Baby genome screening needs more time to gestate.

Science. 2016 Oct 28;354(6311):398-399

Authors: Kaiser J

PMID: 27789817 [PubMed - indexed for MEDLINE]

Rare Head and Neck Tumors Resulting in Upper Airway Compromise.

Pediatr Emerg Care. 2016 Sep;32(9):648-9

Authors: Gupton T

PMID: 27585129 [PubMed - indexed for MEDLINE]

Neutrophilic progression in a case of polycytemia vera mimicking chronic neutrophilic leukemia: clinical and molecular characterization.

Pathol Res Pract. 2015 Apr;211(4):341-3

Authors: Castelli R, Cugno M, Gianelli U, Pancrazzi A, Vannucchi AM

Abstract
BACKGROUND: In a small subset of polycytemia vera (PV), neutrophilia not secondary to reactive conditions or treatment can develop and persist. Clinical significance and morphogenetic alterations associated with this uncommon phenomenon are not well defined.
CASE REPORT: An 81-year-old Caucasian woman, affected by polycytemia vera lasting 17 years, presented in March 2012 with hyperleukocytosis, absolute neutrophilia, and thrombocytosis despite hydroxyurea treatment. All other laboratory parameters were normal, except for an increased neutrophil alkaline phosphatase and lactate dehydrogenase. Reactive neutrophilia due to infection or neoplasia have been ruled out by a total body computerized tomography scan, and by low levels of C reactive protein. Re-evaluation of bone marrow showed hypercellular smears with expansion of granulopoiesis while immature granulocytes were <10% and myeloblasts were <1%. Bone marrow trephine biopsy showed hypercellular marrow, with panmyelosis, increased myeloid/erithroid ratio, polymorphic clusters of megakaryocytes. A loose network of reticulin fibers with many intersections was identified by means of Gomori's silver impregnation. There were no hybrid BCR/ABL gene transcripts of p210, p190 and p230, no mutations in platelet derived growth factor receptors alpha and beta. Flow cytometry on the aspirate showed that CD34+ CD117+ myeloblasts constituted less than 1% of total marrow nucleated cells, mature granulocytes demonstrated persistent expression of CD33. Mutational analysis of the gene CSF3R by PCR amplification revealed no alterations in exons 14-17, including codons 615 and 618. The case presented here represents a possible evolution of PV, albeit very rare.
CONCLUSIONS: The condition described here differs from the CNL for the persistence of morphological pictures typical of myeloproliferative diseases, for absence of CSF3R gene mutations and for the hyper expansion of the mature granulopoietic series. The clinical significance and morphogenetic alterations associated with this uncommon phenomenon are not well defined.

PMID: 25480691 [PubMed - indexed for MEDLINE]

Tracheobronchopathia osteochondroplastica: a review of the literature.

Clin Respir J. 2015 Oct;9(4):386-91

Authors: Ulasli SS, Kupeli E

Abstract
BACKGROUND: Tracheobronchopathia osteochondroplastica (TBPOCP) is an uncommon benign condition affecting the lumen of tracheobronchial tree and characterized by abnormal chondrification and ossification. TBPOCP is more frequent than it has been reported, as it can be asymptomatic or present with non-specific respiratory symptoms.
AIMS: In this article, we provide a review of the English literature on the condition and discuss its clinical features, general principles, diagnostic approaches and current treatment recommendations for TBPOCP.
METHODS: We searched for all papers indexed in Science Citation Index and Science Citation Index - Expanded by using Thomson Reuters Web of Knowledge Web of Science software.
RESULTS: We reviewed a total of 72 scientific publications.
CONCLUSION: In order to highlight, diagnosis, treatment and treatment outcomes of TBPOCP, further review articles and large case series about this orphan disease are needed.

PMID: 24865333 [PubMed - indexed for MEDLINE]

Methylomic changes in individuals with psychosis, prenatally exposed to endocrine disrupting compounds: Lessons from diethylstilbestrol.

