (CVD) events and genetic variants in the ARIC (Atherosclerosis Risk In Communities) study.
METHODS: Fasting plasma RLP-C and LDL-TG levels were measured in 9,334 men and women without prevalent CVD. Participants were followed for incident CVD events (coronary heart disease and ischemic stroke) for up to 16 years. Associations between LDL-TG and RLP-C levels and genetic variants were assessed by whole-exome sequencing using single-variant analysis for common variants and gene-based burden tests for rare variants; both an unbiased and a candidate gene approach were explored.
RESULTS: RLP-C and LDL-TG levels were correlated with triglyceride levels (r = 0.85 and r = 0.64, p < 0.0001). In minimally adjusted analyses, RLP-C and LDL-TG were associated with CVD risk, but in models adjusted for traditional risk factors including lipids, only LDL-TG was associated with incident CHD (hazard ratio: 1.28; 95% confidence interval: 1.10 to 1.50) and stroke (hazard ratio: 1.47; 95% confidence interval: 1.13 to 1.92). A common APOE variant, rs7412, had the strongest association with LDL-TG and RLP-C (p < 5 × 10-8).
CONCLUSIONS: RLP-C and LDL-TG levels were predictive of CVD and associated with APOE variants. LDL-TG may represent a marker of dysfunctional remnant lipoprotein metabolism associated with increased CVD risk. Further research is needed to determine whether LDL-TG plays a causal role in CVD and may be a target for therapy.

PMID: 29976289 [PubMed - in process]

Identification of ANKDD1B variants in an ankylosing spondylitis pedigree and a sporadic patient.

BMC Med Genet. 2018 Jul 05;19(1):111

Authors: Tan Z, Zeng H, Xu Z, Tian Q, Gao X, Zhou C, Zheng Y, Wang J, Ling G, Wang B, Yang Y, Ma L

Abstract
BACKGROUND: Ankylosing spondylitis (AS) is a debilitating autoimmune disease affecting tens of millions of people in the world. The genetics of AS is unclear. Analysis of rare AS pedigrees might facilitate our understanding of AS pathogenesis.
METHODS: We used genome-wide linkage analysis and whole-exome sequencing in combination with variant co-segregation verification and haplotype analysis to study an AS pedigree and a sporadic AS patient.
RESULTS: We identified a missense variant in the ankyrin repeat and death domain containing 1B gene ANKDD1B from a Han Chinese pedigree with dominantly inherited AS. This variant (p.L87V) co-segregates with all male patients of the pedigree. In females, the penetrance of the symptoms is incomplete with one identified patient out of 5 carriers, consistent with the reduced frequency of AS in females of the general population. We further identified a distinct missense variant affecting a conserved amino acid (p.R102L) of ANKDD1B in a male from 30 sporadic early onset AS patients. Both variants are absent in 500 normal controls. We determined the haplotypes of four major known AS risk loci, including HLA-B*27, 2p15, ERAP1 and IL23R, and found that only HLA-B*27 is strongly associated with patients in our cohort.
CONCLUSIONS: Together these results suggest that ANKDD1B variants might be associated with AS and genetic analyses of more AS patients are warranted to verify this association.

PMID: 29976160 [PubMed - in process]

Mosaicism in Cutaneous Disorders.

Annu Rev Genet. 2017 Nov 27;51:123-141

Authors: Lim YH, Moscato Z, Choate KA

Abstract
Genetic mosaicism arises when a zygote harbors two or more distinct genotypes, typically due to de novo, somatic mutation during embryogenesis. The clinical manifestations largely depend on the differentiation status of the mutated cell; earlier mutations target pluripotent cells and generate more widespread disease affecting multiple organ systems. If gonadal tissue is spared-as in somatic genomic mosaicism-the mutation and its effects are limited to the proband, whereas mosaicism also affecting the gametes, such as germline or gonosomal mosaicism, is transmissible. Mosaicism is easily appreciated in cutaneous disorders, as phenotypically distinct mutant cells often give rise to lesions in patterns determined by the affected cell type. Genetic investigation of cutaneous mosaic disorders has identified pathways central to disease pathogenesis, revealing novel therapeutic targets. In this review, we discuss examples of cutaneous mosaicism, approaches to gene discovery in these disorders, and insights into molecular pathobiology that have potential for clinical translation.

PMID: 29178821 [PubMed - indexed for MEDLINE]

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Understanding the phenotypic similarities between IFAP and Olmsted syndrome from a molecular perspective: the interaction of MBTPS2 and TRPV3.

