Publications by authors named "S Hakan Tuna"

77 Publications

The effectiveness of planned discharge education on health knowledge and beliefs in patients with acute myocardial infarction: a randomized controlled trial.

Ir J Med Sci 2021 Mar 17. Epub 2021 Mar 17.

Department of Nursing, Manisa Celal Bayar University, Manisa, Turkey.

Background: To the best of our knowledge, no other studies investigated acute myocardial infarction patients' beliefs and knowledge level after the discharge education.

Aims: The aim of the study was to investigate the effectiveness of planned discharge education on the beliefs and knowledge levels of CVD risk factors, medication compliance, dietary compliance, and individual follow-up in patients with acute myocardial infarction (AMI).

Methods: A double-blind randomized controlled study was carried out with 100 AMI patients. All participants were randomly assigned to the intervention (n = 50) and control groups (n = 50). The first evaluation of all participants in both groups was on the day of discharge. Both groups were re-evaluated after 4 weeks. Patients' beliefs on medication, diet, and individual monitoring were assessed by the Beliefs about Medication Compliance Scale (BMCS), the Beliefs about Dietary Compliance Scale (BDCS), and the Beliefs about Individual Follow-up Scale (BIFS), respectively. The knowledge of CVD risk factors was questioned with the Cardiovascular Disease Risk Factors Knowledge Level (CARRF-KL) Scale.

Results: The mean age of the patients was 59.10 ± 9.38 years in the intervention group and 58.86 ± 9.19 in the control group. After the planned discharge education, beliefs and knowledge levels of CVD risk factors, medication compliance, dietary compliance, and individual follow-up were significantly increased compared with the control group.

Conclusion: Planned discharge education had a positive effect on the knowledge level of cardiovascular diseases risk factors, drug compliance, nutritional compliance, and individual follow-up in patients with acute myocardial infarction.
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http://dx.doi.org/10.1007/s11845-021-02601-7DOI Listing
March 2021

Development and validation of a universal blood donor genotyping platform: a multinational prospective study.

Blood Adv 2020 08;4(15):3495-3506

Department of Pathology, Brigham and Women's Hospital, Boston, MA; and.

Each year, blood transfusions save millions of lives. However, under current blood-matching practices, sensitization to non-self-antigens is an unavoidable adverse side effect of transfusion. We describe a universal donor typing platform that could be adopted by blood services worldwide to facilitate a universal extended blood-matching policy and reduce sensitization rates. This DNA-based test is capable of simultaneously typing most clinically relevant red blood cell (RBC), human platelet (HPA), and human leukocyte (HLA) antigens. Validation was performed, using samples from 7927 European, 27 South Asian, 21 East Asian, and 9 African blood donors enrolled in 2 national biobanks. We illustrated the usefulness of the platform by analyzing antibody data from patients sensitized with multiple RBC alloantibodies. Genotyping results demonstrated concordance of 99.91%, 99.97%, and 99.03% with RBC, HPA, and HLA clinically validated typing results in 89 371, 3016, and 9289 comparisons, respectively. Genotyping increased the total number of antigen typing results available from 110 980 to >1 200 000. Dense donor typing allowed identification of 2 to 6 times more compatible donors to serve 3146 patients with multiple RBC alloantibodies, providing at least 1 match for 176 individuals for whom previously no blood could be found among the same donors. This genotyping technology is already being used to type thousands of donors taking part in national genotyping studies. Extraction of dense antigen-typing data from these cohorts provides blood supply organizations with the opportunity to implement a policy of genomics-based precision matching of blood.
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http://dx.doi.org/10.1182/bloodadvances.2020001894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422129PMC
August 2020

Author Correction: Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans.

Nat Commun 2020 07 22;11(1):3741. Epub 2020 Jul 22.

Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-17572-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376041PMC
July 2020

Evaluation of corrosion resistance of Co-Cr alloys fabricated with different metal laser sintering systems.

J Adv Prosthodont 2020 Jun 18;12(3):114-123. Epub 2020 Jun 18.

Department of Chemistry, Faculty of Science, Hacettepe University, Ankara, Turkey.

