Publications by authors named "Johanna Liinamaa"

23 Publications

  • Page 1 of 1

Association of glucose metabolism and retinopathy signs in non-diabetic individuals in midlife-The Northern Finland Birth Cohort 1966 study.

PLoS One 2020 22;15(10):e0240983. Epub 2020 Oct 22.

Center for Life Course Health Research, University of Oulu, Oulu, Finland.

Diabetic retinopathy is a microvascular complication of hyperglycaemia. Little is known about the association of glucose metabolism and retinopathy signs in the non-diabetic middle-aged population. We studied prevalence of retinopathy in a subsample of Northern Finland Birth Cohort study (NFBC1966) of 1809 subjects, at 47 years of age, without previously diagnosed type 2 diabetes and/or blood pressure-lowering medication. All participants underwent clinical evaluations including an oral glucose tolerance test (glucose and insulin values measured at 0, 30, 60 and 120 min) and HbA1c. The retinopathy signs were diagnosed by fundus photographs and classified according to the Eurodiab classification scheme. The overall prevalence of newly diagnosed retinopathy was 1.4%. The retinopathy signs were significantly associated with increased 30 min, 1-h and 2-h glucose levels and 2-h insulin level in an OGTT. After adjustment with systolic blood pressure, only 30 min glucose, 1-h glucose and 2-h insulin levels were associated with retinopathy signs. Our findings show the potential role of 30 min and 1-h post-load glucose and 2-h insulin levels as risk factors for retinopathy lesions among the participants without previously diagnosed diabetes or hypertensive medication.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240983PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580974PMC
December 2020

Prediabetes influences the structure of the macula: thinning of the macula in the Northern Finland Birth Cohort.

Br J Ophthalmol 2020 Oct 7. Epub 2020 Oct 7.

Ophthalmology, Oulu University Hospital, Oulu, Finland

Background/aim: The aim of this study was to evaluate the effect of prediabetes and diabetes on macular thickness and retinal vascular calibres in our population-based cohort (Northern Finland Birth Cohort).

Methods: The population of 2005 individuals was divided into diabetes (n=57), prediabetes (n=1638) and normal glucose metabolism (NGM) groups (n=310). Total thickness of the macula was measured using Cirrus HD-OCT 4000. Central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) calibres were measured from the fundus images. The diagnosis of diabetes and prediabetes was made according to WHO 2006 diagnostic standards.

Results: Significant macular thinning was observed in subjects with prediabetes (-2.69 μm (95% CI -4.29 to -1.09), p<0.05 and -0.10 mm (95% CI -0.16 to -0.04), p<0.05 for macular cube average thickness and cube volume, respectively) and it was greatest in the pericentral area. Macular cube average thickness and macular cube volume decreased significantly by worsening glucose metabolism. Furthermore, CRAE was decreased by increases in 2-hour post-load glucose, glucose area under the curve and increase in Matsuda index (p<0.001, 0.019 and <0.001, respectively). In mediation analysis, macular thickness had significant average causal mediation effect (ACME) on CRVE and CRAE in subjects with prediabetes.

Conclusion: We detected significant thinning of the macula in subjects with prediabetes. The diameters of retinal arteries were decreased by impaired glucose metabolism. This study provides a new perspective since it revealed that the early and subtle changes caused by prediabetes as macular thinning had significant ACME on retinal vessels, therefore supporting the neurodegenerative theory of diabetes-induced changes in the retina.
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http://dx.doi.org/10.1136/bjophthalmol-2020-317414DOI Listing
October 2020

Icare versus Goldmann in a randomised middle-aged population: The influence of central corneal thickness and refractive errors.

Eur J Ophthalmol 2020 Jun 10:1120672120921380. Epub 2020 Jun 10.

Department of Ophthalmology, Oulu University Hospital, Oulu, Finland.

Purpose: The aim of this study was to compare the measurements of intraocular pressure by two tonometers, the Icare rebound tonometer and the Goldmann applanation tonometer, in a randomised screening study. The influence of refraction and central corneal thickness on the measurements was also evaluated.

Methods: Intraocular pressure was measured with rebound tonometer and Goldmann applanation tonometer in 1266 participants; refraction and central corneal thickness were also determined. One randomised eye of each participant was selected for this report's analysis. A Bland-Altman plot was used to compare the values obtained with the two devices.