Arch Dermatol Res. 2017 Oct;309(8):637-643

Authors: Nemer G, Safi R, Kreidieh F, Usta J, Bergqvist C, Ballout F, Btadini W, Hamzeh N, Abbas O, Kibbi AG, Shimomura Y, Kurban M

Abstract
Ichthyosis Follicularis, Atrichia, and Photophobia (IFAP) is a severe rare genetic disorder caused by mutations in the gene encoding the Membrane-Bound Transcription Factor Peptidase, Site 2 (MBTPS2). Olmsted syndrome is another rare genetic disease with overlapping clinical features caused by mutations in the gene encoding the Transient Receptor Potential Cation Channel, subfamily V (TRPV3). Mutations in MBTPS2 have been recently reported in Olmsted syndrome, underscoring the overlap and the confusion in separating Olmsted from IFAP syndrome. We studied a Lebanese family with IFAP syndrome both, clinically and molecularly, and investigated whether there is a cross relation between TRPV3 and MBTPS2. We identified a recurrent mutation designated p.F475S in MBTPS2 in the affected individuals. This mutation was not found in 100 control individuals from the same population. We determined that TRPV3 regulatory region is a target for MBTPS2. In addition, there was an increased cell death in the cells transfected with the mutant versus the wild-type MBTPS2. In conclusion, we identified a direct regulatory effect of MBTPS2 on TRPV3 which can partially contribute to the overlapping clinical features of IFAP and Olmsted syndromes under a common signaling pathway.

PMID: 28717930 [PubMed - indexed for MEDLINE]

Mohs micrographic surgery of rare cutaneous tumours.

J Eur Acad Dermatol Venereol. 2017 Aug;31(8):1285-1288

Authors: Flohil SC, van Lee CB, Beisenherz J, Mureau MAM, Overbeek LIH, Nijsten T, van den Bos RR

Abstract
BACKGROUND: Recurrence rates after Mohs micrographic surgery (MMS) for rare cutaneous tumours are poorly defined.
OBJECTIVE: To investigate the recurrence rate after MMS for rare cutaneous tumours at a university centre.
METHODS & MATERIALS: Retrospective review of all rare cutaneous tumours treated with MMS at a large university centre between January 2008 and December 2012. To detect all recurrences, patients were linked to The Nationwide Network and registry of histo- and cytopathology (PALGA).
RESULTS: In total, 80 patients with 80 tumours were included. Tumour types included dermatofibrosarcoma protuberans (27), atypical fibroxanthoma (22), Merkel cell carcinoma (8), microcystic adnexal carcinoma (9), sebaceous carcinoma (6), extramammary Paget's disease (2) and other (6). Mean follow-up time was 3.7 years (standard deviation 1.4) during which two atypical fibroxanthomas recurred (2.5%).
CONCLUSION: This large case series shows that MMS is an appropriate treatment for rare cutaneous tumours with a recurrence rate less than 3%. Preferably, MMS for rare cutaneous tumours is performed in experienced multidisciplinary centres to further improve the quality of treatment.

PMID: 27976423 [PubMed - indexed for MEDLINE]

Epidemiology and Genetic Diversity of Rotavirus in Kunming, China, in 2015.

Intervirology. 2018 Jul 05;:1-5

Authors: Kang Y, Cai Y

Abstract
Group A rotavirus (RVA) is a serious public problem in China, with a prevalence of 29.7% in diarrhea cases under 5 years of age. A total of 1,224 fecal specimens were collected in 2015 from children under 5 years of age with acute gastroenteritis in Kunming, China, for detection and characterization of rotavirus. The prevalence of RVA was 28.5%. The frequency of RVA detection was greatest (52%) among children aged 7-12 months. The following strains were the most common types: G9P(8) (58.2%), G3P(8) (14.9%), and G1P(8) (6.9%). The following strains were uncommon types: G3P(4), G8P(9), and G9P(4) (1.1%); G1P(4), G2P(8), and G4P(8) (0.9%); G2P(6), G3P(9), G4P(6), and G9P(6) (0.6%); and G4P(4) (0.3%). G3G1P(8) (5.2%), G1G2P(4) (0.9%), G1G9P(8) (0.6%), and G2P(4)P(8) (0.3%) were mixed types. This study documents the molecular epidemiology, genetics, and diversity of rotavirus strains in children under 5 years of age in Kunming, China, and suggests that it may be important to offer RVA vaccination and scientific evidence to stop and control RVA-related diarrhea.