Purpose: The aim of this study was to evaluate the corrosion resistance of the specimens produced by five different commercial metal laser sintering (MLS) systems with their recommended Co-Cr alloy powders.

Materials And Methods: The MLS machines and the alloy powders used were, ProX 100-ST2724G (St-Pro), Mysint 100-EOS SP2 (SP2-Mys), EOSINT 270-EOS SP2 (SP2-EOS), SLM 100-Starbond CoS (SB-SLM), and MLab Cusing-Remanium® Star (RS-MLab), respectively. Eight specimens from each group were prepared. Open circuit potential (E) and electrochemical impedance spectroscopy (EIS) measurements of polished surfaces of the specimens were conducted in a three-electrode cell using a potentiostat-galvanostat in Fusayama-Meyer artificial saliva (AS). Specimens from each group were immersed in AS and de-ionized water for seven days. E, charge transfer resistance (R) values, and released ions (µg/cm × 7d) in different solutions were determined. The specimen surfaces were observed with SEM/EDS. Results were analyzed statistically.

Results: E values have shifted to potentials that are more positive over time. Steady-state E values were from high to low as follows, SB-SLM, SP2-Mys, SP2-EOS, RS-MLab, and ST-Pro, respectively. After 60 mins, RS-MLab specimens had the highest R value, followed by SP2-Mys, SB-SLM, SP2-EOS, and ST-Pro. In all groups, ion release was higher in AS than that in de-ionized water.

Conclusion: There were small differences among the corrosion resistances of the Co-Cr alloy specimens produced with MLS systems; meanwhile, the corrosion resistances were quite high for all specimens.
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http://dx.doi.org/10.4047/jap.2020.12.3.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314628PMC
June 2020

Whole-genome sequencing of patients with rare diseases in a national health system.

Nature 2020 07 24;583(7814):96-102. Epub 2020 Jun 24.

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
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http://dx.doi.org/10.1038/s41586-020-2434-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610553PMC
July 2020

Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans.

Nat Commun 2020 04 8;11(1):1740. Epub 2020 Apr 8.

Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.

Several strands of evidence question the dogma that human mitochondrial DNA (mtDNA) is inherited exclusively down the maternal line, most recently in three families where several individuals harbored a 'heteroplasmic haplotype' consistent with biparental transmission. Here we report a similar genetic signature in 7 of 11,035 trios, with allelic fractions of 5-25%, implying biparental inheritance of mtDNA in 0.06% of offspring. However, analysing the nuclear whole genome sequence, we observe likely large rare or unique nuclear-mitochondrial DNA segments (mega-NUMTs) transmitted from the father in all 7 families. Independently detecting mega-NUMTs in 0.13% of fathers, we see autosomal transmission of the haplotype. Finally, we show the haplotype allele fraction can be explained by complex concatenated mtDNA-derived sequences rearranged within the nuclear genome. We conclude that rare cryptic mega-NUMTs can resemble paternally mtDNA heteroplasmy, but find no evidence of paternal transmission of mtDNA in humans.
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http://dx.doi.org/10.1038/s41467-020-15336-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142097PMC
April 2020

Large-Scale Whole-Genome Sequencing Reveals the Genetic Architecture of Primary Membranoproliferative GN and C3 Glomerulopathy.

J Am Soc Nephrol 2020 02 9;31(2):365-373. Epub 2020 Jan 9.

Department of Renal Medicine, University College London, London, United Kingdom;

Background: Primary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN.

Methods: We analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource-Rare Diseases Study. We examined copy number, rare, and common variants.

Results: Our analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) (=3.29×10; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 (=1.21×10; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure.

Conclusions: We found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases.
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http://dx.doi.org/10.1681/ASN.2019040433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003307PMC
February 2020

Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses.

J Exp Med 2019 09 24;216(9):1986-1998. Epub 2019 Jun 24.

Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, UK

IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by We describe two patients with homozygous mutations in who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in , and genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.
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http://dx.doi.org/10.1084/jem.20190344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719421PMC
September 2019

Germline selection shapes human mitochondrial DNA diversity.

