Two common human CLDN5 alleles encode different open reading frames but produce one protein isoform.

Ann N Y Acad Sci. 2017 Apr 26;:

Authors: Cornely RM, Schlingmann B, Shepherd WS, Chandler JD, Neujahr DC, Koval M

Abstract
Claudins provide tight junction barrier selectivity. The human CLDN5 gene contains a high-frequency single-nucleotide polymorphism (rs885985), where the G allele codes for glutamine (Q) and the A allele codes for an amber stop codon. Thus, these different CLDN5 alleles define nested open reading frames (ORFs) encoding claudin-5 proteins that are 303 or 218 amino acids in length. Interestingly, human claudin-16 and claudin-23 also have long ORFs. The long form of claudin-5 contrasts with the majority of claudin-5 proteins in the National Center for Biotechnology Information protein database, which are less than 220 amino acids in length. Screening of genotyped human lung tissue by immunoblot revealed only the 218 amino acid form of claudin-5 protein; the long-form claudin-5 protein was not detected. Moreover, when forcibly expressed in transfected cells, the long form of human claudin-5 was retained in intracellular compartments and did not localize to the plasma membrane, in contrast to the 218 amino acid form, which localized to intercellular junctions. This suggests that the 303 amino acid claudin-5 protein is rarely expressed, and, if so, is predicted to adversely affect cell function. Potential roles for upstream ORFs in regulating claudin-5 expression are also discussed.

PMID: 28445614 [PubMed - as supplied by publisher]

CFTR-dependent chloride efflux in cystic fibrosis mononuclear cells is increased by ivacaftor therapy.

Pediatr Pulmonol. 2017 Apr 26;:

Authors: Guerra L, D'Oria S, Favia M, Castellani S, Santostasi T, Polizzi AM, Mariggiò MA, Gallo C, Casavola V, Montemurro P, Leonetti G, Manca A, Conese M

Abstract
AIM: The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) potentiator ivacaftor (Kalydeco®) improves clinical outcome in G551D cystic fibrosis (CF) patients. Here, we have investigated whether ivacaftor has a clinical impact on non-G551D gating mutations and function of circulating leukocytes as well.
METHODS: Seven patients were treated with ivacaftor and evaluated at baseline, and at 1-3 and 6 months. Besides clinical and systemic inflammatory parameters, circulating mononuclear cells (MNC) were evaluated for CFTR-dependent chloride efflux by spectrofluorimetry, neutrophils for oxidative burst by cytofluorimetry and HVCN1 mRNA expression by real time PCR.
RESULTS: Ivacaftor determined a significant decrease in sweat chloride concentrations at all time points during treatment. Body mass index (BMI), FEV1 , and FVC showed an increasing trend. While C-reactive protein decreased significantly at 2 months, the opposite behavior was noticed for circulating monocytes. CFTR activity in MNC was found to increase significantly at 3 and 6 months. Neutrophil oxidative burst peaked at 2 months and then decreased to baseline. HVCN1 mRNA expression was significantly higher than baseline at 1-3 months and decreased after 6 months of treatment. The chloride efflux in MNC correlated positively with both FEV1 and FVC. On the other hand, sweat chloride correlated positively with CRP and WBC, and negatively with both respiratory function tests. A cluster analysis confirmed that sweat chloride, FEV1 , FVC, BMI, and MNC chloride efflux behaved as a single entity over time.
DISCUSSION: In patients with non-G551D mutations, ivacaftor improved both chloride transport in sweat ducts and chloride efflux in MNC, that is, functions directly imputed to CFTR.

PMID: 28445004 [PubMed - as supplied by publisher]

[Newborn Screening on Cystic Fibrosis in Germany: Comparison of the new Screening Protocol with an Alternative Protocol].

