Altered intestinal microbiota composition, antibiotic therapy and intestinal inflammation in children and adolescents with cystic fibrosis.

PLoS One. 2018;13(6):e0198457

Authors: de Freitas MB, Moreira EAM, Tomio C, Moreno YMF, Daltoe FP, Barbosa E, Ludwig Neto N, Buccigrossi V, Guarino A

Abstract
The aim of the present study was to evaluate the effect of cystic fibrosis and antibiotic therapy on intestinal microbiota composition and intestinal inflammation in children and adolescents. A cross-sectional controlled study was conducted with 36 children and adolescents: 19 in the cystic fibrosis group (CFG) and 17 in the control group (CG) matched for age and sex. The CFG was subdivided based on the use of antibiotic therapy (CFAB group) and non-use of antibiotic therapy (CFnAB group). The following data were evaluated: colonization, antibiotic therapy, mutation, breastfeeding, use of infant formula, type of delivery, introduction of solid foods, body mass index, fecal calprotectin and intestinal microbiota composition (fluorescence in situ hybridization). Intestinal inflammation evaluated by fecal calprotectin was significantly higher in the CFG (median: 40.80 µg/g, IQR: 19.80-87.10, p = 0.040) and CFAB group (median: 62.95 µg/g, IQR: 21.80-136.62, p = 0.045) compared to the CG (median: 20.15 µg/g, IQR: 16.20-31.00), and the Bacteroides, Firmicutes, Eubacterium rectale and Faecalibacterium prausnitzii were significantly decreased (p < 0.05) in the CFG compared to the CG, whereas the bacteria Clostridium difficile, Escherichia coli and Pseudomonas aeruginosa were significantly increased in the CFG (p < 0.05). The main differences were found between the CG and CFAB group for Eubacterium rectale (p = 0.006), Bifidobacterium (p = 0.017), Escherichia coli (p = 0.030), Firmicutes (p = 0.002), Pseudomonas aeruginosa (p < 0.001) and Clostridium difficile (p = 0.006). The results of this study confirm intestinal inflammation in patients with CF, which may be related to changes in the composition of the intestinal microbiota.

PMID: 29933382 [PubMed - in process]

Molecular Basis and Differentiation-Associated Alterations of Anion Secretion in Human Duodenal Enteroid Monolayers.

Cell Mol Gastroenterol Hepatol. 2018;5(4):591-609

Authors: Yin J, Tse CM, Avula LR, Singh V, Foulke-Abel J, de Jonge HR, Donowitz M

Abstract
Background & Aims: Human enteroids present a novel tool to study human intestinal ion transport physiology and pathophysiology. The present study describes the contributions of Cl- and HCO3- secretion to total cyclic adenosine monophosphate (cAMP)-stimulated electrogenic anion secretion in human duodenal enteroid monolayers and the relevant changes after differentiation.
Methods: Human duodenal enteroids derived from 4 donors were grown as monolayers and differentiated by a protocol that includes the removal of Wnt3A, R-spondin1, and SB202190 for 5 days. The messenger RNA level and protein expression of selected ion transporters and carbonic anhydrase isoforms were determined by quantitative real-time polymerase chain reaction and immunoblotting, respectively. Undifferentiated and differentiated enteroid monolayers were mounted in the Ussing chamber/voltage-current clamp apparatus, using solutions that contained as well as lacked Cl- and HCO3-/CO2, to determine the magnitude of forskolin-induced short-circuit current change and its sensitivity to specific inhibitors that target selected ion transporters and carbonic anhydrase(s).
Results: Differentiation resulted in a significant reduction in the messenger RNA level and protein expression of cystic fibrosis transmembrane conductance regulator, (CFTR) Na+/K+/2Cl- co-transporter 1 (NKCC1), and potassium channel, voltage gated, subfamily E, regulatory subunit 3 (KCNE3); and, conversely, increase of down-regulated-in-adenoma (DRA), electrogenic Na+/HCO3- co-transporter 1 (NBCe1), carbonic anhydrase 2 (CA2), and carbonic anhydrase 4 (CA4). Both undifferentiated and differentiated enteroids showed active cAMP-stimulated anion secretion that included both Cl- and HCO3- secretion as the magnitude of total active anion secretion was reduced after the removal of extracellular Cl- or HCO3-/CO2. The magnitude of total anion secretion in differentiated enteroids was approximately 33% of that in undifferentiated enteroids, primarily owing to the reduction in Cl- secretion with no significant change in HCO3- secretion. Anion secretion was consistently lower but detectable in differentiated enteroids compared with undifferentiated enteroids in the absence of extracellular Cl- or HCO3-/CO2. Inhibiting CFTR, NKCC1, carbonic anhydrase(s), cAMP-activated K+ channel(s), and Na+/K+-adenosine triphosphatase reduced cAMP-stimulated anion secretion in both undifferentiated and differentiated enteroids.
Conclusions: Human enteroids recapitulate anion secretion physiology of small intestinal epithelium. Enteroid differentiation is associated with significant alterations in the expression of several ion transporters and carbonic anhydrase isoforms, leading to a reduced but preserved anion secretory phenotype owing to markedly reduced Cl- secretion but no significant change in HCO3- secretion.

