Publications by authors named "Anna Molnár"

26 Publications

  • Page 1 of 1

A new method to determine the optimal orientation of Slim Modiolar cochlear implant electrode array insertion.

Ideggyogy Sz 2021 May;74(5-6):191-195

University of Szeged, Department of Oto-Rhino-Laryngology and Head-Neck Surgery, Szeged.

Background And Purpose: Our goal was to determine the optimal orientation of insertion of the Slim Modiolar electrode and develop an easy-to-use method to aid implantation surgery. In some instances, the electrode arrays cannot be inserted in their full length. This can lead to buckling, interscalar dislocation or tip fold-over. In our opinion, one of the possible reasons of tip fold-over is unfavourable orientation of the electrode array. Our goal was to determine the optimal orientation of the Slim Modiolar electrode array relative to clear surgical landmarks and present our method in one specified case.

Methods: For the measurement, we used the preoperative CT scan of one of our cochlear implant patients. These images were processed by an open source and free image visualization software: 3D Slicer. In the first step we marked the tip of the incus short process and then created the cochlear view. On this view we drew two straight lines: the first line represented the insertion guide of the cochlear implant and the second line was the orientation marker (winglet). We determined the angle enclosed by winglet and the line between the tip of the incus short process and the cross-section of previously created two lines. For the calculation we used a self-made python code.

Results: The result of our algorithm for the angle was 46.6055°. To validate this result, we segmented, from the CT scan, the auditory ossicles and the membranaceous labyrinth. From this segmentation we generated a 3D reconstruction. On the 3D view, we can see the position of the previous lines relative to the anatomical structures. After this we rotated the 3D model together with the lines so that the insertion guide forms a dot. In this view, the angle was measured with ImageJ and the result was 46.599°.

Conclusion: We found that our method is easy, fast, and time-efficient. The surgery can be planned individually for each patient, based on their routine preoperative CT scan of the temporal bone, and the implantation procedure can be made safer. In the future we plan to use this method for all cochlear implantation surgeries, where the Slim Modiolar electrode is used.
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http://dx.doi.org/10.18071/isz.74.0191DOI Listing
May 2021

Above-ground parts of white grapevine Vitis vinifera cv. Furmint share core members of the fungal microbiome.

Environ Microbiol Rep 2021 May 5. Epub 2021 May 5.

Department of Plant Anatomy, Institute of Biology, Eötvös Loránd University, Pázmány Péter sétány 1/C, Budapest, 1117, Hungary.

Grapevine (Vitis vinifera) is a reservoir of fungal endophytes that may affect its growth, health status and grape production. Although there is growing interest in comparing fungal communities of mainly red grape varieties across various factors using only high-throughput sequencing, the small-scale mycobiome variations in geographically close vineyards need further examination. We aimed to characterize the fungal microbiome of the above-ground tissues of V. vinifera cv. Furmint in different plant parts, seasons and sites using culture-dependent and culture-independent methods, and in planta fluorescent microscopic visualization techniques. Samples were collected from four sites of the Tokaj wine region in Mád and two reference sites in Eger, Hungary, across different seasons for 2 years. Fungal endophytes of young and mature leaves, flowers and grape bunches were collected at different phenological stages. Based on each technique, Aureobasidium pullulans, Cladosporium spp. and the complex species Alternaria alternata dominated the community at every site, season and plant organ. We found no significant difference among communities in distinct neighbouring vineyards, nor when compared with the distant reference sites. We can conclude that the different shoot parts of the Furmint grapevines harbour a common core group of fungal community in these regions.
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http://dx.doi.org/10.1111/1758-2229.12950DOI Listing
May 2021

Interaction between elevated temperature and different types of Na-salicylate treatment in Brachypodium dystachion.

PLoS One 2020 13;15(1):e0227608. Epub 2020 Jan 13.

Centre for Agricultural Research, Agricultural Institute, Hungarian Academy of Sciences, Martonvásár, Hungary.

Salicylic acid (SA) plays a role in several physiological processes in plants. Exogenously applied SA is a promising tool to reduce stress sensitivity. However, the mode of action may depend on how the treatment was performed and environmental conditions may alter the effects of SA. In the present study the physiological and biochemical effects of different modes of application (soaking seeds prior sowing; spraying leaves with 0.5 mM NaSA) were compared at normal and moderately elevated temperatures (4 h; 35°C) in Brachypodium distachyon (L.) P. Beauv. plants. While soaking the seeds stimulated plant growth, spraying caused mild stress, as indicated by the chlorophyll-a fluorescence induction parameters and changes in certain protective compounds, such as glutathione, flavonoids or antioxidant enzymes. Elevated temperature also caused an increase in the glutathione-S-transferase activity, and this increase was more pronounced in plants pre-treated with NaSA. Both seed soaking or spraying with NaSA and exposure to heat treatment at 35°C reduced the abscisic acid levels in the leaves. In contrast to abscisic acid, the jasmonic acid level in the leaves were increased by both spraying and heat treatment. The present results suggest that different modes of application may induce different physiological processes, after which plants respond differently to heat treatment. Since these results were obtained with a model plants, further experiments are required to clarify how these changes occur in crop plants, especially in cereals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227608PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957344PMC
April 2020

Repeatability, reproducibility and interocular difference in the assessments of optic nerve OCT in children- a Swedish population-based study.

BMC Ophthalmol 2018 Oct 22;18(1):270. Epub 2018 Oct 22.