Klin Padiatr. 2017 Mar;229(2):59-66

Authors: Sommerburg O, Stahl M, Hammermann J, Okun JG, Kulozik A, Hoffmann G, Mall M

Abstract
Background For the new cystic fibrosis (CF) newborn screening program in Germany the Federal Joint Committee (G-BA) implemented a new screening protocol using immunoreactive trypsinogen (IRT) as first and pancreatitis associated protein (PAP) as second tier. Gene analysis with a panel of 31 CFTR-mutations is used as third tier to increase the positive predictive value (PPV) which is known to be low in pure biochemical IRT/PAP protocols. Methods For post hoc analysis the data pool (n=372 906) of a study evaluating a pure biochemical IRT/PAP protocol was used for assessment of the 3-step G-BA protocol in comparison with an alternative screening protocol recommended by the authors. The difference between the 2 protocols is the procedure when IRT>99.9(th) percentile. In the G BA protocol PAP and DNA analysis will be by-passed while in the alternative protocol only the PAP step will be circumvented. Results Both 3-tier IRT/PAP+SN/DNA protocols did not lose sensitivity due to addition of genetic analysis when the results were compared to those of the 2-tier biochemical IRT/PAP protocol. However, the protocols provide different results regarding PPV. The G-BA protocol showed with 351 a much higher number of false-positively detected newborns (PPV 20.2%) when compared to 31 false-positively detected newborns in the alternative protocol (PPV 69.6%). Conclusions The G-BA protocol had a worse performance when compared with the alternative protocol recommended by the authors. The higher number of false-positively detected newborns using the G-BA protocol will lead to more consultations including sweat tests, will create more anxiety in parents, and will result in higher costs after screening.

PMID: 28444650 [PubMed - in process]

[Cystic Fibrosis Screening in Germany].

Klin Padiatr. 2017 Mar;229(2):55-56

Authors: Gortner L

PMID: 28444649 [PubMed - in process]

Emerging Roles of Carbonyl Sulfide (COS) in Chemical Biology: Sulfide Transporter or Gasotransmitter?

Antioxid Redox Signal. 2017 Apr 26;:

Authors: Steiger AK, Zhao Y, Pluth MD

Abstract
SIGNIFICANCE: Carbonyl sulfide (COS) is the most prevalent sulfur-containing gas in Earth's atmosphere and plays important roles in the global sulfur cycle. COS has been implicated in origin of life peptide ligation, is the primary energy source for certain bacteria, and has been detected in mammalian systems. Despite this long and intertwined history with terrestrial biology, limited attention has focused on potential roles of COS as a biological mediator. Recent Advances. Although bacterial COS production is well documented, definitive sources of mammalian COS production have not been confirmed. Enzymatic COS consumption in mammals, however, is well documented and occurs primarily by carbonic anhydrase (CA) mediated conversion to H2S. COS has been detected in ex vivo mammalian tissue culture, as well as in exhaled breath as a potential biomarker for different disease pathologies including cystic fibrosis and organ rejection. Recently, chemical tools for COS delivery have emerged and are poised to advance future investigations into the role of COS in different biological contexts.
CRITICAL ISSUES: Possible roles of COS as an important biomolecule, gasotransmitter, or sulfide transport intermediate remain to be determined. Key advances in both biological and chemical tools for COS research are needed to further investigate these questions.
FUTURE DIRECTIONS: Further evaluation of the biological roles of COS and disentangling the chemical biology of COS from that of H2S is needed to further elucidate these interactions. Chemical tools for COS delivery and modulation may provide a first avenue of investigative tools to answer many of these questions.

PMID: 28443679 [PubMed - as supplied by publisher]

Plastic bronchitis: An unusual complication of acute chest syndrome in adult.

Respir Med Case Rep. 2017;21:93-95

Authors: Feray S, Mora P, Decavele M, Pham T, Hafiani EM, Fartoukh M

Abstract
Plastic bronchitis is used to designate endobronchial plugs of rubber-like consistency that form into bronchial trees. It has been described in several diseases like asthma, cystic fibrosis, pulmonary infection, cyanotic congenital heart disease and in few young children with homozygous sickle cell disease. We report the first sickle cell adult case of plastic bronchitis during acute chest syndrome. He developed severe acute respiratory distress syndrome. This unusual presentation related to obstruction by voluminous casts may alert physicians to focus more on the bronchi in sickle cell patients. Realization of fiberoptic bronchoscopy to diagnose endobronchial injury and preventive measures such as fluidification of sputum at the early stage of thoracic vaso-occlusive crisis are essential.