PMID: 29930980 [PubMed]

Epidemiology and natural history of Pseudomonas aeruginosa airway infections in non-cystic fibrosis bronchiectasis.

ERJ Open Res. 2018 Apr;4(2):

Authors: Woo TE, Lim R, Surette MG, Waddell B, Bowron JC, Somayaji R, Duong J, Mody CH, Rabin HR, Storey DG, Parkins MD

Abstract
The natural history and epidemiology of Pseudomonas aeruginosa infections in non-cystic fibrosis (non-CF) bronchiectasis is not well understood. As such it was our intention to determine the evolution of airway infection and the transmission potential of P. aeruginosa in patients with non-CF bronchiectasis. A longitudinal cohort study was conducted from 1986-2011 using a biobank of prospectively collected isolates from patients with non-CF bronchiectasis. Patients included were ≥18 years old and had ≥2 positive P. aeruginosa cultures over a minimum 6-month period. All isolates obtained at first and most recent clinical encounters, as well as during exacerbations, that were morphologically distinct on MacConkey agar were genotyped by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). A total of 203 isolates from 39 patients were analysed. These were compared to a large collection of globally epidemic and local CF strains, as well as non-CF isolates. We identified four patterns of infection in non-CF bronchiectasis including: 1) persistence of a single strain (n=26; 67%); 2) strain displacement (n=8; 20%); 3) temporary disruption (n=3; 8%); and 4) chaotic airway infection (n=2; 5%). Patterns of infection were not significant predictors of rates of lung function decline or progression to end-stage disease and acquisition of new strains did not associate with the occurrence of exacerbations. Rarely, non-CF bronchiectasis strains with similar pulsotypes were observed in CF and non-CF controls, but no CF epidemic strains were observed. While rare shared strains were observed in non-CF bronchiectasis, whole-genome sequencing refuted patient-patient transmission. We observed a higher incidence of strain-displacement in our patient cohort compared to those observed in CF studies, although this did not impact on outcomes.

PMID: 29930949 [PubMed]

CFTR is required for the migration of Primordial Germ Cells during zebrafish early embryogenesis.

Reproduction. 2018 Jun 21;:

Authors: Liao H, Chen Y, Yulong L, Xue S, Liu M, Lin Z, Liu Y, Chan HC, Zhang X, Sun H

Abstract
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene affect fertility in both sexes. However, the involvement of CFTR in regulating germ cell development remains largely unknown. Here, we used zebrafish model to investigate the role of CFTR in primordial germ cells (PGCs) development. We generated a cftr frameshift mutant zebrafish line using CRISPR/Cas9 technique and investigated the migration of PGCs during early embryo development. Our results showed that loss of Cftr impairs the migration of PGCs from dome stages onwards. The migration of PGCs was also perturbed by treatment of CFTRinh-172, a gating specific CFTR channel inhibitor. Moreover, defected PGCs migration in cftr mutant embryos can be partially rescued by injection of wild-type but not other channel-defective mutants cftr mRNAs. Finally, we observed the elevation of cxcr4b, cxcl12a, rgs14a and ca15b, key factors involved in zebrafish PGCs migration, in cftr mutant zebrafish embryos. Taken together, the present study revealed an important role of CFTR acting as an ion channel in regulating PGCs migration during early embryogenesis. Defect of which may impair germ cell development through elevation of key factors involved in cell motility and response to chemotactic gradient in PGCs.