PLoS One. 2017;12(4):e0174783

Authors: Rivollier F, Chaumette B, Bendjemaa N, Chayet M, Millet B, Jaafari N, Barhdadi A, Lemieux Perreault LP, Provost S, Dubé MP, Gaillard R, Krebs MO, Kebir O

Abstract
BACKGROUND: In the Western world, between 1940 and 1970, more than 2 million people were exposed in utero to diethylstilbestrol (DES). In exposed individuals, and in their descendants, adverse outcomes have been linked to such exposure, including cancers, genital malformations, and less consistently, psychiatric disorders. We aimed to explore whether prenatal DES exposure would be associated with DNA methylation changes, and whether these epigenetic modifications would be associated with increased risk of psychosis.
METHODS: From 247 individuals born from mothers exposed to DES, we selected 69 siblings from 30 families. In each family, at least one sibling was exposed in utero to DES. We performed a methylome-wide association study using HumanMethylation450 DNA Analysis BeadChip® in peripheral blood. We analyzed methylation changes at individual CpGs or regions in exposed (n = 37) versus unexposed individuals (n = 32). We also compared exposed individuals with (n = 7) and without psychosis (n = 30).
RESULTS: There were more individuals with schizophrenia in the DES-exposed group. We found no significant differences between exposed and unexposed individuals with respect to differentially methylated CpGs or regions. The largest difference was in a region near the promoter of an ADAMTS proteoglycanase gene (ADAMTS9). Compared to exposed individuals without psychosis, exposed individuals with psychosis had differential methylation in the region encompassing the gene encoding the zinc finger protein 57 (ZFP57).
CONCLUSIONS: In utero exposure to DES was not associated with methylation changes at specific CpG or regions. In exposed individuals, however, psychosis was associated with specific methylomic modifications that could impact neurodevelopment and neuroplasticity.

PMID: 28406917 [PubMed - in process]

Hepatitis C virus pharmacogenomics in Latin American populations: implications in the era of direct-acting antivirals.

Pharmgenomics Pers Med. 2017;10:79-91

Authors: Trinks J, Caputo M, Hulaniuk ML, Corach D, Flichman D

Abstract
In recent years, great progress has been made in the field of new therapeutic options for hepatitis C virus (HCV) infection. The new direct-acting antiviral agents (DAAs) represent a great hope for millions of chronically infected individuals because their use may lead to excellent cure rates with fewer side effects. In Latin America, the high prevalence of HCV genotype 1 infection and the significant association of Native American ancestry with risk predictive single-nucleotide polymorphisms (SNPs) in IFNL4 and ITPA genes highlight the need to implement new treatment regimens in these populations. However, the universal accessibility to DAAs is still not a reality in the region as their high cost is one of the major, although not the only, limiting factors for their broad implementation. Therefore, under these circumstances, could the assessment of host genetic markers be a useful tool to prioritize DAA treatment until global access to these new drugs can be achieved? This review will summarize the scientific evidences and the potential implications of HCV pharmacogenomics in this rapidly evolving era of anti-HCV drug development.

PMID: 28405170 [PubMed - in process]

Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial.

Lancet Gastroenterol Hepatol. 2016 Dec;1(4):273-282

Authors: Mowat C, Arnott I, Cahill A, Smith M, Ahmad T, Subramanian S, Travis S, Morris J, Hamlin J, Dhar A, Nwokolo C, Edwards C, Creed T, Bloom S, Yousif M, Thomas L, Campbell S, Lewis SJ, Sebastian S, Sen S, Lal S, Hawkey C, Murray C, Cummings F, Goh J, Lindsay JO, Arebi N, Potts L, McKinley AJ, Thomson JM, Todd JA, Collie M, Dunlop MG, Mowat A, Gaya DR, Winter J, Naismith GD, Ennis H, Keerie C, Lewis S, Prescott RJ, Kennedy NA, Satsangi J, TOPPIC Study Group

Abstract
BACKGROUND: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease.
METHODS: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15).
FINDINGS: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27-1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28-0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04-0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42-1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group.
INTERPRETATION: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence.
FUNDING: Medical Research Council.