Science 2019 05 23;364(6442). Epub 2019 May 23.

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.
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http://dx.doi.org/10.1126/science.aau6520DOI Listing
May 2019

Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.

Blood 2019 12;134(23):2082-2091

Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.

A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multidisciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbor variants associated with rare bleeding, thrombotic, or platelet disorders (BTPDs). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count, and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number variants (CNVs) and intronic variants, as pathogenic, likely pathogenic, or variants of uncertain significance. Half of these variants (50.9%) are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPDs. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD.
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http://dx.doi.org/10.1182/blood.2018891192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993014PMC
December 2019

Craniometric Analysis of Skullbase With Magnetic Resonance Imaging in Patients With Chiari Malformation.

J Craniofac Surg 2019 May/Jun;30(3):818-822

Department of Neurosurgery, Katip Celebi University Ataturk Training and Research Hospital, Izmir.

Basilar invagination, Platibasi, increased tentorium angle, and posterior fossa hypoplasia are the anomalies associated with Chiari malformation. When Chiari is symptomatic; tonsillary ectopenia appears to be a definitive criterion for diagnosis and treatment, the detection of additional anomaly may alter the surgical outcome. The aim of this study is to investigate the relationship between tonsillar ectopia and other anomalies.The authors retrospectively reviewed 31 cases which had Chiari Malformation at our Hospital. There were 8 men (25.8%) and 23 female (74.2%). Average age of the samples is 37.93 ± 12.93 years. Seventeen patients (54.8%) had tonsillar ectopia 0 to 5 mm, 14 patients had tonsillar ectopia over 5 mm. Seven patients had syrinx (22.6%), 2 patients had mild hydrocephalus (6.5%). Six patients had surgery for the treatment. The mean length of the clivus was 39.3 mm, supraoksiput length was 40.4 mm, cerebellar hemisphere length was 61.08 mm, Mc Rae line was 33.14 mm, Twinning Line was 79.4mm, and Tentorium-Twinning line angle was 40.35°. There was no significant difference between Tonsillar ectopia, syrinks, and hydrocephalus. Basilar invagination had relationship between platibasi (6 patients had platibasi according to 2 mm criteria, 2 patients had platibasi according to 5 mm criteria (P < 0.05). Patients with syrinx had relationship between Chamberlain line (P < 0.05).In the authors' study, although there was no statistically significant difference between the tonsillary ectopia and the criteria of these anomalies, the relationship between basilar invagination and platibasi was significant.
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http://dx.doi.org/10.1097/SCS.0000000000005171DOI Listing
July 2019

Hepatitis B and C rates are significantly increased in certain solid tumors: A large retrospective study.

J Cancer Res Ther 2018 09;14:S774-S778

Department of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey.

Objective: Hepatitis B virus (HBV) and hepatitis C virus (HCV) are associated with significant morbidity and mortality among cancer patients who received cytotoxic chemotherapy. The aim of current study was to elucidate the prevalence of HBV and HCV among large population of solid cancers and lymphoma and to compare them with large number of control group.

Patients And Methods: Between 2000 and 2014, 8322 cancer patients who were admitted to Oncology Departments were evaluated retrospectively and 3890 patients in whom hepatitis serology were available were included in this study. Their results were compared with control group that consisted of 96,000 subjects.

Results: In control groups, hepatitis B surface antigen (HBsAg) positivity rate was 3.3% and anti-HCV positivity rate was 0.84%. In cancer patients, HBsAg positivity rate was 3.65% and anti-HCV positivity rate was 1.2%. Neither HBsAg positivity rate nor anti-HCV positivity rate was statistically significant between groups (P = 0.12 and P = 0.09, respectively). HBsAg positivity rates of head and neck cancer (5.88%; P = 0.02), rectum (5.6%; P = 0.025), and gastric and esophagus cancer (5.88%; P = 0.025) were significantly higher than control groups. Anti-HCV positivity rate (2.5%; P = 0.0016) was significantly higher in lung cancer when compared with control group.