PMID: 29930176 [PubMed - as supplied by publisher]

Activity of mefloquine and mefloquine derivatives against Echinococcus multilocularis.

Int J Parasitol Drugs Drug Resist. 2018 Jun 15;8(2):331-340

Authors: Rufener R, Ritler D, Zielinski J, Dick L, da Silva ET, da Silva Araujo A, Joekel DE, Czock D, Goepfert C, Moraes AM, de Souza MVN, Müller J, Mevissen M, Hemphill A, Lundström-Stadelmann B

Abstract
The cestode E. multilocularis causes the disease alveolar echinococcosis (AE) in humans. The continuously proliferating metacestode (larval stage) of the parasite infects mostly the liver and exhibits tumor-like growth. Current chemotherapeutical treatment options rely on benzimidazoles, which are rarely curative and have to be applied daily and life-long. This can result in considerable hepatotoxicity and thus treatment discontinuation. Therefore, novel drugs against AE are urgently needed. The anti-malarial mefloquine was previously shown to be active against E. multilocularis metacestodes in vitro, and in mice infected by intraperitoneal inoculation of metacestodes when administered at 100 mg/kg by oral gavage twice a week for 12 weeks. In the present study, the same dosage regime was applied in mice infected via oral uptake of eggs representing the natural route of infection. After 12 weeks of treatment, the presence of parasite lesions was assessed in a liver squeeze chamber and by PCR, and a significantly reduced parasite load was found in mefloquine-treated animals. Assessment of mefloquine plasma concentrations by HPLC and modeling using a two-compartment pharmacokinetic model with first-order absorption showed that >90% of the expected steady-state levels (Cmin 1.15 mg/L, Cmax 2.63 mg/L) were reached. These levels are close to concentrations achieved in humans during long-term weekly dosage of 250 mg (dose applied for malaria prophylaxis). In vitro structure-activity relationship analysis of mefloquine and ten derivatives revealed that none of the derivatives exhibited stronger activities than mefloquine. Activity was only observed, when the 2-piperidylmethanol group of mefloquine was replaced by an amino group-containing residue and when the trifluoromethyl residue on position 8 of the quinoline structure was present. This is in line with the anti-malarial activity of mefloquine and it implies that the mode of action in E. multilocularis might be similar to the one against malaria.

PMID: 29933218 [PubMed - as supplied by publisher]

Proximal Pathway Enrichment Analysis for Targeting Comorbid Diseases via Network Endopharmacology.

Pharmaceuticals (Basel). 2018 Jun 22;11(3):

Authors: Aguirre-Plans J, Piñero J, Menche J, Sanz F, Furlong LI, Schmidt HHHW, Oliva B, Guney E

Abstract
The past decades have witnessed a paradigm shift from the traditional drug discovery shaped around the idea of &ldquo;one target, one disease&rdquo; to polypharmacology (multiple targets, one disease). Given the lack of clear-cut boundaries across disease (endo)phenotypes and genetic heterogeneity across patients, a natural extension to the current polypharmacology paradigm is to target common biological pathways involved in diseases via endopharmacology (multiple targets, multiple diseases). In this study, we present proximal pathway enrichment analysis (PxEA) for pinpointing drugs that target common disease pathways towards network endopharmacology. PxEA uses the topology information of the network of interactions between disease genes, pathway genes, drug targets and other proteins to rank drugs by their interactome-based proximity to pathways shared across multiple diseases, providing unprecedented drug repurposing opportunities. Using PxEA, we show that many drugs indicated for autoimmune disorders are not necessarily specific to the condition of interest, but rather target the common biological pathways across these diseases. Finally, we provide high scoring drug repurposing candidates that can target common mechanisms involved in type 2 diabetes and Alzheimer&rsquo;s disease, two conditions that have recently gained attention due to the increased comorbidity among patients.

PMID: 29932108 [PubMed]

Molecular therapeutic strategies for FGFR3 gene-related skeletal dysplasia.