PMID: 28443234 [PubMed - in process]

Natural Killer Group 2D Ligand Depletion Reconstitutes Natural Killer Cell Immunosurveillance of Head and Neck Squamous Cell Carcinoma.

Front Immunol. 2017;8:387

Authors: Weil S, Memmer S, Lechner A, Huppert V, Giannattasio A, Becker T, Müller-Runte A, Lampe K, Beutner D, Quaas A, Schubert R, Herrmann E, Steinle A, Koehl U, Walter L, von Bergwelt-Baildon MS, Koch J

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous and aggressive tumor originating from the epithelial lining of the upper aero-digestive tract accounting for 300,000 annual deaths worldwide due to failure of current therapies. The natural killer group 2D (NKG2D) receptors on natural killer (NK) cells and several T cell subsets play an important role for immunosurveillance of HNSCC and are thus targeted by tumor immune evasion strategies in particular by shedding of various NKG2D ligands (NKG2DLs). Based on plasma and tumor samples of 44 HNSCC patients, we found that despite compositional heterogeneity the total plasma level of NKG2DLs correlates with NK cell inhibition and disease progression. Strikingly, based on tumor spheroids and primary tumors of HNSCC patients, we found that NK cells failed to infiltrate HNSCC tumors in the presence of high levels of NKG2DLs, demonstrating a novel mechanism of NKG2DL-dependent tumor immune escape. Therefore, the diagnostic acquisition of the plasma level of all NKG2DLs might be instrumental for prognosis and to decipher a patient cohort, which could benefit from restoration of NKG2D-dependent tumor immunosurveillance. Along these lines, we could show that removal of shed NKG2DLs (sNKG2DLs) from HNSCC patients' plasma restored NK cell function in vitro and in individual patients following surgical removal of the primary tumor. In order to translate these findings into a therapeutic setting, we performed a proof-of-concept study to test the efficacy of adsorption apheresis of sNKG2DLs from plasma after infusion of human MICA in rhesus monkeys. Complete removal of MICA was achieved after three plasma volume exchanges. Therefore, we propose adsorption apheresis of sNKG2DLs as a future preconditioning strategy to improve the efficacy of autologous and adoptively transferred immune cells in cellular cancer immunotherapy.

PMID: 28443091 [PubMed - in process]

Peroxisome proliferator-activated receptor-γ agonists attenuate biofilm formation by Pseudomonas aeruginosa.

FASEB J. 2017 Apr 25;:

Authors: Bedi B, Maurice NM, Ciavatta VT, Lynn KS, Yuan Z, Molina SA, Joo M, Tyor WR, Goldberg JB, Koval MH, Hart CM, Sadikot RT