Conclusion: The current study elucidated the prevalence of HBV and HCV among large population of solid cancers and lymphoma and we showed that hepatitis B and C positivity rates are significantly increased in certain solid tumors. Our findings should also be clarified with large prospective studies.
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http://dx.doi.org/10.4103/0973-1482.174544DOI Listing
September 2018

Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans.

J Allergy Clin Immunol 2018 10 2;142(4):1285-1296. Epub 2018 Mar 2.

NIHR BioResource-Rare Diseases, Cambridge Biomedical Campus, Cambridge, United Kingdom.

Background: The genetic cause of primary immunodeficiency disease (PID) carries prognostic information.

Objective: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort.

Methods: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses.

Results: Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21 B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases.

Conclusion: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.
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http://dx.doi.org/10.1016/j.jaci.2018.01.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148345PMC
October 2018

The effects of stabilization splint treatment on the volume of masseter muscle in sleep bruxism patients.

Cranio 2018 Sep 18;36(5):286-293. Epub 2017 Sep 18.

c Faculty of Medicine, Department of Anatomy , Ondokuz Mayıs University , Samsun , Turkey.

Objective: The aim of this study was to evaluate, quantitatively, the volumetric effects of stabilization splint therapy on the masseter muscle of sleep bruxism (SB) patients.

Methods: The magnetic resonance (MR) images of 16 SB patients diagnosed by polysomnography (PSG) who used stabilization splints for four months were obtained before and after the therapy. The masseter muscle volume was calculated using Cavalieri's principle on the MR images.

Results: After the splint therapy, the mean volume of the masseter muscle did not reduce significantly. The fat and/or water content of the muscles did not change either.

Discussion: The stabilization splint therapy had no effect on the volume, fat and/or water content of the masseter muscle; however the discomfort was reduced in the patients. Although the effect of splint therapy is not fully understood, the non-invasive and reversible stabilization splint can be used in SB patients because of its relaxation effect on muscles.
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http://dx.doi.org/10.1080/08869634.2017.1377433DOI Listing
September 2018

Ape1 guides DNA repair pathway choice that is associated with drug tolerance in glioblastoma.

Sci Rep 2017 08 29;7(1):9674. Epub 2017 Aug 29.

Molecular Neuro-Oncology Research Unit, Department of Pediatrics & Adolescent Medicine, Medical University of Vienna, A-1090, Vienna, Austria.

Ape1 is the major apurinic/apyrimidinic (AP) endonuclease activity in mammalian cells, and a key factor in base-excision repair of DNA. High expression or aberrant subcellular distribution of Ape1 has been detected in many cancer types, correlated with drug response, tumor prognosis, or patient survival. Here we present evidence that Ape1 facilitates BRCA1-mediated homologous recombination repair (HR), while counteracting error-prone non-homologous end joining of DNA double-strand breaks. Furthermore, Ape1, coordinated with checkpoint kinase Chk2, regulates drug response of glioblastoma cells. Suppression of Ape1/Chk2 signaling in glioblastoma cells facilitates alternative means of damage site recruitment of HR proteins as part of a genomic defense system. Through targeting "HR-addicted" temozolomide-resistant glioblastoma cells via a chemical inhibitor of Rad51, we demonstrated that targeting HR is a promising strategy for glioblastoma therapy. Our study uncovers a critical role for Ape1 in DNA repair pathway choice, and provides a mechanistic understanding of DNA repair-supported chemoresistance in glioblastoma cells.
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http://dx.doi.org/10.1038/s41598-017-10013-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574897PMC
August 2017

A multicenter family practitioners' research on Chronic Obstructive Pulmonary Disease screening using the COPD Assessment Test.

Prim Health Care Res Dev 2017 11 17;18(6):603-607. Epub 2017 Jul 17.

1Family Medicine,University of Health Sciences Bursa Yuksek Ihtisas Training and Research Hospital,Bursa,Turkey.

Objectives: Spirometry is known to be a gold standard for the diagnosis of chronic obstructive pulmonary disease (COPD). COPD Assessment Test (CAT) is an eight-item questionnaire currently in use to evaluate patients with COPD. In the present study, we aimed to evaluate if CAT is an adequate tool for screening COPD.