J Mol Med (Berl). 2017 Dec;95(12):1303-1313

Authors: Chen J, Liu J, Zhou Y, Liu S, Liu G, Zuo Y, Wu Z, Wu N, Qiu G

Abstract
The FGFR3 gene encodes fibroblast growth factor receptor 3 protein, a negative regulator of chondrogenesis. Gain-of-function mutations result in constitutively activated FGFR3, leading to aberrant signal transduction, and accounting for inhibition of chondrocyte proliferation and differentiation. Generally, these pathogenic mutations maintain FGFR3 in an active state and cause diverse phenotypes in patients with skeletal dysplasia. For decades, studies have revealed the molecular mechanisms of constitutively activated FGFR3 and relevant therapeutic strategies. By modulating the FGFR3-induced signalling pathway with methods such as blocking binding between ligands and receptors, blocking tyrosine kinase activities, or antagonising the FGFR3 downstream signalling pathway, these strategies offer the possibility to ameliorate FGFR3 gene-related skeletal dysplasia phenotypes. In this review, we describe the mechanisms of potential therapeutic targets and underlying regulators and then systematically review molecular therapeutic strategies for FGFR3 gene-related skeletal dysplasia based on current knowledge.

PMID: 29063142 [PubMed - indexed for MEDLINE]

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Agave negatively regulates YAP and TAZ transcriptionally and post-translationally in osteosarcoma cell lines.

Cancer Lett. 2018 Jun 19;:

Authors: Ferraiuolo M, Pulito C, Finch-Edmondson M, Korita E, Maidecchi A, Donzelli S, Muti P, Serra M, Sudol M, Strano S, Blandino G

Abstract
Osteosarcoma (OS) is the most aggressive type of primary solid tumor that develops in bone. Whilst conventional chemotherapy can improve survival rates, the outcome for patients with metastatic or recurrent OS remains poor, so novel treatment agents and strategies are required. Research into new anticancer therapies has paved the way for the utilisation of natural compounds as they are typically less expensive and less toxic compared to conventional chemotherapeutics. Previously published works indicate that Agave exhibits anticancer properties, however potential molecular mechanisms remain poorly understood. In the present study, we investigate the anticancer effects of Agave leaf extract in OS cells suggesting that Agave inhibits cell viability, colony formation, and cell migration, and can induce apoptosis in OS cell lines. Moreover, Agave sensitizes OS cells to cisplatin (CDDP) and radiation, to overcome chemo- and radio-resistance. We demonstrate that Agave extract induces a marked decrease of Yes Associated Protein (YAP) and Tafazzin (TAZ) mRNA and protein expression upon treatment. We propose an initial mechanism of action in which Agave induces YAP/TAZ protein degradation, followed by a secondary event whereby Agave inhibits YAP/TAZ transcription, effectively deregulating the Nuclear Factor kappa B (NF-κB) p65:p50 heterodimers responsible for transcriptional induction of YAP and TAZ.

PMID: 29933048 [PubMed - as supplied by publisher]

Pharmacokinetic and pharmacogenetic markers of irinotecan toxicity.

Curr Med Chem. 2018 Jun 22;:

Authors: Hahn RZ, Antunes MV, Verza SG, Perassolo MS, Suyenaga ES, Schwartsmann G, Linden R

Abstract
BACKGROUND: Irinotecan (IRI) is a widely used chemotherapeutic drug, mostly used for first-line treatment of colorectal and pancreatic cancer. IRI doses are usually established based on patient's body surface area, an approach associated with large inter-individual variability in drug exposure and high incidence of severe toxicity. Toxic and therapeutic effects of IRI are also due to its active metabolite SN-38, reported to be up to 100 times more cytotoxic than IRI. SN-38 is detoxified by the formation of SN-38 glucuronide, through UGT1A1. Genetic polymorphisms in the UGT1A1 gene are associated to higher exposures to SN-38 and severe toxicity. Pharmacokinetic models to describe IRI and SN-38 kinetic profiles are available, with few studies exploring pharmacokinetic and pharmacogenetic-based dose individualization. The aim of this manuscript is to review the available evidence supporting pharmacogenetic and pharmacokinetic dose individualization of IRI in order to reduce the occurrence of severe toxicity during cancer treatment.
METHODS: The PubMed database was searched, considering papers published in the period from 1995-2017, using the keywords irinotecan, pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, either alone or in combination, with original papers being selected based on the presence of relevant data.
CONCLUSIONS: The findings of this review confirm the importance of considering individual patient characteristics to select IRI doses. Currently, the most straightforward approach for IRI dose individualization is UGT1A1 genotyping. However, this strategy is sub-optimal due to several other genetic and environmental contributions to the variable pharmacokinetics of IRI and its active metabolite. The use of dried blood spot sampling could allow the clinical application of complex sampling for the clinical use of limited sampling and population pharmacokinetic models for IRI doses individualization.