Abstract
Pseudomonas aeruginosa is a significant contributor to recalcitrant multidrug- resistant infections, especially in immunocompromised and hospitalized patients. The pathogenic profile of P. aeruginosa is related to its ability to secrete a variety of virulence factors and to promote biofilm formation. Quorum sensing (QS) is a mechanism wherein P. aeruginosa secretes small diffusible molecules, specifically acyl homo serine lactones, such as N-(3-oxo-dodecanoyl)-l-homoserine lactone (3O-C12-HSL), that promote biofilm formation and virulence via interbacterial communication. Strategies that strengthen the host's ability to inhibit bacterial virulence would enhance host defenses and improve the treatment of resistant infections. We have recently shown that peroxisome proliferator-activated receptor γ (PPARγ) agonists are potent immunostimulators that play a pivotal role in host response to virulent P. aeruginosa Here, we show that QS genes in P. aeruginosa (PAO1) and 3O-C12-HSL attenuate PPARγ expression in bronchial epithelial cells. PAO1 and 3O-C12-HSL induce barrier derangements in bronchial epithelial cells by lowering the expression of junctional proteins, such as zonula occludens-1, occludin, and claudin-4. Expression of these proteins was restored in cells that were treated with pioglitazone, a PPARγ agonist, before infection with PAO1 and 3O-C12-HSL. Barrier function and bacterial permeation studies that have been performed in primary human epithelial cells showed that PPARγ agonists are able to restore barrier integrity and function that are disrupted by PAO1 and 3O-C12-HSL. Mechanistically, we show that these effects are dependent on the induction of paraoxonase-2, a QS hydrolyzing enzyme, that mitigates the effects of QS molecules. Importantly, our data show that pioglitazone, a PPARγ agonist, significantly inhibits biofilm formation on epithelial cells by a mechanism that is mediated via paraoxonase-2. These findings elucidate a novel role for PPARγ in host defense against P. aeruginosa Strategies that activate PPARγ can provide a therapeutic complement for treatment of resistant P. aeruginosa infections.-Bedi, B., Maurice, N. M., Ciavatta, V. T., Lynn, K. S., Yuan, Z., Molina, S. A., Joo, M., Tyor, W. R., Goldberg, J. B., Koval, M., Hart, C. M., Sadikot, R. T. Peroxisome proliferator-activated receptor-γ agonists attenuate biofilm formation by Pseudomonas aeruginosa.

PMID: 28442545 [PubMed - as supplied by publisher]

The role of neutrophil elastase inhibitors in lung diseases.

Chest. 2017 Apr 22;:

Authors: Polverino E, Rosales-Mayor E, Dale GE, Dembowsky K, Torres A

Abstract
In many respiratory diseases characterised by an intense inflammatory response, the balance between proteolytic enzymes (proteases, including elastases) and their inhibitors (proteinases inhibitors) is not neutral. In fact, an excess activity of neutrophil elastase (NE) and similar proteases has been reported to cause tissue damage and to alter the remodelling process in many clinical conditions such as pneumonia, respiratory distress and acute lung injury [ALI]. In recent years, several experimental NE inhibitors have been tested in preclinical and clinical studies of different conditions of inflammatory lung injury such as ALI and pneumonia, with contrasting results. This study reviews the literature regarding NE inhibitors in the field of respiratory diseases and reflects on possible future developments. In particular, we highlight potential gaps in the current scientific evidence and discuss potential strategies for focusing investigation on anti-elastases in clinical practice through the selection of targeted populations and proper outcomes.

PMID: 28442313 [PubMed - as supplied by publisher]

Sleep Phase Delay in Cystic Fibrosis: A Potential New Manifestation of Cystic Fibrosis Transmembrane Regulator Dysfunction.

Chest. 2017 Apr 22;:

Authors: Jensen JL, Jones CR, Kartsonaki C, Packer KA, Adler FR, Liou TG

Abstract
BACKGROUND: Cystic fibrosis (CF) transmembrane regulator (CFTR) protein dysfunction causes CF. Improving survival allows detection of increasingly subtle disease manifestations. CFTR dysfunction in the central nervous system (CNS) may disturb circadian rhythm and thus sleep phase. We studied sleep in adults to better understand potential CNS CFTR dysfunction.
METHODS: We recruited participants from April 2012 through April 2015 and administered the Munich Chronotype Questionnaire (MCTQ). We compared free-day sleep measurements between CF and non-CF participants and investigated associations with CF survival predictors.
RESULTS: We recruited 23 female and 22 male adults with CF aged 18-46 years and 26 female and 22 male volunteers aged 18-45 years. Compared to non-CF volunteers, patients with CF had delayed sleep-onset (0.612 hrs, P = 0.015), mid-sleep (1.11 hrs, P < 0.001) and wake-up (1.15 hrs, P < 0.001) times and prolonged sleep latency (7.21 min, P = 0.05) and duration (0.489 hr, P = 0.05). Every hour delay in sleep-onset time was associated with shorter sleep duration by 0.29 hours in CF and 0.75 hours in non-CF (P = 0.007) and longer sleep latency by 0.15 hours in CF and 0.05 in non-CF (P = 0.035). Among patients with CF, FEV1%, prior acute pulmonary exacerbations and weight were independent of all free-day sleep measurements.
CONCLUSION: CF in adults is associated with marked delays in sleep phase consistent with circadian rhythm phase delays. Independence from disease characteristics predictive of survival suggests that sleep phase delay is a primary manifestation of CFTR dysfunction in the CNS.