Results: The correlation between rebound tonometer and Goldmann applanation tonometer was good: the intraclass correlation coefficient (r) between the two methods was 0.735 ( < 0.001). The mean difference (rebound tonometer-Goldmann applanation tonometer) was 0.11 ± 2.3 mmHg. The difference was not statistically significant (95% confidence interval: 0.11 to 0.13,  = 0.09). With increasing central corneal thickness, not only did intraocular pressure values with both devices increase, but the difference between them also increased. Refraction (spherical equivalent) did not influence intraocular pressure or the rebound tonometer-Goldmann applanation tonometer difference. However, high astigmatism (≥2D) exerted an influence on intraocular pressure values taken with Goldmann applanation tonometer.

Conclusion: Measurements with rebound tonometer and Goldmann applanation tonometer are relatively uniform although rebound tonometer slightly overestimated intraocular pressure. Both rebound tonometer and Goldmann applanation tonometer and the difference between these devices were affected by central corneal thickness but not by refraction. Higher astigmatism affected Goldmann applanation tonometer more than rebound tonometer. It is concluded that rebound tonometer is a reliable method for measuring intraocular pressure in a population-based screening study.
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http://dx.doi.org/10.1177/1120672120921380DOI Listing
June 2020

Relation between retinal vessel diameter and posterior segment optical coherence tomography variables in middle-aged Caucasians: the Northern Finland Birth Cohort Eye Study.

Br J Ophthalmol 2020 10 20;104(10):1435-1442. Epub 2020 Jan 20.

Department of Ophthalmology, Oulu University Hospital, Oulu, Finland

Aims: Studying the relationship between retinal vessel diameter (RVD) with (1) macular thickness and volume, (2) retinal nerve fibre layer (RNFL), (3) ganglion cell-inner plexiform layer (GC-IPL) and (4) optic nerve head (ONH) in a population cohort of middle-aged Caucasians.

Methods: We collected data from 3070 individuals. We used a semiautomated computer-assisted programme to measure central retinal arteriolar equivalent and central retinal venular equivalent. Macular and ONH parameters were assessed by optical coherence tomography.

Results: Data from 2155 persons were analysed. A larger RVD was associated with a thicker macula and increased macular volume; each SD increase in average macular thickness and volume was associated with a 3.28 µm and a 3.19 µm increase in arteriolar diameter and a 5.10 µm and a 5.08 µm increase in venular diameter, respectively (p<0.001 for all). A larger rim area, greater GC-IPL and RNFL thicknesses were associated with larger RVD; each SD increase in rim area, GC-IPL thickness and RNFL thickness was associated with a 1.21 µm, 2.68 µm and a 3.29 µm increase in arteriolar diameter and a 2.13 µm, 4.02 µm and 5.04 µm increase in venular diameter, respectively (p<0.001 for all).

Conclusions: Increased macular thickness, macular volume, GC-IPL thickness, RNFL thickness and optic nerve rim area were associated with larger RVDs in all subjects. This study clarified the anatomical correlations between both macular and ONH parameters with RVD for middle-aged Caucasians; these can represent a basis for further studies investigating the vascular aetiology of eye diseases.
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http://dx.doi.org/10.1136/bjophthalmol-2019-314803DOI Listing
October 2020

Diagnostic performance of modern imaging instruments in glaucoma screening.

Br J Ophthalmol 2020 10 16;104(10):1399-1405. Epub 2020 Jan 16.

Department of Ophthalmology, Oulu University Hospital, Oulu, Finland.

Aim: To evaluate the applicability of imaging devices (spectral-domain optical coherence tomography (Cirrus SD-OCT), scanning laser polarimetry (GDx) and scanning laser ophthalmoscopy (Heidelberg Retinal Tomograph, HRT3)) for glaucoma screening in a middle-aged unselected population.

Methods: Participants of the population-based Northern Finland Birth Cohort Eye Study, aged 45 to 49 years, underwent a comprehensive eye examination including modern imaging with five methods (retinal nerve fibre layer (RNFL) and macular ganglion cell layer +inner plexiform layer (GCIPL) analysis and their combination with SD-OCT, GDx and HRT). The performance of the automated classification of the imaging devices was assessed using a clinical glaucoma diagnosis as reference, that is, the '2 out of 3' rule based on the evaluation of optic nerve head and RNFL photographs and visual fields.