PMID: 28404197 [PubMed - in process]

A plea for TDM-based optimisation for treatment of Crohn's disease - Authors' reply.

Lancet Gastroenterol Hepatol. 2017 Feb;2(2):81-82

Authors: Kennedy NA, Keerie C, Mowat C, Satsangi J

PMID: 28403991 [PubMed - in process]

Pharmacogenetics of aromatase inhibitors in endocrine responsive breast cancer: lessons learnt from tamoxifen and CYP2D6 genotyping.

Anticancer Agents Med Chem. 2017 Apr 12;:

Authors: Baatjes KJ, Conradie M, Apffelstaedt JP, Kotze M

Abstract
BACKGROUND: Genetics play a significant role in drug metabolism of endocrine therapy of breast cancer. These aspects have been studied extensively in patients on tamoxifen, but the pharmacogenetics of aromatase inhibitors are less established. In contrast to the protective effect of tamoxifen, aromatase inhibitors are linked with an increased risk for bone loss and fractures.
OBJECTIVE: This review outlines key issues around implementation of pharmacogenetics of cytochrome P450 and tamoxifen as a model for optimal use of aromatase inhibitors in postmenopausal women with estrogen receptor positive breast cancer.
METHODS: Lessons learnt from the association between tamoxifen and CYP2D6 genotyping were applied to identify polymorphisms with the potential to change clinical decision-making in patients on aromatase inhibitors. The ability of next generation sequencing to supersede single-gene analysis was furthermore evaluated in a subset of breast cancer patients on aromatase inhibitors selected from a central genomics database.
RESULTS: Methodological flaws in major randomised controlled trials and continued referral to incorrect results in expert consensus statements are important factors delaying the implementation of CYP2D6 pharmacogenetics in tamoxifen treatment. This highlighted the importance of a clinical pipeline including comprehensive genotyping, to define the target population most likely to benefit from aromatase inhibitor pharmacogenetics.
CONCLUSION: The clinical utility of CYP2D6 genotyping is well-established in patients at increased risk of tamoxifen resistance due to cumulative risk. The pharmacogenetics of CYP19A1 requires further clarification in terms of bone risk assessment for appropriate use in the treatment algorithm of high-risk patients at the onset of aromatase inhibitors.

PMID: 28403774 [PubMed - as supplied by publisher]

Molecular detection and species identification of Enterocytozoon bieneusi isolated from immunocompetent Orang Asli in Malaysia.

Parasitol Int. 2017 Apr;66(2):163-165

Authors: Ashikin A, Al-Mekhlafi HM, Moktar N, Anuar TS

Abstract
Most studies of opportunistic infections focus on immunocompromised patients. However, there is a lack of information on microsporidiosis in healthy people (immunocompetent) worldwide. This study aimed to detect and identify microsporidia species in immunocompetent Orang Asli living in Pahang, Malaysia. Orang Asli is a collective term for a group of indigenous people that usually reside in the interior regions of Peninsular Malaysia. They comprise about 0.7% of the total population in Malaysia and 76% of them lived below the poverty line i.e., poor housing conditions with the lack of access to safe drinking water and adequate sanitation, contaminated environment, high illiteracy rate and unhygienic practices by these people. Stool samples were collected from 209 Orang Asli and analyzed for detecting the presence of Enterocytozoon bieneusi and Encephalitozoon intestinalis by polymerase chain reaction assay targeting small subunit ribosomal RNA gene. E. bieneusi was detected in 8 individuals (3.83%). This infection was commonly found in males than females (5.2% vs. 2.7%). All infected Orang Asli were adults, with a mean age of 44years. Diarrhea and other gastrointestinal symptoms were reported in one case (12.5%) among individuals infected with this species. These findings clearly show that exposure to E. bieneusi may actually be common than reported. The accurate detection and identification of microsporidian species by molecular technique will improve therapy, clinical manifestations and prognosis of this infection, as no antiparasitic therapy has been approved for E. bieneusi. It is hoped that these findings will allow the formulation of better health management and disease prevention advisories, and improvement in the standards of health in similar communities.