PMID: 28442311 [PubMed - as supplied by publisher]

Feasibility and normal values of an integrated conductivity (Nanoduct™) sweat test system in healthy newborns.

J Cyst Fibros. 2017 Apr 22;:

Authors: Kuehni CE, Schindler M, Mazur A, Malzacher A, Hornung R, Barben J

Abstract
BACKGROUND: Nanoduct™ is a simple and practical sweat analysis system measuring conductivity in situ. It requires only three microlitres of sweat, making it especially applicable to newborns.
METHODS: We measured conductivity in 260 healthy term infants at the age of four days, and again at four weeks to determine the proportion of successful tests, test duration, and normal values for sweat conductivity in newborns.
RESULTS: Sufficient sweat was collected in 159/260 of four-day olds (61%), and in 225/239 of four-week olds (94%). Mean (sd) test duration was 27 (5) and 25 (5) min. Mean (sd, range) conductivity was 53mmol/l (16, 8-114) at age four days, and 36 (9, 12-64) at four weeks.
CONCLUSIONS: Determination of sweat conductivity using Nanoduct™ cannot be recommended for four-day old newborns. However, at the age of four weeks the success rate is high (94%), and conductivity values at that age are comparable to older healthy children.

PMID: 28442278 [PubMed - as supplied by publisher]

Carbamoyl phosphate synthetase 1 deficiency diagnosed by whole exome sequencing.

J Clin Lab Anal. 2017 Apr 26;:

Authors: Zhang G, Chen Y, Ju H, Bei F, Li J, Wang J, Sun J, Bu J

Abstract
BACKGROUND: Carbamoyl Phosphate Synthetase 1 deficiency (CPS1D) is a rare autosomal recessive inborn metabolic disease characterized mainly by hyperammonemia. The fatal nature of CPS1D and its similar symptoms with other urea cycle disorders (UCDs) make its diagnosis difficult, and the molecular diagnosis is hindered due to the large size of the causative gene CPS1. Therefore, the objective of the present study was to investigate the clinical applicability of exome sequencing in molecular diagnosis of CPS1D in Chinese population.
METHODS: We described two Chinese neonates presented with unconsciousness and drowsiness due to deepening encephalopathy with hyperammonemia. Whole exome sequencing was performed. Candidate mutations were validated by Sanger sequencing. In-silicon analysis was processed for the pathogenicity predictions of the identified mutations.
RESULTS: Two compound heterozygous mutations in the gene carbamoyl phosphate synthetase 1(CPS1) were identified. One is in Case 1 with two novel missense mutations (c.2537C>T, p. Pro846Leu and c.3443T>A, p.Met1148Lys), and the other one is in Case 2 with a novel missense mutation (c.1799G>A, p.Cys600Tyr) and a previously reported 12-bp deletion (c.4088_4099del, p.Leu 1363_Ile1366del). Bioinformatics deleterious predictions indicated pathogenicity of the missense mutations. Conversation analysis and homology modeling showed that the substituted amino acids were highly evolutionary conserved and necessary for enzyme stability or function.
CONCLUSION: The present study initially and successfully applied whole exome sequencing to the molecular diagnosis of CPS1D in Chinese neonates, indicating its applicability in cost-effective molecular diagnosis of CPS1D. Three novel pathogenic missense mutations were identified, expanded the mutational spectrum of the CPS1 gene.

PMID: 28444906 [PubMed - as supplied by publisher]

Novel SLC25A32 mutation in a patient with a severe neuromuscular phenotype.