Results: We examined 6060 eyes of 3039 subjects; in the clinical evaluation, glaucomatous damage was found in 33 subjects (1.1%) in 43 eyes. The following sensitivities were obtained; RNFL analysis (53%), GCIPL analysis (50%), OCT combination analysis (61%), GDx (56%) and HRT (31%) with corresponding specificities of 95%, 92%, 90%, 88% and 96%. The area under the curve values were 0.76, 0.73, 0.75, 0.75 and 0.73, respectively. Post-test probabilities of glaucoma after positive imaging finding with each of these methods in this unselected population were 11%, 7%, 6%, 5% and 7%, respectively.

Conclusion: Screening capabilities of the OCT, GDx and HRT were rather similar. The accuracy of all evaluated parameters was only moderate and thus screening with these parameters alone is not reliable.
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http://dx.doi.org/10.1136/bjophthalmol-2019-314795DOI Listing
October 2020

Novel variants and phenotypes widen the phenotypic spectrum of GABRG2-related disorders.

Seizure 2019 Jul 19;69:99-104. Epub 2019 Mar 19.

PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Division of Pediatric Neurology, Oulu University Hospital, Oulu, Finland.

Purpose: Next-generation sequencing (NGS) has made genetic testing of patients with epileptic encephalopathies easier - novel variants are discovered and new phenotypes described. Variants in the same gene - even the same variant - can cause different types of epilepsy and neurodevelopmental disorders. Our aim was to identify the genetic causes of epileptic encephalopathies in paediatric patients with complex phenotypes.

Methods: NGS was carried out for three patients with epileptic encephalopathies. Detailed clinical features, brain magnetic resonance imaging and electroencephalography were analysed. We searched the Human Gene Mutation Database for the published GABRG2 variants with clinical description of patients and composed a summary of the variants and their phenotypic features.

Results: We identified two novel de novo GABRG2 variants, p.P282T and p.S306F, with new phenotypes including neuroradiological evidence of neurodegeneration and epilepsy of infancy with migrating focal seizures (EIMFS). One patient carried previously reported p.P83S variant with autism spectrum disorder (ASD) phenotype that has not yet been described related to GABRG2 disorders and a more severe epilepsy phenotype than reported earlier. In all, the literature search yielded twenty-two articles describing 27 different variants that were divided into two categories: those with self-limiting epilepsies and febrile seizures and those with more severe drug-resistant epileptic encephalopathies.

Conclusion: This study further expands the genotypic and phenotypic spectrum of epilepsies associated with GABRG2 variants. More knowledge is still needed about the influence of the environment, genetic background and other epilepsy susceptibility genes on the phenotype of the specific GABRG2 variants.
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http://dx.doi.org/10.1016/j.seizure.2019.03.010DOI Listing
July 2019

Relationship between retinal vessel diameter with both retinal nerve fibre layer thickness and optic nerve head parameters in middle-aged Caucasians: the Northern Finland Birth Cohort Eye study.

Acta Ophthalmol 2019 Aug 10;97(5):532-538. Epub 2018 Dec 10.

Department of Ophthalmology, Oulu University Hospital, Oulu, Finland.

Purpose: To study the normal relationship between retinal vessel diameter (RVD) with retinal nerve fibre layer (RNFL) thickness and optic nerve head (ONH) parameters in a cohort of middle-aged Caucasians.

Methods: We investigated 3070 individuals (6140 eyes). Central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were measured in the right eye using a semi-automated computer-assisted program. Retinal nerve fibre layer (RNFL) thickness and ONH parameters were assessed with Heidelberg retinal tomography (HRT).

Results: Data from 2217 persons were analysed including RNFL, CRAE, CRVE, sex, body mass index, mean arterial pressure, diabetes status, smoking status, optic disc area, rim area, spherical refraction and intraocular pressure. A larger RVD was associated with a thicker mean global RNFL thickness especially in global and inferior segments of the retina and with larger optic discs. Each 10 μm increase in the retinal arteriolar calibre was associated with a 5.58 μm increase in mean global RNFL thickness; the corresponding value for a 10 μm increase in venular calibre was 3.79 μm (p < 0.001 for both). Retinal venular calibre displayed consistent associations with RNFL thickness in both genders (p < 0.001 for all), whereas the association of arteriolar calibre and RNFL was more prominent in men (p < 0.001).

Conclusion: We found strong associations between larger RVD and thicker RNFL in all subjects. This study helps to clarify the association between RVD, RNFL thickness and ONH parameters and provides normal values for middle-aged Caucasians that will help in future studies investigating the role of vascular aetiology in systemic and eye diseases.
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http://dx.doi.org/10.1111/aos.13992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767424PMC
August 2019

Fluoxetine does not enhance the effect of perceptual learning on visual function in adults with amblyopia.