PMID: 28115231 [PubMed - indexed for MEDLINE]

Cereblon and IRF4 Variants Affect Risk and Response to Treatment in Multiple Myeloma.

Arch Immunol Ther Exp (Warsz). 2016 Dec;64(Suppl 1):151-156

Authors: Butrym A, Łacina P, Rybka J, Chaszczewska-Markowska M, Mazur G, Bogunia-Kubik K

Abstract
Multiple myeloma (MM) is a plasma-cell malignancy derived from an early precursor of the B-cell lineage characterised by bone-marrow infiltration, lytic bone lesions, and the presence of a monoclonal protein in serum and/or urine. Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B-cell development and function that is required during immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells. Immunomodulatory drugs, derivatives of thalidomide, are commonly used in therapy against MM. They are known to target a protein called cereblon (CRBN); however, the exact mechanism remains unknown. The present study aimed to assess the association of two (rs12203592 and rs872071) polymorphisms within the IRF4 gene and two (rs711613 and rs1045433) in the CRBN gene with MM susceptibility, progression, and response to treatment. For this purpose, 144 MM patients and 126 healthy individuals were genotyped for the IRF4 and CRBN alleles. The presence of the IRF4 (rs872071) G allele was more frequently detected in patients than healthy individuals (OR 1.78; P = 0.034), and this relationship was especially pronounced in women (OR 2.83; P = 0.012). The CRBN (rs711613) A allele-carriers were better responders to the treatment (P = 0.012), in particular to thalidomide including therapy (P = 0.023). These results underline the prognostic significance of the IRF4 and CRBN polymorphisms in patients with MM.

PMID: 28083618 [PubMed - indexed for MEDLINE]

Significance of Polymorphism and Expression of miR-146a and NFkB1 Genetic Variants in Patients with Rheumatoid Arthritis.

Arch Immunol Ther Exp (Warsz). 2016 Dec;64(Suppl 1):131-136

Authors: Bogunia-Kubik K, Wysoczańska B, Piątek D, Iwaszko M, Ciechomska M, Świerkot J

Abstract
MicroRNA-146a (miR-146a) has been shown to play an important role in the regulation of inflammatory innate immune responses, and found to be differentially expressed in rheumatoid arthritis (RA). Through NF-κB pathway, this molecule is able to stimulate the release of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-17. It has been also suggested that single-nucleotide polymorphisms (SNPs) in miRNA sequences may alter miRNA expression and that miR-146a rs2910164 SNP may contribute to RA development. These observations prompted us to analyze the potential associations between the miR-146a-3p (rs2910164, G > C) and NFkB1 (rs28362491, ins/del ATTG) polymorphisms and miR-146a-5p expression in patients' sera in relation to clinical outcome of the treatment as well as predisposition to RA. Genotyping was performed in 111 patients and 130 healthy individuals while 16 controls and 13 RA patients (before and after three months of therapy with TNF-α inhibitors (TNFi)) were studied for the circulating miR-146a-5p serum expression level. Patients carrying the NFkB1 ins/ins genotype were characterized by worse response to TNFi treatment (p = 0.023). In patients, before TNFi therapy, expression levels of miR-146a-5p were less (0.422 ± 0.171) as compared to those detected after three months of treatment (1.809 ± 0.658, p = 0.033) and observed for healthy controls (5.302 ± 2.112, p = 0.048). Moreover, patients with higher circulating miR-146a-5p levels after three months of TNFi administration were more frequently carrying the rs2910164-C allele (p = 0.032). These results support the hypothesis that miR-146a might be involved in pathogenesis of RA and imply that miR-146a-3p polymorphism may be associated with miR-146a-5p levels in serum after anti-TNF-α treatment.

PMID: 28083614 [PubMed - indexed for MEDLINE]

An Association Between Functional Polymorphisms of the Interleukin 1 Gene Complex and Schizophrenia Using Transmission Disequilibrium Test.