PMID: 29932028 [PubMed - as supplied by publisher]

Identification of genetic correlates of response to Risperidone: Findings of a multicentric schizophrenia study from India.

Asian J Psychiatr. 2017 Oct;29:174-182

Authors: Kaur G, Gupta D, Chavan BS, Sinhmar V, Prasad R, Tripathi A, Garg PD, Gupta R, Khurana H, Gautam S, Margoob MA, Aneja J

Abstract
Risperidone is most commonly used as an antipsychotic in India for treatment of schizophrenia. However, the response to treatment with risperidone is affected by many factors, genetic factors being one of them. So, we attempted to evaluate the association between dopamine D2 (DRD2) receptor, serotonergic (5HT2A) receptor and CYP2D6 gene polymorphisms and response to treatment with risperidone in persons with schizophrenia from North India. It was a multicentric 12-weeks prospective study, undertaken in patients diagnosed with schizophrenia according to International Classification of Diseases 10th revision, Diagnostic Criteria for Research module (ICD-10 DCR). Patients were treated with incremental dosages of risperidone. Nine gene polymorphisms from three genes viz. DRD2, 5-HT2A and CYP2D6 along with socio-demographical and clinical variables were analyzed to ascertain the association in response to risperidone treatment. The change in the Positive and Negative Syndrome Scale (PANSS) was used to measure the outcome. Significant differences in the frequencies of single nucleotide proteins (SNPs) rs180498 (Taq1D) and rs 6305 (C516T) polymorphisms were found amongst the groups defined according to percent decline in PANSS. The CYP2D6*4 polymorphism differed significantly when drop outs were excluded from analysis. Presence of DRD2 Taq 1 D2D2 and 5-HT2A C516T CT genotypes in patients were more likely to be associated with non-response to risperidone. Ser311Cys (rs1801028) mutation was absent in the North Indian patients suffering from schizophrenia.

PMID: 28692863 [PubMed - indexed for MEDLINE]

Next-generation sequencing improves treatment efficacy and reduces hospitalization in children with drug-resistant epilepsy.

CNS Neurosci Ther. 2018 Jun 22;:

Authors: Peng J, Pang N, Wang Y, Wang XL, Chen J, Xiong J, Peng P, Zhu CH, Kessi MB, He F, Yin F

Abstract
BACKGROUND: The purposes of this study were three-fold: (i) to determine the contribution of known genes to the causation of a broad-spectrum of pediatric drug-resistant epilepsy (DRE), (ii) to compare the diagnostic yield and cost among different next-generation sequencing (NGS) approaches, and especially (iii) to assess how NGS approaches can benefit patients by improving diagnosis and treatment efficiency.
METHODS: This study enrolled 273 pediatric DRE patients with no obvious acquired etiology. Seventy-four patients underwent whole-exome sequencing (WES), 141 patients had epilepsy-related gene panel testing, and another 58 patients had clinical WES gene panel testing. We obtained these patients' seizure and hospitalization frequency by periodic follow-up phone calls and outpatient visits.
RESULTS: Genetic diagnosis was achieved in 86 patients (31.5%) and involved 93 likely disease-causing mutations in 33 genes. In this study, the detection rates of the epilepsy-related gene panel, the clinical WES gene panel, and WES were 32.6% (46/141), 44.8% (26/58), and 17.3% (13/74), respectively. Moreover, 34 patients accepted corrective therapy according to their mutant genes, after which 52.9% (18/34) became seizure-free and 38.2% (13/34) achieved seizure reduction. In the end, patients with either positive or negative genetic results had significantly fewer hospitalization incidents (times/half year) than before (positive genetic results group 0.58 ± 1.14 vs 0.10 ± 0.26; negative genetic results group 0.72 ± 1.65 vs 0.12 ± 0.33).
CONCLUSIONS: These results offer further proof that NGS approaches represent powerful tools for establishing a definitive diagnosis. Moreover, this study indicated how NGS can improve treatment efficacy and reduce hospitalization in children with DRE.