Sci Rep 2018 08 27;8(1):12830. Epub 2018 Aug 27.

Department of Ophthalmology, University of Tampere, School of Medicine, 33014, Tampere, Finland.

Amblyopia is a common visual disorder that is treatable in childhood. However, therapies have limited efficacy in adult patients with amblyopia. Fluoxetine can reinstate early-life critical period-like neuronal plasticity and has been used to recover functional vision in adult rats with amblyopia. We conducted a Phase 2, randomized (fluoxetine vs. placebo), double-blind, multicenter clinical trial examined whether or not fluoxetine can improve visual acuity in amblyopic adults. This interventional trial included 42 participants diagnosed with moderate to severe amblyopia. Subjects were randomized to receive either 20 mg fluoxetine (n = 22) or placebo (n = 20). During the 10-week treatment period, all subjects performed daily computerized perceptual training and eye patching. At the primary endpoint, the mean treatment group difference in visual acuity improvement was only 0.027 logMAR units (95% CI: -0.057 to 0.110; p = 0.524). However, visual acuity had significantly improved from baseline to 10 weeks in both fluoxetine (-0.167 logMAR; 95% CI: -0.226 to -0.108; p < 0.001) and placebo (-0.194 logMAR; 95% CI: -0.254 to -0.133; p < 0.001) groups. While this study failed to provide evidence that fluoxetine enhances neuroplasticity, our data support other recent clinical studies suggesting that improvement of vision can be accomplished in adults with amblyopia.
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http://dx.doi.org/10.1038/s41598-018-31169-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110780PMC
August 2018

Evaluating refraction and visual acuity with the Nidek autorefractometer AR-360A in a randomized population-based screening study.

Acta Ophthalmol 2018 Jun 30;96(4):384-389. Epub 2017 Nov 30.

Department of Ophthalmology, Oulu University Hospital, Oulu, Finland.

Purpose: The evaluation of visual acuity (VA) and refraction in the Northern Finland Birth Cohort Eye study was performed using the Nidek AR-360A autorefractometer. The accuracy of the method for this population-based screening study was assessed.

Methods: Measurements of the refractive error were obtained from the right eyes of 1238 subjects (mean age 47), first objectively with the AR-360A and then subjectively by an optometrist. Agreement with the subjective refraction was calculated for sphere, cylinder, mean spherical equivalent (MSE), cylindrical vectors J and J and presbyopic correction (add). Visual acuity (VA) was measured using an ETDRS chart and the autorefractometer.

Results: The refractive error measured with the AR-360A was higher than the subjective refraction performed by the optometrist for sphere (0.007 D ± 0.24 D p = 0.30) and also for cylinder (-0.16 D ± 0.20 D p < 0.0005). The bias between the measurements of MSE, J and J was low: -0.07 D ± 0.22 D (p = 0.002), 0.01 D ± 0.43 D (p = 0.25) and -0.01 D ± 0.42 D (p = 0.43), respectively. The amount of add measured by the autorefractometer was higher than the subjective 0.35 D ± 0.29 D (p < 0.0005). There was a statistically significant correlation between VA (p < 0.0005) and the difference between the subjective and objective refraction. In 99.2% of the measurements, visual values were within one decimal line of each other.

Conclusion: The Nidek AR-360A autorefractometer is an accurate tool for determining the refraction and VA in a clinical screening trial.
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http://dx.doi.org/10.1111/aos.13636DOI Listing
June 2018

Factors Affecting the Visual Outcome of Pituitary Adenoma Patients Treated with Endoscopic Transsphenoidal Surgery.

World Neurosurg 2017 Sep 2;105:422-431. Epub 2017 Jun 2.

Department of Ophthalmology, Oulu University Hospital, Oulu, Finland; MRC Oulu, University of Oulu, Oulu, Finland; PEDEGO Research Unit, University of Oulu, Oulu, Finland. Electronic address:

Objective: To evaluate visual acuity (VA) and visual fields (VF) quantitatively before and after endoscopic transsphenoidal surgery (ETS), with special attention to prognostic factors such as the pituitary adenoma (PA) suprasellar extension (SSE), volume and the patients' age.

Methods: Medical records of 47 patients with PA undergoing ETS were evaluated. VA, VF, preoperative visual impairment score (VISpre) and postoperative visual impairment score (VISpost) were determined. The PA SSE, volume, chiasmal contact, and their correlation with visual function were assessed preoperatively and postoperatively.