Department of Neuroscience/Ophthalmology, Uppsala University, SE-751 85, Uppsala, Sweden.

Background: The aim was, first, to collect normative data of the optic nerve head and the peripapillary retinal nerve fibre layer (RNFL) thickness assessed with Cirrus SD-OCT, in healthy children in a population-based study; second, using these data, to examine repeatability, reproducibility and the interocular difference.

Methods: One-hundred and ten eyes from 57 children aged 6-15 born at term, were examined. Best-corrected visual acuity and refraction were assessed. Both eyes were examined and the interocular difference was calculated. Repeatability was calculated by one examiner performing three assessments. Thereafter, a second examiner repeated the assessments to calculate reproducibility.

Results: Mean RNFL thickness was 99.2 (SD 8.8) μm, mean disc area 1.89 (SD 0.37) mm and mean rim area 1.52 (SD 0.26) mm. No significant correlations with age, gender or refraction were found. Repeatability and reproducibility were good overall. There was interocular symmetry between the eyes.

Conclusions: Normal values for optic nerve head and RNFL thickness assessed with Cirrus SD-OCT were gathered to obtain a normal material in children. High repeatability and reproducibility indicated reliability of assessments performed by different examiners on different occasions. Overall, good correlation between right and left eyes was found.
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http://dx.doi.org/10.1186/s12886-018-0940-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196413PMC
October 2018

The Effects of Different mTOR Inhibitors in EGFR Inhibitor Resistant Colon Carcinoma Cells.

Pathol Oncol Res 2019 Oct 7;25(4):1379-1386. Epub 2018 Jun 7.

1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, H-1085, Hungary.

Several monoclonal antibodies and inhibitors targeting signalling pathways are being used in personalised medicine. Anti-EGFR antibodies seem to be effective, however, therapy resistance often occurs in colon carcinoma cases. mTOR inhibitors (mTORIs) could have a potential role in the breakthrough of therapy resistance. The mTOR activity related protein expression patterns and the in vitro effects of EGFR inhibitors (EGFRIs), mTORIs and their combinations were studied in different colon carcinoma cell lines (with different genetic backgrounds). Alamar Blue test and flow cytometry were used to analyse the in vitro proliferation and apoptotic effects of cetuximab, gefitinib, cisplatin, rapamycin, PP242 and NVP-BEZ235. The expressions of mTOR activity related proteins (p-70S6K, p-S6, Rictor, p-mTOR, Raptor) were studied by Western blot, immunocytochemistry and Duolink staining. The EGFRI resistance of the studied colon carcinoma cell lines related to their known mutations were confirmed, neither gefitinib nor cetuximab inhibited the proliferation or induced apoptosis in vitro. Individual differences in Rictor and Raptor expressions were detected by Western blot and immunocytochemistry beside elevated mTOR activity of these different colon carcinoma cell lines. These expression patterns correlated to the mTORIs sensitivity differences, moreover, mTORIs could enhance the effects of EGFRIs and other in vitro treatments. Our results suggest that mTORI combinations could be helpful in both EGFRI and platinum-based therapy of colon carcinomas. Moreover, we suggest determining both mTOR complex activity and mutations in Akt/mTOR signalling pathways for selecting the appropriate mTORIs and patients in potential future combination treatments.
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http://dx.doi.org/10.1007/s12253-018-0434-4DOI Listing
October 2019

Reduction of Rod and Cone Function in 6.5-Year-Old Children Born Extremely Preterm.

JAMA Ophthalmol 2017 08;135(8):854-861

Department of Neuroscience/Ophthalmology, Uppsala University, Uppsala, Sweden.

Importance: The function of rods and cones in children born extremely preterm has not yet been fully investigated.

Objective: To compare retinal function via full-field electroretinographic (ffERG) recordings in 6.5-year-old children born extremely preterm with children born at term.

Design, Setting, And Participants: A subcohort study was conducted from July 1, 2010, to January 15, 2014, of the national Extremely Preterm Infants in Sweden Study, including preterm children (<27 weeks' gestational age) and children born at term, at 6.5 years of age and living in the Uppsala health care region in Sweden. Full-field electroretinography was performed binocularly, using DTL electrodes and electroretinographic (ERG) protocols with flash strengths of 0.009, 0.17, 3.0, and 12.0 candelas (cd)/s/m2, together with 30-Hz flicker and 3.0 cd/s/m2 single-cone flash.

Main Outcomes And Measures: The ffERG recordings were analyzed, and their associations with gestational age and retinopathy of prematurity were examined.

Results: Adequate ffERG recordings were obtained from 52 preterm children (19 girls and 33 boys; mean [SD] age at examination, 6.6 [0.1] years) and 45 children born at term (22 girls and 23 boys; mean [SD] age at examination, 6.6 [0.1] years). Lower amplitudes of the combined rod and cone responses (the a-wave of the dark-adapted ERG protocol of 3.0 cd/s/m2: mean difference, -48.9 μV [95% CI, -80.0 to -17.9 μV]; P=.003; the a-wave of the dark-adapted ERG protocol of 12.0 cd/s/m2: mean difference, -55.7 μV [95% CI, -92.5 to -18.8 μV]; P = .004), as well as of the isolated cone response (30-Hz flicker ERG: mean difference, -12.1 μV [95% CI, -22.5 to -1.6 μV]; P = .03), were found in the preterm group in comparison with the group born at term. The implicit time of the combined rod and cone responses (the a-wave of the dark-adapted ERG protocol of 12.0 cd/s/m2) was longer (mean difference, 1.2 milliseconds [95% CI, 0.3-2.0 milliseconds]; P = .01) in the preterm group, as were the isolated cone responses (30-Hz flicker ERG: mean difference, 1.2 milliseconds [95% CI, 0.5-1.8 milliseconds]; P < .001), than in the group born at term. No association was found between the ffERG recordings and gestational age or retinopathy of prematurity in the preterm group.