PMID: 29933521 [PubMed - as supplied by publisher]

Advances in the Genetics of Youth-Onset Type 2 Diabetes.

Curr Diab Rep. 2018 Jun 22;18(8):57

Authors: Todd JN, Srinivasan S, Pollin TI

Abstract
PURPOSE OF REVIEW: To provide an update on knowledge the role of genetics in youth-onset type 2 diabetes (T2D).
RECENT FINDINGS: The prevalence in youth of T2D, once thought to be exclusively a disease of adults, has increased by over 35% since 2001. Youth with T2D tend to have higher rates of complications, more aggressive disease, with more rapid loss of beta-cell function and a less favorable response to treatment than adults. Obesity is the most important risk factor for T2D, and the rise in childhood overweight and obesity appears responsible for the dramatic increase in T2D in youth. However, some obese children do not develop T2D, consistent with genetic differences in susceptibility to the disease in the setting of obesity and insulin resistance, currently far less well characterized in youth than in adults. Recent studies have begun to show associations of several established adult T2D genetic risk variants with youth-onset T2D and related glycemic quantitative traits, including the strongest known cross-population T2D genetic contributor TCF7L2. Maturity-onset diabetes of the young (MODY), a diabetes subtype distinct from type 1 diabetes (T1D) and T2D, is now known to result from a highly penetrant gene mutation in one of several genes. MODY has been shown to account for or contribute to at least 4.5% of clinically diagnosed T2D, even among those who are overweight or obese, impacting treatment decisions. The recently formed ProDiGY (Progress in Diabetes Genetics in Youth) Consortium is using genome-wide association studies and whole exome sequencing to understand the genetic architecture of T2D in youth, including how it differs from that of adults. The limited amount of research conducted to date on the genetics of youth-onset T2D, which tends to be a more aggressive disease than adult T2D, suggests some overlap with genes involved in adult T2D and a sizeable influence of highly penetrant monogenic diabetes variants. The ProDiGY Consortium is expected to provide a more comprehensive understanding of youth T2D genetics.

PMID: 29931398 [PubMed - in process]

Clinical exome sequencing in dementias: a preliminary study.

Psychiatr Danub. 2018 Jun;30(2):216-219

Authors: Zalar B, Maver A, Kovanda A, Peterlin A, Peterlin B

Abstract
BACKGROUND: Dementias are clinically and genetically heterogeneous group of neurodegenerative disorders. Often, dementias with genetic etiology are clinically indistinguishable from non-genetic ones. The aim of this retrospective study was to evaluate the yield of clinical exome sequencing in dementias, potentially associated with monogenic genetic predisposition.
SUBJECTS AND METHODS: For this purpose 20 consecutive patients younger than 65 years were studied in the period from January 2014 to December 2017; 14 with the diagnosis of Frontotemporal dementia (FTD), 3 with early-onset Alzheimer disease (EOAD) and 3 with unspecified dementia. In addition to clinical exome sequencing including 57 genes associated with dementia, C9orf72 hexanucleotide expansion as tested in all patients.
RESULTS: We found genetic etiology in 6 patients: 2 mutations in the PSEN1 gene (p.Pro264Ser and p.Phe105Cys) in the EOAD patients, C9orf72 expansion and MAPT (c.1920+16C>T), mutation in the FTD group of patients as well as MAPT (c.1920+16C>T) mutation and likely pathogenic mutation in the TYROBP mutation (p.Asp32Asn) in patients with unspecified diagnosis.
CONCLUSIONS: Our preliminary results imply significant diagnostic yield in identifying rare genetic causes of dementia, combining comprehensive clinical exome sequencing and targeted C9orf72 expansion testing.

PMID: 29930232 [PubMed - in process]

Idiopathic Scoliosis Families Highlight Actin-Based and Microtubule-Based Cellular Projections and Extracellular Matrix in Disease Etiology.