Results: The final cohort included 47 patients. VA improved in 54 of 76 eyes (71.0%) after ETS, and 69 of 76 eyes (90.7%) gained normal VA. Postoperative VF recovery occurred in 32 of 37 eyes (86.5%). The mean change in VIS was 12.0 (95% confidence interval [CI], 7.7-16.3) and improved in all patients with tumor-related visual impairment (n = 25). However, visual outcome was poorer when VISpre was greater than 40. When VISpre was 21-40, age linearly correlated with VIS improvement (P = 0.03); younger patients had satisfactory and older poorer visual outcome. The mean SSE in patients with VF defects (n = 20) was 16.6 mm (95% CI, 13.3-19.9). Mean SSE in patients with no VF defects (n = 23) was 6.6 mm (95% CI, 4.9-8.3; P < 0.001), and the cutoff value for visual perturbations was 9.5 mm for SSE and 8.6 mL for PA volume (P < 0.001 for both).

Conclusions: The visual outcome after ETS for PAs was excellent, and serious complications were rare. Severe preoperative visual impairment resulted in poorer postoperative visual outcomes. The SSE of the PA was the most important predictor of visual outcome after ETS.
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http://dx.doi.org/10.1016/j.wneu.2017.05.144DOI Listing
September 2017

Elevated Levels of Plasma IgA Autoantibodies against Oxidized LDL Found in Proliferative Diabetic Retinopathy but Not in Nonproliferative Retinopathy.

J Diabetes Res 2016 20;2016:2614153. Epub 2016 Dec 20.

PEDEGO Research Unit, Department of Ophthalmology, Medical Research Center (MRC Oulu), Oulu University Hospital and University of Oulu, Oulu, Finland; Research Unit of Internal Medicine, Medical Research Center Oulu (MRC Oulu), Oulu University Hospital and University of Oulu, Oulu, Finland.

. This study investigated the association of autoantibodies binding to oxidized low-density lipoproteins (oxLDL) in diabetic retinopathy (DR). . Plasma from 229 types 1 and 2 patients with DR including diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) was analysed with ELISA-based assay to determine IgA, IgG, and IgM autoantibody levels binding to oxLDL. The controls were 106 diabetic patients without retinopathy (NoDR) and 139 nondiabetic controls (C). . PDR group had significantly higher IgA autoantibody levels than DME or NoDR: mean 94.9 (SD 54.7) for PDR, 75.5 (41.8) for DME ( = 0.001), and 76.1 (48.2) for NoDR ( = 0.008). There were no differences in IgG, IgM, or IgA that would be specific for DR or for DME. Type 2 diabetic patients had higher levels of IgA autoantibodies than type 1 diabetic patients (86.0 and 65.5, resp., = 0.004) and the highest levels in IgA were found in type 2 diabetic patients with PDR (119.1, > 0.001). . IgA autoantibodies were increased in PDR, especially in type 2 diabetes. The high levels of IgA in PDR, and especially in type 2 PDR patients, reflect the inflammatory process and enlighten the role of oxLDL and its autoantibodies in PDR.
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http://dx.doi.org/10.1155/2016/2614153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206457PMC
May 2017

A 6-month study comparing efficacy, safety, and tolerability of the preservative-free fixed combination of tafluprost 0.0015% and timolol 0.5% versus each of its individual preservative-free components.

Adv Ther 2014 Dec 2;31(12):1228-46. Epub 2014 Dec 2.

Department of Ophthalmology, Mainz University Medical Center, Langenbeckstr. 1, 55101, Mainz, Germany,

Introduction: The efficacy, safety and tolerability of the preservative-free (PF) fixed combination (FC) of tafluprost 0.0015% and timolol 0.5% (once daily) were compared to those of the individual components (PF tafluprost 0.0015% once daily and PF timolol 0.5% twice daily) in patients with open-angle glaucoma or ocular hypertension inadequately controlled on prior timolol or prostaglandin monotherapy for 6 months.

Methods: A stratified, double-masked, randomized, multicenter phase III study was conducted. A total of 189 prior timolol users were randomized within the timolol stratum (TS) to receive either FC (n = 95) or timolol 0.5% (TIM; n = 94). Furthermore, a total of 375 prior prostaglandin analog (PGA) users were randomized within the prostaglandin stratum (PS) to receive either FC (n = 188) or tafluprost 0.0015% (TAF; n = 187). To be eligible for participation in the study, the patients were required to have an intraocular pressure (IOP) of ≥22 mmHg when on timolol (TIM) or of ≥20 mmHg when on PGA in either treated eye at the screening and end-of-run-in visits. In addition to these, the study included visits at baseline, 2 and 6 weeks, 3 and 6 months and at a post-study visit. IOP was measured at 8 a.m., 10 a.m., 4 p.m., and 8 p.m.