Conclusions And Relevance: Both rod function and cone function were reduced in children born extremely preterm when compared with children born at term. There was no association with retinopathy of prematurity in the preterm group, which suggests that being born extremely preterm may be one of the main reasons for a general retinal dysfunction.
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http://dx.doi.org/10.1001/jamaophthalmol.2017.2069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710295PMC
August 2017

[Role of the homograft bypass in extremity inferior's reconstructions].

Magy Seb 2017 03;70(1):5-12

Városmajori Szív- és Érgyógyászati Klinika, Semmelweis Egyetem 1122 Budapest, Városmajor utca 68.

Introduction: Vascular homografts are used for limb salvage in cases of graft infection after previous reconstructive vascular surgery or inadequate autologous veins. During multi-organ donation the thoracic aorta segment, aortic bifurcation, iliac arteries, femoral arteries, popliteal arteries, femoral veins and greater saphenous veins can be harvested. Our aim was to optimize the use of homografts by analyzing the results of previous procedures.

Methods: The patient information was processed retrospectively, using the clinical computer system. 162 procedures were performed on 144 patients between 2007 and 2014. The short- and long-term patency, hemorrhagic complication rate, amputation rate and mortality was examined in our study. The location, graft type and length of cryopreservation were taken into consideration. Aortoiliac and femoropopliteal reconstructions with arterial and venous homografts were examined.

Results: The mean age of the patients was 63.6 ± 10.7 years, the mean follow-up period was 36 ± 28 months. The primary patency rates at the postoperative 1, 3 and 6 months were 83.7%, 75.0% and 63.4%. In this study the arterial and deep venous homografts had better primary patency rates compared to the superficial venous homografts: at the postoperative 1, 3, 6 months the arterial homograft results were 85.6%, 78.6% and 74.3%, the greater saphenous vein homograft results were 81.4%, 70.4% and 47.7% in the same intervals.

Conclusion: The reconstructive surgical procedures in septic area mean serious challenge for the vascular surgeons. The AB0 compatibility of the graft and the recipient did not result better long-term outcomes compared to the non-compatible grafts. According to our data the ideal choice of homogenous graft is an arterial homograft which was not cryopreserved longer than 6 months.
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http://dx.doi.org/10.1556/1046.70.2017.1.1DOI Listing
March 2017

CENTRAL MACULAR THICKNESS IN 6.5-YEAR-OLD CHILDREN BORN EXTREMELY PRETERM IS STRONGLY ASSOCIATED WITH GESTATIONAL AGE EVEN WHEN ADJUSTED FOR RISK FACTORS.

Retina 2017 Dec;37(12):2281-2288

Department of Clinical Neuroscience, Astrid Lindgren Children's Hospital, Karolinska Institutet, Stockholm, Sweden.

Purpose: To assess the macular thickness in 6.5-year-old children born extremely preterm (EPT) in comparison with children born at term and to investigate risk factors associated with the macular thickness in the preterm group.

Methods: A population-based study of 6.5-year-old children born before the gestational age of 27 weeks and age-matched control subjects. Macular assessments with optical coherence tomography were performed, and the results were compared with neonatal risk factors and sex.

Results: Adequate optical coherence tomography measurements were obtained from 134 children born EPT (mean gestational age of 25 weeks [range 23-26]) and 145 control subjects. The mean (range) of central macula thickness was significantly increased (P < 0.001) in the EPT group (right eyes: 282 μm [238-356], left eyes: 283 μm [229-351]), compared with the control group (right eyes: 249 μm [208-293], left eyes: 248 μm [207-290]). A multiple linear mixed model analysis of the EPT group revealed gestational age, retinopathy of prematurity, and male gender as important risk factors for an increased macular thickness. The macular thickness decreased by 3.9 μm per gestational week, when adjusted for retinopathy of prematurity and sex.

Conclusion: Extremely preterm birth constitutes a substantial risk factor for a thick central macula, even when adjusted for retinopathy of prematurity and male gender.
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http://dx.doi.org/10.1097/IAE.0000000000001469DOI Listing
December 2017

mTOR activity and its prognostic significance in human colorectal carcinoma depending on C1 and C2 complex-related protein expression.

J Clin Pathol 2017 May 11;70(5):410-416. Epub 2016 Oct 11.

1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.

Aims: Tumour heterogeneity and altered activation of signalling pathways play important roles in therapy resistance. The PI3K/Akt/mTOR signalling network is a well-known regulator of several functions that contribute to tumour growth. mTOR exists in two functionally different multiprotein complexes. We aimed to determine mTOR activity-related proteins in clinically followed, conventionally treated colon carcinomas and to analyse the correlation between clinical data and mTORC1 and mTORC2 activity.