Methods: In total, 600 persons aging ⩾40 years old were randomly selected from three different family practice units located in the city center. CAT was asked to the participants and a spirometry was used to assess pulmonary obstruction. Pulmonary obstruction was defined as forced expiratory volume in first second/forced vital capacity (FEV1/FVC)<70% and then COPD diagnosis was confirmed with the reversibility test. The relationship between CAT results and pulmonary function test values was evaluated.

Results: In this sampling, the prevalence of COPD was 4.2%. Reliability of the CAT in the study group was acceptable (Cronbach's α: 0.84). The CAT scores was significantly higher in patients with COPD (P<0.001). There was a significant negative correlation between CAT score and FEV1, FVC and FEV1/FVC ratio (r=-0.31, P<0.001; r=-0.26, P<0.001; r=0.18, P=0.001). Among smokers, phlegm was the predominating symptom (P=0.01). Sensitivity of CAT was 66.67% and its specificity was 75.15% to determine COPD.

Conclusions: CAT is a reliable questionnaire and there is an apparent relationship between the total CAT scores and COPD. However, CAT's ability to screen COPD is limited since it may miss the symptom-free cases.
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http://dx.doi.org/10.1017/S1463423617000408DOI Listing
November 2017

Platelet function is modified by common sequence variation in megakaryocyte super enhancers.

Nat Commun 2017 07 13;8:16058. Epub 2017 Jul 13.

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.

Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type-matched epigenomic data and promoter long-range interactions. We identify potential regulatory functions for 423 of 565 (75%) non-coding variants associated with platelet traits and we demonstrate, through ex vivo and proof of principle genome editing validation, that variants in super enhancers play an important role in controlling archetypical platelet functions.
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http://dx.doi.org/10.1038/ncomms16058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511350PMC
July 2017

Expanded repertoire of variants responsible for platelet dysfunction and severe bleeding.

Blood 2017 08 21;130(8):1026-1030. Epub 2017 Jun 21.

School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.

Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterized. Pathogenic variants in , which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in 3 pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic variants, we compared high-throughput sequencing and phenotype data from 2042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5422 controls. Eleven cases harbored 11 different, previously unreported variants that were biallelic and likely pathogenic. The variants included 5 high-impact variants predicted to prevent CalDAG-GEFI expression and 6 missense variants affecting the CalDAG-GEFI CDC25 domain, which mediates Rap1 activation during platelet inside-out αIIbβ3 signaling. Cases with biallelic variants had abnormal mucocutaneous, surgical, and dental bleeding from childhood, requiring ≥1 blood or platelet transfusion in 78% of cases. Platelets displayed reduced aggregation in response to adenosine 5'-diphosphate and epinephrine, but variable aggregation defects with other agonists. There were no other consistent clinical or laboratory features. These data enable definition of human CalDAG-GEFI deficiency as a nonsyndromic, recessive PFD associated with a moderate or severe bleeding phenotype and complex defects in platelet aggregation.
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http://dx.doi.org/10.1182/blood-2017-03-776773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785798PMC
August 2017

The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease.

Cell 2016 11;167(5):1415-1429.e19

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. Electronic address:

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.
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http://dx.doi.org/10.1016/j.cell.2016.10.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300907PMC
November 2016

Letter to the Editor: Platelet-rich plasma versus steroid injection for subacromial impingement syndrome.

J Orthop Surg (Hong Kong) 2016 08;24(2):282

Department of Orthopedic Surgery and Traumatology, Haydarpasa Numune Education and Research Hospital, Istanbul, Turkey.

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http://dx.doi.org/10.1177/1602400240DOI Listing
August 2016

Letter to the Editor: A clinical and ultrasonographic study of risk factors for elbow injury in young baseball players.

J Orthop Surg (Hong Kong) 2016 08;24(2):279

Department of Orthopaedic Surgery, Gunma University Graduate School of Medicine, Gunma, Japan.

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http://dx.doi.org/10.1177/1602400234DOI Listing
August 2016

Limbus Vertebra Presenting with Inflammatory Low Back Pain: A Case Report.