Eur J Hum Genet. 2017 Apr 26;:

Authors: Hellebrekers DMEI, Sallevelt SCEH, Theunissen TEJ, Hendrickx ATM, Gottschalk RW, Hoeijmakers JGJ, Habets DD, Bierau J, Schoonderwoerd KG, Smeets HJM

Abstract
In a 51-year-old patient of consanguineous parents with a severe neuromuscular phenotype of early-onset ataxia, myoclonia, dysarthria, muscle weakness and exercise intolerance, exome sequencing revealed a novel homozygous variant (c.-264_31delinsCTCACAAATGCTCA) in the mitochondrial FAD-transporter gene SLC25A32. Flavin adenine dinucleotide (FAD) is an essential co-factor for many mitochondrial enzymes and impaired mitochondrial FAD-transport was supported by a reduced oxidative phosphorylation complex II activity in the patient's muscle, decreased ATP production in fibroblasts, and a deficiency of mitochondrial FAD-dependent enzymes. Clinically, the patient showed improvement upon riboflavin treatment, which is a precursor of FAD. Our results confirm the recently reported case of SLC25A32 as a cause of riboflavin-responsive disease. Our patient showed a more severe clinical phenotype compared with the reported patient, corresponding with the (most likely) complete absence of the SLC25A32-encoding MFT (Mitochondrial Folate Transporter) protein.European Journal of Human Genetics advance online publication, 26 April 2017; doi:10.1038/ejhg.2017.62.

PMID: 28443623 [PubMed - as supplied by publisher]

Next-Gen Sequencing Analysis and Algorithms for PDX and CDX Models.

Mol Cancer Res. 2017 Apr 25;:

Authors: Khandelwal G, Girotti MR, Smowton C, Taylor S, Wirth C, Dynowski M, Frese KK, Brady G, Dive C, Marais R, Miller C

Abstract
Patient-derived xenograft (PDX) and CTC-derived explant (CDX) models are powerful methods for the study of human disease. In cancer research, these methods have been applied to multiple questions including the study of metastatic progression, genetic evolution and therapeutic drug responses. Since PDX and CDX models can recapitulate the highly heterogeneous characteristics of a patient tumor, as well as their response to chemotherapy, there is considerable interest in combining them with next-generation sequencing (NGS) in order to monitor the genomic, transcriptional, and epigenetic changes that accompany oncogenesis. When used for this purpose, their reliability is highly dependent on being able to accurately distinguish between sequencing reads that originate from the host, and those that arise from the xenograft itself. Here we demonstrate that failure to correctly identify contaminating host reads, when analyzing DNA- and RNA-sequencing (DNA-Seq and RNA-Seq) data from PDX and CDX models is a major confounding factor that can lead to incorrect mutation calls and a failure to identify canonical mutation signatures associated with tumorigenicity. In addition, a highly sensitive algorithm and open source software tool for identifying and removing contaminating host sequences is described. Importantly, when applied to PDX and CDX models of melanoma, these data demonstrate its utility as a sensitive and selective tool for the correction of PDX- and CDX-derived whole exome and RNA-Seq data.
IMPLICATIONS: This study describes a sensitive method to identify contaminating host reads in xenograft and explant DNA and RNA sequencing data, and is applicable to other forms of deep sequencing.

PMID: 28442585 [PubMed - as supplied by publisher]

Missense mutations in the WD40 domain of AHI1 cause non-syndromic retinitis pigmentosa.

J Med Genet. 2017 Apr 25;:

Authors: Nguyen TT, Hull S, Roepman R, van den Born LI, Oud MM, de Vrieze E, Hetterschijt L, Letteboer SJF, van Beersum SEC, Blokland EA, Yntema HG, Cremers FPM, van der Zwaag PA, Arno G, van Wijk E, Webster AR, Haer-Wigman L