Arch Immunol Ther Exp (Warsz). 2016 Dec;64(Suppl 1):161-168

Authors: Kapelski P, Skibinska M, Maciukiewicz M, Pawlak J, Dmitrzak-Weglarz M, Szczepankiewicz A, Zaremba D, Twarowska-Hauser J

Abstract
IL1 gene complex has been implicated in the etiology of schizophrenia. To assess whether IL1 gene complex is associated with susceptibility to schizophrenia in Polish population we conducted family-based study. Functional polymorphisms from IL1A (rs1800587, rs17561, rs11677416), IL1B (rs1143634, rs1143643, rs16944, rs4848306, rs1143623, rs1143633, rs1143627) and IL1RN (rs419598, rs315952, rs9005, rs4251961) genes were genotyped in 143 trio with schizophrenia. Statistical analysis was performed using transmission disequilibrium test. We have found a trend toward an association of rs1143627, rs16944, rs1143623 in IL1B gene with the risk of schizophrenia. Our results show a protective effect of allele T of rs4251961 in IL1RN against schizophrenia. We also performed haplotype analysis of IL1 gene complex and found a trend toward an association with schizophrenia of GAGG haplotype (rs1143627, rs16944, rs1143623, rs4848306) in IL1B gene, haplotypes: TG (rs315952, rs9005) and TT (rs4251961, rs419598) in IL1RN. Haplotype CT (rs4251961, rs419598) in IL1RN was found to be associated with schizophrenia. After correction for multiple testing associations did not reach significance level. Our results might support theory that polymorphisms of interleukin 1 complex genes (rs1143627, rs16944, rs1143623, rs4848306 in IL1B gene and rs4251961, rs419598, rs315952, rs9005 in IL1RN gene) are involved in the pathogenesis of schizophrenia, however, none of the results reach significance level after correction for multiple testing.

PMID: 28083609 [PubMed - indexed for MEDLINE]

Diagnosis of biofilm infections in cystic fibrosis patients.

APMIS. 2017 Apr;125(4):339-343

Authors: Høiby N, Bjarnsholt T, Moser C, Jensen PØ, Kolpen M, Qvist T, Aanaes K, Pressler T, Skov M, Ciofu O

Abstract
Chronic Pseudomonas aeruginosa biofilm lung infection in cystic fibrosis patients is the best described biofilm infection in medicine. The initial focus can be the paranasal sinuses and then follows repeated colonization and infection of the lungs by aspiration. The matrix of the biofilms is dominated by alginate and the pathogenesis of tissue damage is immune complex-mediated chronic inflammation dominated by polymorphonuclear leukocytes and their products (DNA, oxygen radicals and proteases). The P. aeruginosa biofilm infection can be diagnosed by microscopy of lung tissue, sputum and mucus from the paranasal sinuses, where aggregates of the bacteria are found surrounded by the abundant alginate matrix. Specific PNA-FISH probes can be used to identify P. aeruginosa and other pathogens in situ in the biofilms. Growth of mucoid colonies from the locations mentioned above is also diagnostic for biofilm infection. Rise of specific anti-P. aeruginosa antibodies is likewise diagnostic, IgG in serum in case of lung infection, sIgA in saliva or nasal secretions in case of paranasal sinus infection. Similar approaches have been developed to diagnose chronic biofilm infections in cystic fibrosis caused by other pathogens e.g., Stenotrophomonas, Burkholderia multivorans, Achromobacter xylosoxidans and Mycobacterium abscessus complex.

PMID: 28407432 [PubMed - in process]

Biofilms and host response - helpful or harmful.

APMIS. 2017 Apr;125(4):320-338

Authors: Moser C, Pedersen HT, Lerche CJ, Kolpen M, Line L, Thomsen K, Høiby N, Jensen PØ

Abstract
Biofilm infections are one of the modern medical world's greatest challenges. Probably, all non-obligate intracellular bacteria and fungi can establish biofilms. In addition, there are numerous biofilm-related infections, both foreign body-related and non-foreign body-related. Although biofilm infections can present in numerous ways, one common feature is involvement of the host response with significant impact on the course. A special characteristic is the synergy of the innate and the acquired immune responses for the induced pathology. Here, we review the impact of the host response for the course of biofilm infections, with special focus on cystic fibrosis, chronic wounds and infective endocarditis.