J Clin Diagn Res 2016 Mar 1;10(3):YD01-2. Epub 2016 Mar 1.

Faculty, Department of Physical Medicine and Rehabilitation, Medical Faculty, Akdeniz University , Turkey .

Limbus vertebra is a condition characterized by marginal interosseous herniation of the nucleus pulposus, and causes non specific symptoms like low back pain, back pain, muscle spasms and radiculopathy. It is frequently confused with vertebral fracture, infection, schmorl nodule or tumour because it has not a spesific symptom. It usually causes mechanical low back pain rather than inflammatory low back pain. We reported a patient presented with inflammatory low back pain and diagnosed with anterior limbus vertebra because it is rare and the patient has atypical clinical presentation.
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http://dx.doi.org/10.7860/JCDR/2016/17985.7429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843374PMC
March 2016

Is There an Association between Restless Legs Syndrome and Urticaria?

J Korean Med Sci 2016 May 29;31(5):790-4. Epub 2016 Mar 29.

Department of Dermatology and Venereology, Akdeniz University School of Medicine, Antalya, Turkey .

Restless legs syndrome (RLS) is a disease characterized by the urge to move the legs and sleep disturbances. Similarly, chronic spontaneous urticaria (CSU) is a dermatological disease characterized by pruritus and sleep disorders. In this study, we aimed to determine the prevalence and severity of RLS in patients with chronic spontaneous urticaria (CSU) and to compare the quality of sleep of patients with and without RLS in the CSU group using the Pittsburgh Sleep Quality Index. A total of 130 patients with CSU and 100 healthy controls were included in this study. The frequency of RLS, frequency of sleep disturbances, and average score of RLS in patients with CSU were statistically significantly higher than control groups (respectively P = 0.008, P = 0.009, P = 0.004). Subjective sleep quality, sleep latency and habitual sleep efficiency scores in patients with RLS were statistically significantly higher than patients without RLS (respectively P = 0.016, P = 0.007, P = 0.035). We claimed that pruritus of urticaria may decrease the quality of sleep in patients with RLS and it may trigger and worsen the restless legs syndrome. Furthermore, RLS and CSU may share a common etiology.
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http://dx.doi.org/10.3346/jkms.2016.31.5.790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835607PMC
May 2016

The relationship between femoral cartilage thickness and muscle strength in knee osteoarthritis.

Clin Rheumatol 2016 Aug 18;35(8):2073-2077. Epub 2016 Apr 18.

Department of Physical Medicine and Rehabilitation, Hacettepe University Medical School, Ankara, Turkey.

To explore whether femoral cartilage thickness is related (and changes) with muscle strength in subjects with knee osteoarthritis (OA). Forty patients (27 F, 13 M) with knee OA-who were under quadriceps muscle strengthening program-were enrolled in the study. Isokinetic/isometric knee muscle strength measurements (at 30-60° angles and 60-180° velocity) were performed at baseline, end of the muscle strengthening program, and third month control visit using a biodex dynamometer. Femoral cartilage thicknesses (at medial/lateral condyle and intercondylar area) were measured using ultrasonography. Seventy-nine knees of 40 patients (27 F, 13 M) aged 52.03 ± 11.72 years (range, 26-71) were analyzed. Mean VAS scores on the first and third months were significantly lower than the initial values (p < 0.001, p = 0.049). Isometric peak torque and total work values at 180 °/s were significantly higher than the baseline measurements at first and third month controls (all p < 0.05). Cartilage thicknesses (at three sites) were significantly higher than the baseline measurements (all p < 0.05) on the third month but not on the first month (all p > 0.05). Femoral cartilage thicknesses were positively correlated with isometric strength values at baseline and third month. We propose that femoral cartilage thicknesses increase on the third month of strengthening therapy. Since this late-phase thickening parallels the earlier increase in muscle strength (starting, on the first month), we speculate that regeneration rather than edema might be the primary underlying cause.
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http://dx.doi.org/10.1007/s10067-016-3271-4DOI Listing
August 2016

A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders.