G3 (Bethesda). 2018 Jun 21;:

Authors: Baschal EE, Terhune EA, Wethey CI, Baschal RM, Robinson KD, Cuevas MT, Pradhan S, Sutphin BS, Taylor MRG, Gowan K, Pearson CG, Niswander LA, Jones KL, Miller NH

Abstract
Idiopathic scoliosis (IS) is a structural lateral spinal curvature of ≥10 that affects up to 3% of otherwise healthy children and can lead to life-long problems in severe cases. It is well-established that IS is a genetic disorder. Previous studies have identified genes that may contribute to the IS phenotype, but the overall genetic etiology of IS is not well understood. We used exome sequencing to study five multigenerational families with IS. Bioinformatic analyses identified unique and low frequency variants (minor allele frequency ≤5%) that were present in all sequenced members of the family. Across the five families, we identified a total of 270 variants with predicted functional consequences in 246 genes, and found that eight genes were shared by two families. We performed GO term enrichment analyses, with the hypothesis that certain functional annotations or pathways would be enriched in the 246 genes identified in our IS families. Using three complementary programs to complete these analyses, we identified enriched categories that include stereocilia and other actin-based cellular projections, cilia and other microtubule-based cellular projections, and the extracellular matrix (ECM). Our results suggest that there are multiple paths to IS and provide a foundation for future studies of IS pathogenesis.

PMID: 29930198 [PubMed - as supplied by publisher]

Genetic mechanisms of human hypertension and their implications for blood pressure physiology.

Physiol Genomics. 2017 Nov 01;49(11):630-652

Authors: Seidel E, Scholl UI

Abstract
Hypertension, or elevated blood pressure, constitutes a major public health burden that affects more than 1 billion people worldwide and contributes to ~9 million deaths annually. Hereditary factors are thought to contribute to up to 50% of interindividual blood pressure variability. Blood pressure in the general population approximately shows a normal distribution and is thought to be a polygenic trait. In rare cases, early-onset hypertension or hypotension are inherited as Mendelian traits. The identification of the underlying Mendelian genes and variants has contributed to our understanding of the physiology of blood pressure regulation, emphasizing renal salt handling and the renin angiotensin aldosterone system as players in the determination of blood pressure. Genome-wide association studies (GWAS) have revealed more than 100 variants that are associated with blood pressure, typically with small effect sizes, which cumulatively explain ~3.5% of blood pressure trait variability. Several GWAS associations point to a role of the vasculature in the pathogenesis of hypertension. Despite these advances, the majority of the genetic contributors to blood pressure regulation are currently unknown; whether large-scale exome or genome sequencing studies will unravel these factors remains to be determined.

PMID: 28887369 [PubMed - indexed for MEDLINE]

Anti-PCSK9 treatment: Is ultra-low LDL always good?

Cardiovasc Res. 2018 Jun 20;:

Authors: Noto D, Giammanco A, Barbagallo CM, Cefalù AB, Averna MR

Abstract
Anti-pcsk9 (proprotein convertase subtilisin kexin 9) monoclonal antibodies (Mab) are novel, potent lipid-lowering drugs. They demonstrated to improve the lipid profile in high cardiovascular risk patients. Anti-pcsk9 Mab inhibit the targeted LDL-receptor degradation induced by pcsk9 protein and are able to reduce LDL cholesterol (LDL-C) levels on top of conventional lipid-lowering therapy.Though these drugs proved to be very safe in the short term, little is known about the possible long term effects, due to the short period of their marketing. The genetic low-cholesterol syndromes (LCS) represent the natural models of the lipid-lowering anti-PCSK9 therapy, and a valuable opportunity to predict the long term effects of these drugs. By looking at the clinical features of such models we could be able to foresee possible drug-induced side effects. In the present review the correspondences and discordances between the side effects of anti-pcsk9 therapy and the corresponding LCS models will be examined in the attempt to forecast possible long term consequences of these novel lipid lowering agents.

PMID: 29931148 [PubMed - as supplied by publisher]

The safety, tolerability, and pharmacokinetic profile of GSK2838232, a novel 2nd generation HIV maturation inhibitor, as assessed in healthy subjects.