Results: In the TS, a significant reduction from baseline IOP was seen with FC and TIM throughout the study. Average diurnal IOP change from baseline at month 3 was -8.55 mmHg (32%) for FC and -7.35 mmHg (28%) for TIM. The model-based treatment difference (FC-TIM) was -0.885 mmHg [95% confidence interval (CI) -1.745 to -0.024; p = 0.044] demonstrating the superiority of FC over TIM. In the PS, a significant reduction in IOP was seen with both FC and TAF throughout the study. The average diurnal IOP change from baseline at month 3 was -8.61 mmHg (33%) for FC and -7.23 mmHg (28%) for TAF. The model-based treatment difference (FC-TAF) was -1.516 mmHg (95% CI -2.044 to -0.988; p < 0.001) demonstrating the superiority of FC over TAF. In the TS, related ocular adverse events (AEs) were more frequent for patients treated with FC compared to TIM (16.8% versus 6.4%), whereas related non-ocular AEs were more frequent with TIM compared to FC (2.1% versus 0.0%). In the PS, AEs were similarly distributed between FC and TAF. The frequency of conjunctival hyperemia of FC was low (6.4%).

Conclusion: The preservative-free fixed combination of tafluprost and timolol provided a substantial and significant IOP reduction in both strata. The IOP reduction was superior to both tafluprost 0.0015% and timolol 0.5% when given as monotherapies. Overall, the study treatments were safe and well tolerated.

Funding: Santen Oy, Tampere, Finland.
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http://dx.doi.org/10.1007/s12325-014-0163-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271134PMC
December 2014

The IL-8, VEGF, and CFH polymorphisms and bevacizumab in age-related macular degeneration.

Ophthalmology 2014 Apr 15;121(4):973-973.e1. Epub 2014 Feb 15.

Department of Ophthalmology, Helsinki University Central Hospital, Finland.

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http://dx.doi.org/10.1016/j.ophtha.2013.11.035DOI Listing
April 2014

Interleukin 8 promoter polymorphism predicts the initial response to bevacizumab treatment for exudative age-related macular degeneration.

Retina 2013 Oct;33(9):1815-27

*Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland †Department of Medical Genetics, University of Helsinki, Helsinki, Finland Departments of ‡Ophthalmology, Institute of Clinical Medicine, and §Internal Medicine, Clinical Research Center and Biocenter Oulu, University of Oulu, Oulu, Finland ¶Department of Clinical Chemistry, Oulu University Hospital, Oulu, Finland **Department of Biosciences, University of Helsinki, Helsinki, Finland.

Purpose: To study the association of single-nucleotide polymorphisms of interleukin 8, vascular endothelial growth factor, erythropoietin, complement factor H, complement component C3, and LOC387715 genes with the response to bevacizumab treatment in exudative age-related macular degeneration.

Methods: Clinical records, smoking history, optical coherence tomography, and angiographies of 96 bevacizumab-treated exudative age-related macular degeneration patients were analyzed retrospectively. Blood DNA was collected. Based on the disappearance of intra- or subretinal fluid in optical coherence tomography, patients were graded as responders, partial responders, or nonresponders after 3 initial treatment visits and a median time of 3.5 months.

Results: Interleukin 8 promoter polymorphism -251A/T was significantly associated with persisting fluid in optical coherence tomography. The A allele was more frequent in nonresponders than in responders (P = 0.033). In multivariate modeling, the AA genotype of -251A/T (P = 0.043) and occult (P = 0.042) or predominantly classic (P = 0.040) lesions predicted poorer outcome. Visual acuity change was better in responders than in nonresponders (P = 0.006). Baseline lesion size (P = 0.006) and retinal cysts after the treatment (P < 0.001) correlated with less visual acuity gain.

Conclusion: The A allele and the homozygous AA genotype of interleukin 8 -251A/T were associated with anatomical nonresponse to bevacizumab treatment.
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http://dx.doi.org/10.1097/IAE.0b013e318285cf92DOI Listing
October 2013

Ang-2 upregulation correlates with increased levels of MMP-9, VEGF, EPO and TGFβ1 in diabetic eyes undergoing vitrectomy.