PMID: 29975941 [PubMed - as supplied by publisher]

Further Support for the Involvement of Genetic Variants Related to the Serotonergic Pathway in the Antidepressant Response in Children and Adolescents After a 12-Month Follow-Up: Impact of the HTR2A rs7997012 Polymorphism.

J Child Adolesc Psychopharmacol. 2018 Jul 05;:

Authors: Gassó P, Blázquez A, Rodríguez N, Boloc D, Torres T, Mas S, Lafuente A, Lázaro L

Abstract
OBJECTIVE: Fluoxetine is an effective and well-tolerated pharmacological treatment for children and adolescents with major depressive disorder (MDD). However, a high percentage of patients do not respond. There is a substantial genetic contribution to this variable clinical outcome. Based on previous genetic results of our group and given the lack of pharmacogenetics studies of antidepressant response with a long follow-up period, we evaluated the influence of single nucleotide polymorphisms (SNPs) in genes related to the serotonergic pathway on remission and recovery in children and adolescents diagnosed with MDD after 12 months of initiating fluoxetine treatment.
METHODS: The assessment was performed in 46 patients. All of them were visited at least once a month during the 12-month follow-up. Psychiatrists interviewed patients and their parents to explore clinical improvement. A total of 75 genotyped SNPs in 10 candidate genes were included in the genetic association analysis with remission and recovery. Bonferroni correction for multiple testing was applied to avoid false positive results.
RESULTS: The HTR2A rs7997012 SNP was significantly associated after Bonferroni correction with clinical improvement. Particularly, the homozygotes for the major allele (GG) showed the highest percentage of remitters and the highest score reductions on the Clinical Global Impressions-Severity (CGI-S) scale. Moreover, although the results were on the border of statistical significance, the GG homozygotes also tended to experience fewer readmissions during the follow-up period Conclusions: These results provide more evidence of the involvement of genetic variants related to the serotonergic pathway in the antidepressant response. Studies with larger cohorts are needed to integrate all relevant variants into clinical predictors of antidepressant response.

PMID: 29975559 [PubMed - as supplied by publisher]

An Unnecessary Pain: Using Pharmacogenetics for Statin-related Skeletal Muscle Toxicity.

Cureus. 2018 Apr 30;10(4):e2557

Authors: Alzghari SK

Abstract
Statins are an important class of medications in reducing the risk of cardiovascular events as well as overall mortality. However, a well-known adverse effect of statins is skeletal muscle toxicity, which may lead to abrupt discontinuation of the statin. In turn, patients may miss out on the benefits of statin therapy. An important factor to consider is a patient's solute carrier organic anion transporter 1B1 (SLCO1B1) gene T521C polymorphism status. Herein, an overview of the pharmacogenetics of SLCO1B1 is provided as well as recommendations for use in practice.

PMID: 29974012 [PubMed]

Preface to Special Issue on 'Cytochrome P450 Variation in Pharmacogenomics'.

J Pers Med. 2018 Jul 04;8(3):

Authors: Rettie AE, Liggett SB

PMID: 29973520 [PubMed]

Terpyridine-Micelles for Inhibiting Bacterial Biofilm Development.

ACS Infect Dis. 2018 Jul 05;:

Authors: Qiao J, Purro M, Liu Z, Xiong MP

Abstract
Iron plays a critical role in bacterial infections and is especially critical for supporting biofilm formation. Until recently, Fe(III) was assumed to be the most relevant form of iron to chelate in therapeutic antimicrobial strategies due to its natural abundance under normal oxygen and physiologic conditions. Recent clinical data obtained from cystic fibrosis (CF) patients found that there is actually quite an abundance of Fe(II) present in sputum and that there exists a significant relationship between sputum Fe(II) concentration and severity of the disease. A biocompatible mixed micelle formed from the self-assembly of poly (lactic-co-glycolic acid)-block-methoxy poly(ethylene glycol) (PLGA-b-mPEG) and poly(lactic-co-glycolic acid)-block-poly(terpyridine)5 [PLGA-b-p(Tpy)5] polymers was prepared to chelate Fe(II) (Tpy‒micelle). Tpy-micelles showed high selectivity for Fe(II) over Fe(III), decreased biofilm mass more effectively under anaerobic conditions at >4 µM Tpy-micelles, reduced bacteria growth in biofilms by >99.9% at 128 µM Tpy-micelles, effectively penetrated throughout a 1-day old biofilm and inhibited biofilm development in a concentration-dependent manner. This study reveals that Fe(II) chelating Tpy-micelles are a promising addition to Fe(III) chelating strategies to inhibit biofilm formation in CF lung infections.

PMID: 29974746 [PubMed - as supplied by publisher]