Methods: Immunohistochemistry was performed with different antibodies on tissue microarray blocks from 103 patients with human colorectal adenocarcinoma. mTORC1- and mTORC2-related activity were scored on different stainings including analysis of the expression of Raptor and Rictor-specific elements of mTORC1 and C2 complexes. The staining scores and clinical/survival data were compared and analysed.

Results: Detailed characterisation showed stage and grade independent high mTOR activity in 74% of cases. High mTOR activity was present in mTORC1 and/or mTORC2 complexes; >60% of cases had mTORC2-related high mTOR activity. Based on our analysis, high mTOR activity and Rictor overexpression could be markers of a bad prognosis. Combined phosphoprotein and Rictor/Raptor expression evaluation revealed even stronger statistical correlation with prognosis.

Conclusions: The presented staining panel could be appropriate and highly recommended for the accurate specification of mTORC1 and C2 activity of tumour tissues. This could help in the selection of mTOR inhibitors and can provide information about prognosis, which may guide decisions about the intensity of therapy.
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http://dx.doi.org/10.1136/jclinpath-2016-203913DOI Listing
May 2017

Techniques and technologies for the bioanalysis of Sativex®, metabolites and related compounds.

Bioanalysis 2016 Apr 23;8(8):829-45. Epub 2016 Mar 23.

Centre for Forensic Science, University of Technology Sydney, Ultimo, NSW, 2007, Australia.

Sativex(®) is an oromucosal spray indicated for the treatment of moderate-to-severe spasticity in multiple sclerosis and is also an effective analgesic for advanced cancer patients. Sativex contains Δ(9)-tetrahydrocannabinol (THC) and cannabidiol in an approximately 1:1 ratio. The increasing prevalence of medicinal cannabis products highlights the importance of reliable bioanalysis and re-evaluation of the interpretation of positive test results for THC, as legal implications may arise in workplace, roadside and sports drug testing situations. This article summarizes published research on the bioanalysis of THC and cannabidiol, with particular focus on Sativex. Common screening and confirmatory testing of blood, urine, oral fluid and hair samples are outlined. Correlations between matrices and current analytical pitfalls are also addressed.
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http://dx.doi.org/10.4155/bio-2015-0021DOI Listing
April 2016

Macular function measured by binocular mfERG and compared with macular structure in healthy children.

Doc Ophthalmol 2015 Dec 18;131(3):169-76. Epub 2015 Oct 18.

Department of Neuroscience/Ophthalmology, Uppsala University, Uppsala, Sweden.

Purpose: To create normative data in children from binocular multifocal ERG (mfERG) recordings and compare results with the macular thickness.

Methods: Forty-nine 5- to 15-year-old healthy, full-term children were examined with Espion Multifocal System, using DTL electrodes. The stimulus matrix consisted of 37 hexagonal elements. Amplitudes, implicit times and response densities (presented in three rings) of the first-order component P1 were analyzed. Measurements of macular thickness were performed with spectral-domain Cirrus OCT.

Results: There were no significant differences between right and left eyes regarding mfERG recordings. Median P1 implicit times of Rings 1-3 of the 46 right eyes were 30.0, 30.0 and 30.8 ms and response densities 20.5, 10.9 and 7.6 nV/deg(2), respectively. Implicit time was longer in boys than in girls (p = 0.009, 0.039, 0.005 in Rings 1-3) and was correlated with age (r s = 0.417, 0.316, 0.274 in Rings 1-3). Implicit time in Ring 1 correlated significantly with the inner circle of the OCT measurements (p = 0.014).

Conclusion: Binocular mfERG with DTL electrodes is a reliable test of the central macular function in children and correlates with macular structure. As previously not shown, there was a significant difference in implicit time between boys and girls.
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http://dx.doi.org/10.1007/s10633-015-9513-yDOI Listing
December 2015

Rapid elimination of Carboxy-THC in a cohort of chronic cannabis users.

Int J Legal Med 2016 Jan 2;130(1):147-52. Epub 2015 Aug 2.

Centre for Forensic Science, University of Technology Sydney (UTS), Broadway, Sydney, NSW, 2007, Australia.

Urinary 11-nor-Δ(9)-tetrahydrocannabinol-9-carboxylic acid (Carboxy-THC) concentrations, normalised to creatinine output, have been demonstrated to be a useful tool in the interpretation of the results of a series of urine tests for cannabis. These tests, often termed historical data, can be used to identify potential chronic cannabis users who may present occupational health and safety risks within the workplace. Conversely, the data can also be used to support employee claims of previous regular, rather than recent, cannabis use. This study aimed at examining the mean elimination of Carboxy-THC in 37 chronic users undergoing voluntary abstinence over a 2-week period. Urine specimens were collected prior to the study and after 1 and 2 weeks of abstinence. Carboxy-THC levels in urine were measured by gas chromatography-mass spectrometry (GC-MS) following alkaline hydrolysis, organic solvent extraction and derivatisation to form its pentafluoropropionic derivative. The creatinine-normalised Carboxy-THC concentrations declined rapidly over the 2 weeks of abstinence period and the majority of chronic cannabis users (73%) reduced their urinary Carboxy-THC levels to below the 15-μg/L confirmatory cutoff within that time. The study further highlights the value of historical urinary Carboxy-THC data as a means of identifying potential occupational health and safety risks among chronic cannabis users.
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http://dx.doi.org/10.1007/s00414-015-1241-zDOI Listing
January 2016

Rapamycin can restore the negative regulatory function of transforming growth factor beta 1 in high grade lymphomas.