Acta Ophthalmol 2013 Sep 26;91(6):531-9. Epub 2012 Oct 26.

Unit of Vitreoretinal Surgery, Department of Ophthalmology, Helsinki University Central Hospital, Finland.

Purpose: Angiogenesis in diabetic retinopathy (DR) is a multifactorial process regulated by hypoxia-induced growth factors and inflammatory cytokines. In addition to the angiogenic switch, the proteolytic processing and altered synthesis of the extracellular matrix are critical steps in this disease. This study was performed to evaluate the levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 (MMP-2 and MMP-9), angiopoietin-1 and angiopoietin-2 (Ang-1 and Ang-2), vascular endothelial growth factor (VEGF), erythropoietin (EPO) and transforming growth factor-β1 (totalTGFβ1) in the vitreous of diabetic eyes undergoing vitrectomy compared with control eyes operated because of macular hole or pucker.

Methods: Prospective consecutive controlled observational study performed in the unit of vitreoretinal surgery in Finland during the years 2006-2008. Vitreous samples were collected before the start of the conventional 3-ppp vitrectomy. Vitreous MMP-2 and MMP-9, Ang-1 and Ang-2, VEGF, EPO and TGFβ1 concentrations were measured from 69 patients with Type 1 or 2 diabetes and 40 controls.

Results: Comparison of eyes with DR with controls revealed that the mean vitreous concentrations of proMMP-2 (p = 0.0015), totalMMP-2 (p = 0.0011), proMMP-9 (p = 0.00001), totalMMP-9 (p < 0.00001), Ang-2 (p < 0.00001), VEGF (p < 0.00001), EPO (p < 0.00001) and totalTGFβ1 (p = 0.000026) were significantly higher in the former group. A multivariate logistic regression analysis suggested intravitreal Ang-2 concentration being the key marker of PDR (p = 0.00025) (OR = 1507.9).

Conclusion: The main new finding is that the intravitreal concentrations of Ang-2 correlated significantly with MMP-9, VEGF, EPO and TGFβ1 levels in diabetic eyes undergoing vitrectomy. Thus, these factors could promote retinal angiogenesis synergistically.
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http://dx.doi.org/10.1111/j.1755-3768.2012.02473.xDOI Listing
September 2013

Elevated messenger RNA expression and plasma protein levels of osteopontin and matrix metalloproteinase types 2 and 9 in patients with ascending aortic aneurysms.

J Thorac Cardiovasc Surg 2013 Apr 7;145(4):1117-1123. Epub 2012 May 7.

Institute of Clinical Medicine, Department of Internal Medicine, Clinical Research Center, Oulu University Hospital and Biocenter Oulu, University of Oulu, Oulu, Finland.

Objective: Ascending aortic aneurysms result from a degenerative process in the aortic wall, characterized by the loss of smooth muscle cells and elastic fibers. We hypothesized that there would be changes in plasma protein and aortic tissue messenger RNA levels of osteopontin, matrix metalloproteinase type 2, matrix metalloproteinase type 9, and tissue inhibitor of matrix metalloproteinases type 1 in ascending aortic aneurysm samples.

Methods: Plasma, aortic tissue, and aortic mRNA samples were collected from patients with an ascending aortic aneurysm or an abdominal aortic aneurysm and from control individuals. Plasma protein levels of osteopontin, matrix metalloproteinase (MMP) types 2 and 9, and tissue inhibitor of matrix metalloproteinases type 1 were determined by quantitative sandwich enzyme-linked immunosorbent assay. Aortic mRNA levels of these same proteins were analyzed with the quantitative real-time polymerase chain reaction (RT-PCR) method and protein levels from the aortic tissues were assayed by immunostaining. Quantitative RT-PCR results were estimated by the normalized expression method (ΔΔCt).

Results: Plasma protein levels were significantly elevated for osteopontin, MMP-2, and MMP-9 in the samples of ascending and abdominal aortic aneurysm group compared with controls. Plasma protein levels of MMP-9 were higher in the nonoperated compared with the operated ascending aortic aneurysm group. Aortic osteopontin, MMP-2, and MMP-9 mRNA levels were increased for ascending aortic aneurysm samples.

Conclusions: This study reveals an important role of osteopontin, MMP-2 and MMP-9 in the development of ascending and abdominal aortic aneurysm.
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http://dx.doi.org/10.1016/j.jtcvs.2012.04.008DOI Listing
April 2013

Vascular endothelial growth factor gene variation and the response to photodynamic therapy in age-related macular degeneration.