PMID: 28407429 [PubMed - in process]

Microenvironmental characteristics and physiology of biofilms in chronic infections of CF patients are strongly affected by the host immune response.

APMIS. 2017 Apr;125(4):276-288

Authors: Jensen PØ, Kolpen M, Kragh KN, Kühl M

Abstract
In vitro studies of Pseudomonas aeruginosa and other pathogenic bacteria in biofilm aggregates have yielded detailed insight into their potential growth modes and metabolic flexibility under exposure to gradients of substrate and electron acceptor. However, the growth pattern of P. aeruginosa in chronic lung infections of cystic fibrosis (CF) patients is very different from what is observed in vitro, for example, in biofilms grown in flow chambers. Dense in vitro biofilms of P. aeruginosa exhibit rapid O2 depletion within <50-100 μm due to their own aerobic metabolism. In contrast, in vivo investigations show that P. aeruginosa persists in the chronically infected CF lung as relatively small cell aggregates that are surrounded by numerous PMNs, where the activity of PMNs is the major cause of O2 depletion rendering the P. aeruginosa aggregates anoxic. High levels of nitrate and nitrite enable P. aeruginosa to persist fueled by denitrification in the PMN-surrounded biofilm aggregates. This configuration creates a potentially long-term stable ecological niche for P. aeruginosa in the CF lung, which is largely governed by slow growth and anaerobic metabolism and enables persistence and resilience of this pathogen even under the recurring aggressive antimicrobial treatments of CF patients. As similar slow growth of other CF pathogens has recently been observed in endobronchial secretions, there is now a clear need for better in vitro models that simulate such in vivo growth patterns and anoxic microenvironments in order to help unravel the efficiency of existing or new antimicrobials targeting anaerobic metabolism in P. aeruginosa and other CF pathogens. We also advocate that host immune responses such as PMN-driven O2 depletion play a central role in the formation of anoxic microniches governing bacterial persistence in other chronic infections such as chronic wounds.

PMID: 28407427 [PubMed - in process]

A short history of microbial biofilms and biofilm infections.

APMIS. 2017 Apr;125(4):272-275

Authors: Høiby N

Abstract
The observation of aggregated microbes surrounded by a self-produced matrix adhering to surfaces or located in tissues or secretions is old since both Leeuwenhoek and Pasteur have described the phenomenon. In environmental and technical microbiology, biofilms, 80-90 years ago, were already shown to be important for biofouling on submerged surfaces, for example, ships. The concept of biofilm infections and their importance in medicine was, however, initiated in the early 1970s by the observation of heaps of Pseudomonas aeruginosa cells in sputum and lung tissue from chronically infected cystic fibrosis patients. The term biofilm was introduced into medicine in 1985 by J. W. Costerton. During the following decades, the number of published biofilm articles and methods for studying biofilms increased rapidly and it was shown that adhering and nonadhering biofilm infections are widespread in medicine. The medical importance of biofilm infections is now generally accepted and guidelines for prophylaxis, diagnosis, and treatment have been published.

PMID: 28407426 [PubMed - in process]

Antibiotic treatment of biofilm infections.

APMIS. 2017 Apr;125(4):304-319

Authors: Ciofu O, Rojo-Molinero E, Macià MD, Oliver A

Abstract
Bacterial biofilms are associated with a wide range of infections, from those related to exogenous devices, such as catheters or prosthetic joints, to chronic tissue infections such as those occurring in the lungs of cystic fibrosis patients. Biofilms are recalcitrant to antibiotic treatment due to multiple tolerance mechanisms (phenotypic resistance). This causes persistence of biofilm infections in spite of antibiotic exposure which predisposes to antibiotic resistance development (genetic resistance). Understanding the interplay between phenotypic and genetic resistance mechanisms acting on biofilms, as well as appreciating the diversity of environmental conditions of biofilm infections which influence the effect of antibiotics are required in order to optimize the antibiotic treatment of biofilm infections. Here, we review the current knowledge on phenotypic and genetic resistance in biofilms and describe the potential strategies for the antibiotic treatment of biofilm infections. Of note is the optimization of PK/PD parameters in biofilms, high-dose topical treatments, combined and sequential/alternate therapies or the use antibiotic adjuvants.