Cytokine 2015 Jun 17;73(2):219-24. Epub 2015 Mar 17.

Semmelweis University, 1st Department of Pathology and Experimental Cancer Research, Budapest 1085, Üllői út 26., Hungary. Electronic address:

TGF-β1 (transforming growth factor beta 1) is a negative regulator of lymphocytes, inhibiting proliferation and switching on the apoptotic program in normal lymphoid cells. Lymphoma cells often lose their sensitivity to proapoptotic/anti-proliferative regulators such as TGF-β1. Rapamycin can influence both mTOR (mammalian target of rapamycin) and TGF-β signaling, and through these pathways it is able to enhance TGF-β induced anti-proliferative and apoptotic responses. In the present work we investigated the effect of rapamycin and TGF-β1 combination on cell growth and on TGF-β and mTOR signalling events in lymphoma cells. Rapamycin, an inhibitor of mTORC1 (mTOR complex 1) did not elicit apoptosis in lymphoma cells; however, the combination of rapamycin with exogenous TGF-β1 induced apoptosis and restored TGF-β1 dependent apoptotic machinery in several lymphoma cell lines with reduced TGF-β sensitivity in vitro. In parallel, the phosphorylation of p70 ribosomal S6 kinase (p70S6K) and ribosomal S6 protein, targets of mTORC1, was completely eliminated. Knockdown of Smad signalling by Smad4 siRNA had no influence on apoptosis induced by the rapamycin+TGF-β1, suggesting that this effect is independent of Smad signalling. However, apoptosis induction was dependent on early protein phosphatase 2A (PP2A) activity, and in part on caspases. Rapamycin+TGF-β1 induced apoptosis was not completely eliminated by a caspase inhibitor. These results suggest that high mTOR activity contributes to TGF-β resistance and lowering mTORC1 kinase activity may provide a tool in high grade B-cell lymphoma therapy by restoring the sensitivity to normally available regulators such as TGF-β1.
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http://dx.doi.org/10.1016/j.cyto.2015.02.024DOI Listing
June 2015

Macular thickness assessed with spectral domain OCT in a population-based study of children: normative data, repeatability and reproducibility and comparison with time domain OCT.

Acta Ophthalmol 2015 Aug 27;93(5):470-5. Epub 2015 Feb 27.

Department of Neuroscience/Ophthalmology, Uppsala University, Uppsala, Sweden.

Purpose: To collect data on macular thickness assessed with Cirrus OCT in healthy children in a population-based study, to examine the repeatability and reproducibility, and to compare the values with Stratus OCT.

Methods: Fifty-eight 6- to 15-year-old children, born at term, were examined. Best-corrected visual acuity and refraction were assessed. One examiner performed three OCT assessments, and the repeatability was calculated. Thereafter, a second examiner repeated the examinations to calculate the reproducibility. One eye was randomized to be included in the normal material. Finally, the second examiner assessed the macular thickness with the Stratus OCT.

Results: The mean value (±SD) of central macular thickness was 255 ± 17 μm, and the total macular volume was 10.3 ± 0.5 mm(3) . No correlations were found between macular thickness and age, gender or refraction. The coefficients of variance (CoVs) for both repeatability and reproducibility were <1.21%, and the intraclass correlations (ICCs) were over 0.86. The Cirrus OCT showed a 29% thicker central macular thickness than the Stratus OCT.

Conclusion: Normal values for macular thickness assessed with Cirrus OCT in healthy full-term children in a population-based study were reported. The assessments showed high repeatability and reproducibility. The values of Cirrus and Stratus OCT differed and the techniques were not interchangeable.
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http://dx.doi.org/10.1111/aos.12695DOI Listing
August 2015

The detection of THC, CBD and CBN in the oral fluid of Sativex® patients using two on-site screening tests and LC-MS/MS.

Forensic Sci Int 2014 May 12;238:113-9. Epub 2014 Mar 12.

National Cannabis Prevention and Information Centre, UNSW Medicine, Randwick 2031, NSW, Australia.

Sativex(®) is an oromucosal spray used to treat spasticity in multiple sclerosis sufferers in some European countries, the United Kingdom, Canada and New Zealand. The drug has also recently been registered by the Therapeutic Goods Administration (TGA) in Australia for treatment of multiple sclerosis. Sativex(®) contains high concentrations of Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), with the former being the subject of random roadside drug tests across Australia to detect cannabis use. This pilot study aims to determine whether or not patients taking Sativex(®) will test positive to THC using these roadside screening tests. Detectable levels of THC, CBD and cannabinol (CBN) in their oral fluid were also confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The study was a double-blind, placebo controlled design. Oral fluid was tested prior to and immediately after dosing with either Sativex(®) or placebo at intervals up to 2h after the dose. Two Sativex(®) doses were studied. The low dose contained 5.4mg THC, the high dose 21.6mg THC. Results indicate that the primary screening test used in Australian roadside drug testing, the DrugWipe(®) II Twin, often gave a false negative response for THC, even with high concentrations present. However, secondary screening test, Cozart(®) DDS (used by police after a DrugWipe test gives a positive result), gave true positive results in all cases where patients were being treated with Sativex(®). Confirmatory testing showed high concentrations of THC and CBD (>5356ng/mL THC and >3826ng/mL CBD) in the oral fluid shortly after dosing and also elevated concentrations of CBN. Levels dropped quickly but remained at detectable concentrations (>67.6ng/mL) two hours after drug administration. The average concentration ratio of THC/CBD across all positive samples was 1.10 (%RSD 19.9) reflecting the composition of the Sativex(®) spray. In conclusion, Sativex(®) users may test positive for THC by roadside drug testing within 2-3h of use. Confirmatory analysis can identify Sativex(®) treatment through use of THC/CBD ratios, however, these ratios would unlikely be sufficient to differentiate non-medicinal cannabis use from Sativex(®) use if both are taken concurrently.
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http://dx.doi.org/10.1016/j.forsciint.2014.03.004DOI Listing
May 2014

Recovery of spiked Δ9-tetrahydrocannabinol in oral fluid from polypropylene containers.