Abstract
BACKGROUND: Recent findings suggesting that Abelson helper integration site 1 (AHI1) is involved in non-syndromic retinal disease have been debated, as the functional significance of identified missense variants was uncertain. We assessed whether AHI1 variants cause non-syndromic retinitis pigmentosa (RP).
METHODS: Exome sequencing was performed in three probands with RP. The effects of the identified missense variants in AHI1 were predicted by three-dimensional structure homology modelling. Ciliary parameters were evaluated in patient's fibroblasts, and recombinant mutant proteins were expressed in ciliated retinal pigmented epithelium cells.
RESULTS: In the three patients with RP, three sets of compound heterozygous variants were detected in AHI1 (c.2174G>A; p.Trp725* and c.2258A>T; p.Asp753Val, c.660delC; p.Ser221Glnfs*10 and c.2090C>T; p.Pro697Leu, c.2087A>G; p.His696Arg and c.2429C>T; p.Pro810Leu). All four missense variants were present in the conserved WD40 domain of Jouberin, the ciliary protein encoded by AHI1, with variable predicted implications for the domain structure. No significant changes in the percentage of ciliated cells, nor in cilium length or intraflagellar transport were detected. However, expression of mutant recombinant Jouberin in ciliated cells showed a significantly decreased enrichment at the ciliary base.
CONCLUSIONS: This report confirms that mutations in AHI1 can underlie autosomal recessive RP. Moreover, it structurally and functionally validates the effect of the RP-associated AHI1 variants on protein function, thus proposing a new genotype-phenotype correlation for AHI1 mutation associated retinal ciliopathies.

PMID: 28442542 [PubMed - as supplied by publisher]

The pharmacotherapy of cirrhosis: concerns and proposed investigations and solutions.

J Clin Pharm Ther. 2016 Dec;41(6):587-591

Authors: Hilscher MB, Odell LJ, Myhre LJ, Prokop L, Talwalkar J

Abstract
WHAT IS KNOWN AND OBJECTIVE: The presence of cirrhosis has a multifaceted impact on hepatic drug metabolism. An area of concern and uncertainty in the care of patients with cirrhosis is the safe use of both prescription and over-the-counter medications.
COMMENT: Retrospective studies indicate a high incidence of adverse drug reactions (ADRs) among patients with cirrhosis related to use of certain medication classes including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and non-steroidal anti-inflammatory drugs. Conversely, use of appropriate medications, such as statins, may be decreased in this population due to fear of precipitating hepatotoxicity.
WHAT IS NEW AND CONCLUSION: Pharmacotherapy in cirrhosis is an area of uncertainty and heterogeneity in clinical practice. Prescribing and dosing guidelines are needed to decrease the risk of serious ADRs in this high-risk patient population.

PMID: 27576303 [PubMed - indexed for MEDLINE]

Letter in response to "Efficacy and effectiveness of anti-digoxin antibodies in chronic digoxin poisonings from the DORA study (ATOM-1)".

Clin Toxicol (Phila). 2017 01;55(1):63

Authors: Wang JJ, Regina A, Hoffman RS

PMID: 27491930 [PubMed - indexed for MEDLINE]

Further evidence that a variant of the gene NUDT15 may be an important predictor of azathioprine-induced toxicity in Chinese subjects: a case report.

J Clin Pharm Ther. 2016 Oct;41(5):572-4

Authors: Ailing Z, Jing Y, Jingli L, Yun X, Xiaojian Z

Abstract
WHAT IS KNOWN AND OBJECTIVE: Thiopurine methyltransferase (TPMT) enzyme is an important component in the metabolism of azathioprine (AZA). Its mutation may lead to AZA-induced toxicity. The dysfunctional genetic variant TPMT *3C is of low frequency among Asians. Moreover, AZA-induced toxicity still occurs in some patients with normal TPMT activity. This suggests that additional factors, including other genetic variants, may contribute to such toxicity. Recent studies described a strong association between a variant of the NUDT15, a gene that mediates the hydrolysis of some nucleoside diphosphate derivatives, and thiopurine-related myelosuppression in Asians. We report the first case of a Chinese patient with AZA-induced severe toxicity with no clinically significant TPMT variant but with the NUDT15 c.415C>T allele.
CASE SUMMARY: A 40-year-old Chinese patient with PBC-AIH overlap syndrome had been receiving for one month, azathioprine (50 mg/day) and methylprednisolone (24 mg/day) based on his TPMT*3C wild-type genotype. The patient developed serious myelosuppression and hair loss. AZA was stopped, and the patient was given liver-protective drugs and supportive treatment. TPMT and NUDT15 gene sequencing suggests that NUDT15 c.415C>T mutation was the likely cause of the adverse reaction.
WHAT IS NEW AND CONCLUSION: NUDT15 c.415C>T may be another predictor of AZA-induced leukocytopenia. If further well-controlled studies validate this association with sufficient predictive power, NUDT15 and TPMT genotyping before starting AZA treatment may become appropriate.