Blood 2016 06 15;127(23):2791-803. Epub 2016 Apr 15.

Department of Haematology, University of Cambridge, National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, and National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom; Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, United Kingdom;

Inherited bleeding, thrombotic, and platelet disorders (BPDs) are diseases that affect ∼300 individuals per million births. With the exception of hemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialized tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs. This approach causes delays and a conclusive molecular diagnosis is often never reached, which can compromise treatment and impede rapid identification of affected relatives. To address this unmet diagnostic need, we designed a high-throughput sequencing platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants, short insertions/deletions, and large copy number variants (though not inversions) which are subjected to automated filtering for diagnostic prioritization, resulting in an average of 5.34 candidate variants per individual. We sequenced 159 and 137 samples, respectively, from cases with and without previously known causal variants. Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology, whereas the remainder had an a priori highly uncertain etiology. All previously detected variants were recapitulated and, when the etiology was suspected but unknown or uncertain, a molecular diagnosis was reached in 56 of 61 and only 8 of 76 cases, respectively. The latter category highlights the need for further research into novel causes of BPDs. The ThromboGenomics platform thus provides an affordable DNA-based test to diagnose patients suspected of having a known inherited BPD.
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http://dx.doi.org/10.1182/blood-2015-12-688267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016734PMC
June 2016

A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss.

Blood 2016 06 24;127(23):2903-14. Epub 2016 Feb 24.

School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.

Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MKs). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping, and similarity regression. We describe 2 unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was linked to reduced proplatelet formation from cultured MKs, cell clustering, and abnormal cortical filamentous actin. Similarly, in platelets, there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Overexpression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease and provides new insight into the autoregulation of DIAPH1 activity.
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http://dx.doi.org/10.1182/blood-2015-10-675629DOI Listing
June 2016

Common Mistakes in the Dual-Energy X-ray Absorptiometry (DXA) in Turkey. A Retrospective Descriptive Multicenter Study.

Acta Medica (Hradec Kralove) 2016;59(4):117-123

Department of Physical Medicine and Rehabilitation, Beyhekim State Hospital of Konya, Konya, Turkey.

Background: Osteoporosis is a widespread metabolic bone disease representing a global public health problem currently affecting more than two hundred million people worldwide. The World Health Organization states that dual-energy X-ray absorptiometry (DXA) is the best densitometric technique for assessing bone mineral density (BMD). DXA provides an accurate diagnosis of osteoporosis, a good estimation of fracture risk, and is a useful tool for monitoring patients undergoing treatment. Common mistakes in BMD testing can be divided into four principal categories: 1) indication errors, 2) lack of quality control and calibration, 3) analysis and interpretation errors, and 4) inappropriate acquisition techniques. The aim of this retrospective multicenter descriptive study is to identify the common errors in the application of the DXA technique in Turkey.

Methods: All DXA scans performed during the observation period were included in the study if the measurements of both, the lumbar spine and proximal femur were recorded. Forearm measurement, total body measurements, and measurements performed on children were excluded. Each examination was surveyed by 30 consultants from 20 different centers each informed and trained in the principles of and the standards for DXA scanning before the study.

Results: A total of 3,212 DXA scan results from 20 different centers in 15 different Turkish cities were collected. The percentage of the discovered erroneous measurements varied from 10.5% to 65.5% in the lumbar spine and from 21.3% to 74.2% in the proximal femur. The overall error rate was found to be 31.8% (n = 1021) for the lumbar spine and 49.0% (n = 1576) for the proximal femur.

Conclusion: In Turkey, DXA measurements of BMD have been in use for over 20 years, and examination processes continue to improve. There is no educational standard for operator training, and a lack of knowledge can lead to significant errors in the acquisition, analysis, and interpretation.
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http://dx.doi.org/10.14712/18059694.2017.38DOI Listing
June 2017

The relation of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and mean platelet volume with the presence and severity of Behçet's syndrome.

Kaohsiung J Med Sci 2015 Dec 10;31(12):626-31. Epub 2015 Dec 10.

Department of Ophthalmology, Akdeniz University School of Medicine, Antalya, Turkey.