Forensic Sci Int 2013 Apr 4;227(1-3):69-73. Epub 2012 Dec 4.

Centre for Forensic Science, University of Technology Sydney (UTS), Broadway, NSW 2007, Australia.

Oral fluid is currently used by Australian and international law enforcement agencies and employers to detect recent use of cannabis and other drugs of abuse. The main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol (THC), is highly lipophilic and losses occur when in contact with plastic, possibly due to its adsorption onto the plastic surface. This study aims to investigate factors governing the interaction of THC with plastic and search for ways of overcoming such interaction so to improve THC recovery. As polypropylene is one of the most common types of plastic used in collection devices, it was the focus of this study. All experiments were done by preparing neat oral fluid samples spiked with THC in 2-mL polypropylene centrifuge tubes. Samples were transferred with or without prior addition of Triton(®) X-100 (0.25%) to glass tubes containing d3-THC as internal standard and 0.1M phosphate buffer was then added. Samples were extracted by liquid-liquid extraction using hexane/ethyl acetate (9:1, v/v), dried and analysed by gas chromatography-mass spectrometry (GC-MS) after derivatisation. No significant difference was found in terms of THC loss to plastic when the concentration ranged from 25 to 1000 ng/mL in the same volume of oral fluid. Varying the oral fluid volume (0.5-1.5 mL) while keeping THC at a constant concentration showed an upward trend with more loss associated with lower volumes. The use of Triton(®) X-100 significantly decreased the adherence of THC to the plastic tubes and increased the THC transfer (>96%) at all volumes tested. Degradation of THC during storage was also studied over a 4-week period and it was found that azide did not seem to play a significant role in preserving THC in oral fluid.
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http://dx.doi.org/10.1016/j.forsciint.2012.11.006DOI Listing
April 2013

Quantifying the clinical significance of cannabis withdrawal.

PLoS One 2012 26;7(9):e44864. Epub 2012 Sep 26.

National Cannabis Prevention and Information Centre, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, New South Wales, Australia.

Background And Aims: Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt.

Methods And Results: A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment scores during a one-week baseline phase and two weeks of monitored abstinence from cannabis with a one month follow up. Functional impairment from withdrawal symptoms was strongly associated with symptom severity (p=0.0001). Participants with more severe cannabis dependence before the abstinence attempt reported greater functional impairment from cannabis withdrawal (p=0.03). Relapse to cannabis use during the abstinence period was associated with greater functional impairment from a subset of withdrawal symptoms in high dependence users. Higher levels of functional impairment during the abstinence attempt predicted higher levels of cannabis use at one month follow up (p=0.001).

Conclusions: Cannabis withdrawal is clinically significant because it is associated with functional impairment to normal daily activities, as well as relapse to cannabis use. Sample size in the relapse group was small and the use of a non-treatment seeking population requires findings to be replicated in clinical samples. Tailoring treatments to target withdrawal symptoms contributing to functional impairment during a quit attempt may improve treatment outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044864PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458862PMC
April 2013

A rapid and sensitive method for the identification of delta-9-tetrahydrocannabinol in oral fluid by liquid chromatography-tandem mass spectrometry.

Forensic Sci Int 2012 Feb 1;215(1-3):92-6. Epub 2011 Mar 1.

Centre for Forensic Science, University of Technology, Sydney, Broadway, NSW 2007, Australia.

A fast and sensitive method was developed for detecting delta-9-tetrahydrocannabinol (THC) in oral fluid by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method is suitable for samples of small volume and low concentration. For method development and validation, neat oral fluid (200 μL) spiked with THC and d(3)-THC (internal standard) was extracted via liquid-liquid extraction (LLE). The LLE method had an extraction efficiency of 75% with no significant matrix effects observed in either diluted or neat oral fluid samples. LC was performed on a Zorbax Eclipse XDB-C18 Rapid Resolution HT column (2.1 mm × 50 mm, 1.8 μm particle size) with positive electrospray ionisation and selected reaction monitoring. The total run time was an efficient 3.5 min in isocratic elution mode. The limit of quantification was 1 ng/mL and the analysis was linear over the range of 1-500 ng/mL with a correlation coefficient of 0.9998. The imprecision (RSD) of the method was 13% and inaccuracy (MRE) was 4%. The method was subsequently applied to two neat oral fluid samples taken from a chronic cannabis smoker. It was also applied to buffer diluted residual oral fluid samples (n=48) collected using the Cozart RapiScan(®) system through the Roadside Drug Testing Program (RDTP) in NSW, Australia. A stability study was performed that revealed freezing or refrigerating resulted in comparable decreases in THC recovery from neat oral fluid at the end of two weeks of storage. Storage at room temperature even for one day invoked significant losses and is not recommended.
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http://dx.doi.org/10.1016/j.forsciint.2011.01.045DOI Listing
February 2012

Reduction of temazepam to diazepam and lorazepam to delorazepam during enzymatic hydrolysis.