PMID: 27381176 [PubMed - indexed for MEDLINE]

Anticholinergic medicines in an older primary care population: a cross-sectional analysis of medicines' levels of anticholinergic activity and clinical indications.

J Clin Pharm Ther. 2016 Oct;41(5):486-92

Authors: Magin PJ, Morgan S, Tapley A, McCowan C, Parkinson L, Henderson KM, Muth C, Hammer MS, Pond D, Mate KE, Spike NA, McArthur LA, van Driel ML

Abstract
WHAT IS KNOWN AND OBJECTIVES: Adverse clinical outcomes have been associated with cumulative anticholinergic burden (to which low-potency as well as high-potency anticholinergic medicines contribute). The clinical indications for which anticholinergic medicines are prescribed (and thus the 'phenotype' of patients with anticholinergic burden) have not been established. We sought to establish the overall prevalence of prescribing of anticholinergic medicines, the prevalence of prescribing of low-, medium- and high-potency anticholinergic medicines, and the clinical indications for which the medicines were prescribed in an older primary care population.
METHODS: This was a cross-sectional analysis of a cohort study of Australian early-career general practitioners' (GPs') clinical consultations - the Registrar Clinical Encounters in Training (ReCEnT) study. In ReCEnT, GPs collect detailed data (including medicines prescribed and their clinical indication) for 60 consecutive patients, on up to three occasions 6 months apart. Anticholinergic medicines were categorized as levels 1 (low-potency) to 3 (high-potency) using the Anticholinergic Drug Scale (ADS).
RESULTS: During 2010-2014, 879 early-career GPs (across five of Australia's six states) conducted 20 555 consultations with patients aged 65 years or older, representing 35 506 problems/diagnoses. Anticholinergic medicines were prescribed in 10·4% [95% CIs 9·5-10·5] of consultations. Of the total anticholinergic load of prescribed medicines ('community anticholinergic load') 72·7% [95% CIs 71·0-74·3] was contributed by Level 1 medicines, 0·8% [95% CIs 0·5-1·3] by Level 2 medicines and 26·5% [95% CIs 24·8-28·1] by Level 3 medicines. Cardiac (40·0%), Musculoskeletal (16·9%) and Respiratory (10·6%) were the most common indications associated with Level 1 anticholinergic prescription. For Level 2 and 3 medicines (combined data), Psychological (16·1%), Neurological (16·1%), Musculoskeletal (15·7%) and Urological (11·1%) indications were most common.
WHAT IS NEW AND CONCLUSION: Anticholinergic medicines are frequently prescribed in Australian general practice, and the majority of the 'community' anticholinergic burden is contributed by 'low'-anticholinergic potency medicines whose anticholinergic effects may be largely 'invisible' to prescribing GPs. Furthermore, the clinical 'phenotype' of the patient with high anticholinergic burden may be very different to common stereotypes (patients with urological, psychological or neurological problems), potentially making recognition of risk of anticholinergic adverse effects additionally problematic for GPs.

PMID: 27349795 [PubMed - indexed for MEDLINE]

Comparison of high-dose intravenous immunoglobulin (IVIG) in a 5% and a 10% solution does not reveal a significantly different spectrum of side-effects.

J Eur Acad Dermatol Venereol. 2016 Dec;30(12):e186-e188

Authors: Rappold LC, Denk K, Enk AH, Hadaschik EN

PMID: 26551028 [PubMed - indexed for MEDLINE]