Behçet's syndrome (BS) is associated with chronic inflammation and endothelial dysfunction. Although there have been extensive investigations on neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and mean platelet volume (MPV) in many diseases, their roles in BS is unclear. The purpose of the present study was to evaluate NLR, PLR, and MPV levels in BS patients and explore their clinical significance. The study included 254 patients with BS and 173 healthy individuals. Age, sex, age of onset, duration of disease, smoking, Behçet activity score, total white blood counts, neutrophil, platelet, and T lymphocyte counts of the patients were recorded. White blood cell (WBC), neutrophil, platelet, NLR, and PLR were significantly higher in patients with BS when compared with healthy controls (all p < 0.001). Lymphocyte counts and MPVs of the BS group were not statistically different from healthy controls (all p > 0.05). In the BS group, PLR and MPV were significantly different among the three severity groups (p = 0.037 and p = 0.016, respectively). We showed that any laboratory markers were not associated with joint, eye, central nervous system, large vessel, or gastrointestinal involvement in BS. NLR was shown to be an independent factor for BS by multivariate analysis. We suggest that NLR can be considered to be a diagnostic criterion of BS given the support of the findings from larger prospective studies.
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http://dx.doi.org/10.1016/j.kjms.2015.10.010DOI Listing
December 2015

Type D personality, anxiety, depression and personality traits in patients with isolated itching of the external auditory canal.

J Laryngol Otol 2016 Jan 26;130(1):50-5. Epub 2015 Nov 26.

Department of Otorhinolaryngology,Dicle University School of Medicine,Diyarbakir,Turkey.

Objective: This study evaluated type D personality, anxiety, depression and personality traits in patients with isolated itching of the external auditory canal.

Method: A hundred consecutive out-patients with isolated itching of the external auditory canal and 100 controls were enrolled in the study. The Type D Scale, the abbreviated form of the Eysenck Personality Questionnaire Revised and the Hospital Anxiety and Depression Scale were used for data collection. Patients were also evaluated using the Modified Itch Severity Scale.

Results: In all, 43 per cent of patients and 15 per cent of controls met the criteria for a type D personality. Patients with a type D personality had higher anxiety and itching severity but lower extraversion compared with those without a type D personality. Multiple linear regression analysis showed that extraversion and type D personality were independently associated with itch severity.

Conclusion: These data suggest that clinicians should consider psychological and personality features when evaluating and treating patients with isolated itching of the external auditory canal.
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http://dx.doi.org/10.1017/S0022215115003011DOI Listing
January 2016

Open tuber calcaneus fracture caused by a meat cleaver: A case report.

Ann Med Surg (Lond) 2015 Sep 18;4(3):221-4. Epub 2015 Jul 18.

Department of Orthopaedics, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey.

Introduction: Avulsion fractures of the tuber calcanei classically occur after falling on the foot, due to the forced dorsiflexion and the sudden contraction of the Achilles tendon. Direct trauma to the back of the leg and a direct penetrating injury are also infrequent causes and may be observed predominantly in younger patients.

Presentation Of Case: We present a case of an open tuber calcaneus fracture resulting from a penetrating trauma in a 37-year-old patient. The fracture was reduced through the open wound and fixed using two cannulated screws. Bone union was radiologically and clinically observed at the end of the first year.

Discussion: During a physical altercation, the posterior of the patient's heel was struck directly with a meat cleaver. The position of the patient during the trauma can be considered to have increased the severity and depth of the injury. In addition, even though the injury radiologically resembled an avulsion fracture and was caused by direct trauma, the fact that it was open and that the mechanism of injury differed from the norm means that it should not be evaluated as a classic avulsion fracture in the full sense. Emergency open reduction and internal fixation were applied to an open calcaneal tuberosity fracture, and the patient was started on intravenous antibiotic therapy.

Conclusion: Surgical techniques are successful in the treatment of open tuber calcanei fractures and an open intervention is usually required. Using cannulated screws is a good treatment option.
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http://dx.doi.org/10.1016/j.amsu.2015.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624570PMC
September 2015