Anal Bioanal Chem 2011 Apr 6;400(1):153-64. Epub 2011 Feb 6.

Centre for Forensic Science, University of Technology, Sydney (UTS), Broadway, NSW 2007, Australia.

It has been previously reported that treatment of urinary oxazepam by commercial β-glucuronidase enzyme preparations, from Escherichia coli, Helix pomatia and Patella vulgata, results in production of nordiazepam (desmethyldiazepam) artefact. In this study, we report that this unusual reductive transformation also occurs in other benzodiazepines with a hydroxyl group at the C3 position such as temazepam and lorazepam. As determined by liquid chromatography-mass spectrometry analysis, all three enzyme preparations were found capable of converting urinary temazepam into diazepam following enzymatic incubation and subsequent liquid-liquid extraction procedures. For example, when H. pomatia enzymes were used with incubation conditions of 18 h and 50 °C, the percentage conversion, although small, was significant--approximately 1% (0.59-1.54%) in both patient and spiked blank urines. Similarly, using H. pomatia enzyme under these incubation conditions, a reductive transformation of urinary lorazepam into delorazepam (chlordesmethyldiazepam) occurred. These findings have both clinical and forensic implications. Detection of diazepam or delorazepam in biological samples following enzyme treatment should be interpreted with care.
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http://dx.doi.org/10.1007/s00216-011-4723-yDOI Listing
April 2011

[Successful surgical removal of a mesencephalic cavernous angioma, which was responsible for progressive neurological deficits].

Ideggyogy Sz 2008 Jul;61(7-8):244-9

Szegedi Tudományegyetem, Szent-Györgyi Albert Klinikai Központ, Idegsebészeti Klinika, Szeged.

Cavernous angiomas comprise 5-10% of all vascular malformations in the central nervous system, occurring most frequently in the supratentorial region, and 20% of them in the brain stem. According to literature, brain stem cavernous angiomas occur most frequently in the pons (60%), and equally in the mesencephalon (20%) and in medulla oblongata. In clinical evaluation the authors describe the successful removal of a mesencephalic cavernous angioma causing progressive neurological deficits and symptoms. The authors present a case of a 51 year old female, who had developed 1 year prior to her admittance: fatigue, weakness in the right upper limb and fingers, right lower limb ataxia. One month later, her lower right limb developed sensory deficits. The first neurological exploration indicated dysarthria, moderate facial and right hemiparesis, hemihypaesthesia and ataxia. CT and MR imaging indicated multilobulated cavernomas in the mesencephalon. After conservative treatment the patient became almost symptom free, and thus neurosurgical treatment was not discussed. Later on her symptoms fluctuated, but after 6 month she suddenly developed progressive right hemiparesis, right facial weakness, serious dysphasia, and emotional incontinence combined with continuous spastic sobbings. The control MRI showed enlargement of the cavernomas and new extravasation. Surgery was indicated for removing the cavernomas. The left infratentorial, supracerebellar approach revealed a blood engorged cavernoma in the center of the mesencephalon, almost dividing it. The cavernomas and accompanying haematoma was extirpated. The patient's neurological symptoms rapidly improved after surgery, her dysphasia as well as motor weakness have disappeared. Six days after surgery, we discharged a neurologically symptomless and self-supporting patient. The literature and the presented case indicates that the correct timing and proper surgery allows brain stem cavernomas to be safely removed, or significantly bated, which results in the massive regression of neurological symptoms.
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July 2008

Bcl-2 antisense oligonucleotide inhibits the proliferation of childhood leukemia/lymphoma cells of the B-cell lineage.

Pathol Oncol Res 2008 Sep 25;14(3):275-9. Epub 2008 Jun 25.

Department of Pediatrics, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.

An 18-mer phosphorothioate bcl-2 antisense oligonucleotide (ASO) inhibited colony formation of three B-cell leukemia/lymphoma cell lines in a dose dependent manner in the range of 0.125-0.5 micromol/l. The scrambled cogener had no detectable effect. A decrease in BCL-2 protein and apoptotic DNA fragmentation was detected in the studied cell lines and primary blast cells of two children with acute lymphoblastic leukemia. Neither BCL-2 protein level, nor DNA integrity was affected by the scrambled control indicating the specific effect ASO. As far as we know, this is the first report on the effects of bcl-2 ASO on childhood leukemia/lymphoma cell samples.
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http://dx.doi.org/10.1007/s12253-008-9076-2DOI Listing
September 2008

Pharmacokinetics and pharmacodynamics of levofloxacin in critically ill patients with ventilator-associated pneumonia.

Int J Antimicrob Agents 2007 Aug 13;30(2):162-8. Epub 2007 Jun 13.

Department of Clinical Pharmacy, Faculty of Pharmacy, University of Szeged, H-6725 Szeged, Szikra u. 8, Hungary.