Pharmacol Res Perspect. 2018 Jul;6(4):e00408

Authors: Johnson M, Jewell RC, Peppercorn A, Gould E, Xu J, Lou Y, Davies M, Baldwin S, Tenorio AR, Burke M, Jeffrey J, Johns BA

Abstract
This work aimed to assess the safety, tolerability, pharmacokinetics (PK), and relative bioavailability of GSK2838232, an investigational HIV maturation inhibitor. GSK2838232 was administered over four dose-escalation studies in healthy subjects which assessed single oral doses (5-250 mg) and repeat doses (up to 200 mg once or twice daily) ±100 mg ritonavir (RTV) once daily. GSK2838232 administration (up to 250 mg) to 124 subjects across four studies resulted in few mild adverse events (AEs) with similar frequencies to placebo. There were no clearly identified drug-related AEs. GSK2838232 tested fasted was quickly absorbed with a tmax of 2-3 hours. With food, the absorption was delayed and more variable, with ~60% increase in AUC and Cmax. Overall, following single doses GSK2838232 AUC and Cmax generally exhibited proportional PK from 50 to 100 mg dose without RTV and from 50 to 250 mg with RTV and following repeated doses of 20-200 mg with RTV. In relative bioavailability studies, a micronized formulation was found to be suitable for development. At steady state, RTV increased GSK2838232 AUC and Cmax by 10- and 3-fold, respectively. Half-life was prolonged from ~17 hours nonboosted to ~34 hours with RTV. This boosting effect was also seen in repeat-dose GSK2838232 studies, which achieved the targeted plasma exposure with GSK2838232 as a once-daily regimen of up to 200 mg with RTV. The results of these studies demonstrated a favorable safety and PK profile for GSK2838232 and support its investigation for the treatment of HIV infection.

PMID: 29930812 [PubMed - in process]

Stevens-Johnsons syndrome or drug-induced lupus - a clinical dilemma: A case report and review of the literature.

Biomed Rep. 2018 Jul;9(1):37-41

Authors: Bojinca VC, Bojinca M, Gheorghe M, Birceanu A, Iosif CI, Balanescu SM, Balanescu AR

Abstract
Tumor necrosis factor inhibitors are the first biological agents used in the treatment of rheumatoid arthritis (RA) to have yielded satisfactory results in terms of clinical improvement and radiologic progression, but they are also associated with the possibility of occurrence of a number of autoimmune systemic events [drug-induced lupus (DIL), vasculitis, sarcoidosis] and localized adverse events [uveitis, psoriasis, interstitial lung disease, erythema multiforme including the major form Stevens-Johnson syndrome (SJS)]. During treatment with TNF inhibitors, many patients develop positivity for antinuclear, antihistone and anti-double stranded DNA antibodies, though only a minority of patients will develop clinical manifestations and approximately less than 1% will fulfill the classification criteria for systemic lupus erythematosus. Mucocutaneous manifestations are the most frequent manifestations of DIL following treatment with TNF inhibitors, and can be severe and occasionally difficult to differentiate from erythema multiforme/SJS. Stopping the causative drug (the TNF inhibitor) and general supportive measures are usually sufficient in mild forms, but in moderate to severe forms, systemic glucocorticoids and sometimes immunosuppressive drugs are required. The present report presents the case of a patient with rheumatoid arthritis who developed severe recurrent cutaneous reactions and positive autoantibodies during TNF inhibitor treatment, with difficulties in differential diagnosis and treatment. A review of the literature is also presented.

PMID: 29930803 [PubMed]

Management of Subfoveal Perfluorocarbon Liquid: A Review.

Ophthalmologica. 2018;240(1):1-7

Authors: Liu W, Gao M, Liang X

Abstract
Perfluorocarbon liquid (PFCL) has been widely used in vitreoretinal surgeries, especially in retinal detachment treatment. A prominent complication of intraoperative PFCL application is inadvertent subretinal PFCL retention. Subfoveal PFCL, even in small amounts, receives much attention due to its potential side effect on the macular structure and function. Whether to observe with follow-up or to deal with surgery is often an intractable problem in the management of subfoveal PFCL. Safety and necessity are the 2 key issues in considering surgical treatment, that is, can we avoid surgically induced macular injury and will surgery be beneficial for the recovery of vision? Herein, the authors review sub-foveal PFCL retention with its risk factors, morphological manifestations, pathological studies, clinical natural consequences, and different surgical methods with their outcomes. Analysis of the existing literature shows that visual acuity improved significantly after subfoveal PFCL removal or displacement and was positively correlated with visual acuity before the operation.

PMID: 29669355 [PubMed - indexed for MEDLINE]