PMID: 28407419 [PubMed - in process]

Abnormal Rab11-Rab8-vesicles cluster in enterocytes of patients with Microvillus Inclusion Disease.

Traffic. 2017 Apr 13;:

Authors: Vogel GF, Janecke AR, Krainer IM, Gutleben K, Witting B, Mitton SG, Mansour S, Ballauff A, Roland JT, Engevik AC, Cutz E, Müller T, Goldenring JR, Huber LA, Hess MW

Abstract
Microvillus Inclusion Disease (MVID) is a congenital enteropathy characterized by accumulation of vesiculo-tubular endomembranes in the subapical cytoplasm of enterocytes, historically termed "secretory granules". However, neither their identity nor pathophysiological significance is well defined. Using immunoelectron microscopy and tomography we studied biopsies from MVID patients (3x Myosin 5b mutations, 1x Syntaxin3 mutation) and compared them to controls and genome-edited CaCo2 cell models, harboring relevant mutations. Duodenal biopsies from two patients with novel Myosin 5b mutations and typical clinical symptoms showed unusual ultrastructural phenotypes: aberrant subapical vesicles and tubules were prominent in the enterocytes, though other histological hallmarks of MVID were almost absent (ectopic intra-/intercellular microvilli, brush border atrophy). We identified these enigmatic vesiculo-tubular organelles as Rab11-Rab8-positive recycling compartments of altered size, shape and location harboring the apical SNARE Syntaxin3, apical transporters Sodium-Hydrogen Exchanger 3 (NHE3) and cystic fibrosis transmembrane conductance regulator (CFTR). Our data strongly indicate that in MVID disrupted trafficking between cargo vesicles and the apical plasma membrane is the primary cause of a defect of epithelial polarity and subsequent facultative loss of brush border integrity, leading to malabsorption. Furthermore, they support the notion that mislocalization of transporters, such as NHE3 substantially contributes to the reported sodium loss diarrhea.

PMID: 28407399 [PubMed - as supplied by publisher]

Clinical Outcomes Associated with Achromobacter Species Infection in Patients with Cystic Fibrosis.

Ann Am Thorac Soc. 2017 Apr 13;:

Authors: Somayaji R, Stanojevic S, Tullis DE, Stephenson AL, Ratjen F, Waters V

Abstract
RATIONALE: Achromobacter species are increasingly identified in individuals with cystic fibrosis (CF), but the clinical outcomes in these patients remain poorly understood.
OBJECTIVES: We aimed to determine the association of Achromobacter infection on clinical outcomes in pediatric and adult patients with CF.
METHODS: A cohort study of pediatric and adult CF patients was conducted from 1997 - 2014 in Toronto, Canada. Achromobacter spp infection was categorized as no history of infection, intermittent, and chronic infection (≥ 2 positive cultures in preceding 12 months). Cox models were used to estimate risk of death or transplantation. Mixed effects models were used to assess odds of pulmonary exacerbations (PEx) and effect on lung function (FEV1%) by Achromobacter spp category.
RESULTS: A total of 1103 patients were followed over 18 years; 88 patients (7.3%) had ≥ 1 culture for Achromobacter species. Chronic Achromobacter infection was associated with a greater risk of death or transplantation compared to patients with no history of infection (adjusted HR 2.03 [95% CI 1.05 - 3.95], p = 0.036). PEx were more common in patients with chronic infection but after adjusting for confounding factors, the effect was no longer significant. The chronic group had lower FEV1%, but it did not worsen after developing chronic infection.
CONCLUSIONS: Patients with CF and chronic Achromobacter infection are at increased risk of death or transplant.

PMID: 28406714 [PubMed - as supplied by publisher]