The pharmacokinetics of levofloxacin and outcome of levofloxacin therapy in critically ill patients with ventilator-associated pneumonia (VAP) were assessed. Further theoretical considerations regarding the pharmacokinetic/pharmacodynamic (PK/PD) appropriateness of levofloxacin therapy were made. Twelve patients completed the study, all of whom were treated with a standard intravenous levofloxacin regimen (2x500 mg on Day 1, then 1x500 mg daily). The maximum free plasma levofloxacin concentration (fC(max,ss)) and the area under the free concentration-time curve (fAUC) were 8.13+/-1.64 mg/L and 49.63+/-15.60 mgh/L, respectively. Optimal PK/PD target parameters were achieved in 10 patients; clinical success was attained in 11 of the 12 patients who completed the study. Bacterial eradication was obtained in 9 of the 11 cases with microbiologically confirmed bacteriological aetiology. Intravenous levofloxacin therapy (500 mg/day) was proven to be an effective regimen in this limited number of patients with VAP. However, theoretical considerations based on PK/PD indices predict that, with the current susceptibility breakpoint of 2mg/L, even higher levofloxacin doses (e.g. 1000 mg) could result in treatment failures in infections caused by pathogens labelled as levofloxacin-susceptible in the microbiology report.
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http://dx.doi.org/10.1016/j.ijantimicag.2007.03.016DOI Listing
August 2007

[Late metastases of abdominal cutaneous malignant melanoma in the small and large bowels].

Orv Hetil 2005 Sep;146(39):2029-31

Fejér Megyei Szent György Kórház, Sebészeti Osztály, Székesfehérvár.

The authors reported the case of a 56 years old man, who was operated with abdominal cutaneous malignant melanoma 5 years ago. He had chemo-immunotherapy. His complaints were epigastric pain, melena, hematochezia, anorexia, lack of appetite, fatigue. The upper panendoscopy showed tumor mass in the duodenojejunal flexure and the colonoscopy showed tumor in the large bowel. The patient underwent jejunal resection and right hemicolectomy. The authors survey the metastases of malignant melanoma as well as their clinical signs, therapeutic measures and prognosis.
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September 2005

[Late metastases of cutaneous malignant melanoma on the abdominal wall to the small and large bowel].

Magy Seb 2005 Aug;58(4):241-4

Fejér Megyei Szent György Kórház Sebészeti Osztály.

We describe the case of a 56 years old man, who was operated on with abdominal wall skin malignant melanoma 5 years ago. He received postoperative DTIC + Intron A treatment. Five years later he presented with complaints of epigastric pain, melena, hematochezia, anorexia and fatigue. Upper gastrointestinal tract endoscopy showed a tumour mass in the duodeno-jejunal flexure and colonoscopy showed a tumour in the large bowel. Histology verified anaplastic carcinoma. The patient was operated on. We found metastases in the small and the large bowel The patient underwent resection of the jejunum and right hemicolectomy. We describe the different types of metastases of malignant melanomas symptoms, therapies and prognosis.
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August 2005

[Non-alcoholic steatohepatitis: a childhood case].

Orv Hetil 2002 Aug;143(32):1899-903

Fejér Megyei Szent György Kórház, Ujszülött-Csecsemó-Gyermek Osztály, Székesfehérvár.

Introduction: A significant part of cryptogenic cirrhosis among adult patients shows that it can be the result of "burn-out" non-alcoholic steatohepatitis beginning in childhood.

Aim: Describing the case of a 15-year-old boy the aim of the authors is to raise attention to the fact that doctors should think of the possibility of having a fatty liver in presence of certain etiological features.

Patient: Although he was asymptomatic, the screening test revealed an elevated serum aspartate aminotransferase level. Abdominal ultrasound examination raised the possibility of a diffuse liver damage. The liver biopsy demonstrated the features of steatosis in the absence of alcohol abuse.

Results: On the basis of these results, NASH was diagnosed. The presence of a severe fatty liver at such an early age is quite unusual. In the background, the authors verified familial combined hyperlipidaemia and heterozygous mutation of the cystic fibrosis gene for delta F508 as genetic predisposing factor. The clinical condition was accelerated and worsened by the fact, that the patient has grown fat since his infancy. It did not prove possible to achieve a weight reduction with a fat- and cholesterol-poor diet, increased physical activity and medical treatment. However, there was significant improvement in the laboratory findings.

Conclusions: The conclusion drawn from this case, on one hand, is that doctors should think of the possibility of a fatty liver in case of an elevated isolate serum transaminase level in connection with obese or over weight patients. On the other hand the role of other coexisting etiological features must emerge in the background of severe steatohepatitis.
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August 2002

Benzo[b]-1,8-naphthyridine derivatives: synthesis and reversal activity on multidrug resistance.

Anticancer Res 2002 Jul-Aug;22(4):2097-101

GERCTOP/UMR CNRS 6009, Faculté de Pharmacie, Marseille, France.

A series of benzo[b]-1,8-naphthyridine derivatives branched with various side-chains and substituents were prepared with the aim of being investigated as multidrug resistance (MDR) modulators. The syntheses were achieved from 2-halonicotinic acid and suitable aryl-amines according to a three-step procedure. All the derivatives were tested in vitro on mouse T-Lymphoma cell line L5178 transfected by MDR1 gene and the chemosensitizing properties of the compounds were compared to those of verapamil and propranolol, as well as to several other tricyclic derivatives like phenothiazines and acridines. Most of the compounds tested reversed the MDR of tumour cells more effectively than the reference drugs did and they showed more potent chemosensitizing activity than phenothiazine and acridine derivatives have.
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September 2002