Ophthalmology 2010 Jan 6;117(1):103-8. Epub 2009 Nov 6.

Department of Ophthalmology, Helsinki University Hospital, Helsinki, Finland.

Purpose: To evaluate the role of vascular endothelial growth factor (VEGF) gene polymorphisms in exudative age-related macular degeneration (AMD).

Design: Retrospective, comparative case series.

Participants: Patients with recent exudative AMD (n = 162) and age-matched subjects without AMD (n = 85).

Methods: Fluorescein angiography (FA), clinical examination, and single nucleotide polymorphism (SNP) genotyping.

Main Outcome Measures: The frequencies of 3 VEGF gene SNPs were analyzed, 1 at the promoter site (rs699947, A-->C) and 2 intronic SNPs (rs2146323, A-->C, and rs3025033, A-->G), in relation to the risk of AMD, to choroidal neovascular (CNV) lesion size and configuration, and to the anatomic response to photodynamic therapy (PDT). These SNPs were chosen to cover all the haploblocks of the VEGF gene. The 86 patients who had undergone PDT were classified as either PDT responders or PDT nonresponders based on the outcome of PDT after the last treatment session. For the PDT responders, the treating physician had deemed the lesion to be clinically dry and without leakage from CNV in FA at a visit scheduled at least 12 weeks after the last PDT treatment. For the PDT nonresponders, the PDT sessions had been discontinued by the treating retina specialist because of an apparently poor response and a still exudative lesion after several PDT sessions.

Results: The presence of exudative AMD or lesion size or configuration was not associated with the SNPs studied here. The frequencies of the rs699947 were significantly different in PDT nonresponders and PDT responders. The AA, AC, and CC genotypes were 14%, 39%, and 46%, respectively, in PDT nonresponders, compared with 40%, 48%, and 12%, respectively, in the PDT responders (P = 0.0008). The corresponding frequencies for the rs2146323 AA, AC, and CC genotypes were 4%, 32%, and 64%, respectively, in nonresponders and 24%, 38%, and 38%, respectively, in responders (P = 0.0369). The genotypes of the rs3025033 SNP were distributed evenly between the responders and nonresponders.

Conclusions: The VEGF gene polymorphic SNPs at rs699947 and rs2146323 are strong determinants of the anatomic outcome after PDT, but the SNPs studied were not associated with the presence of exudative AMD or with the CNV lesion size or configuration.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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http://dx.doi.org/10.1016/j.ophtha.2009.06.037DOI Listing
January 2010

Characterization of metabolic interrelationships and in silico phenotyping of lipoprotein particles using self-organizing maps.

J Lipid Res 2010 Feb 5;51(2):431-9. Epub 2009 Sep 5.

Department of Biomedical Engineering and Computational Science, Helsinki University of Technology, Espoo, Finland.

Plasma lipid concentrations cannot properly account for the complex interactions prevailing in lipoprotein (patho)physiology. Sequential ultracentrifugation (UCF) is the gold standard for physical lipoprotein isolations allowing for subsequent analyses of the molecular composition of the particles. Due to labor and cost issues, however, the UCF-based isolations are usually done only for VLDL, LDL, and HDL fractions; sometimes with the addition of intermediate density lipoprotein (IDL) particles and the fractionation of HDL into HDL(2) and HDL(3) (as done here; n = 302). We demonstrate via these data, with the lipoprotein lipid concentration and composition information combined, that the self-organizing map (SOM) analysis reveals a novel data-driven in silico phenotyping of lipoprotein metabolism beyond the experimentally available classifications. The SOM-based findings are biologically consistent with several well-known metabolic characteristics and also explain some apparent contradictions. The novelty is the inherent emergence of complex lipoprotein associations; e.g., the metabolic subgrouping of the associations between plasma LDL cholesterol concentrations and the structural subtypes of LDL particles. Importantly, lipoprotein concentrations cannot pinpoint lipoprotein phenotypes. It would generally be beneficial to computationally enhance the UCF-based lipoprotein data as illustrated here. Particularly, the compositional variations within the lipoprotein particles appear to be a fundamental issue with metabolic and clinical corollaries.
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http://dx.doi.org/10.1194/jlr.D000760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803246PMC
February 2010

Polymorphism of the manganese superoxide dismutase gene but not of vascular endothelial growth factor gene is a risk factor for diabetic retinopathy.

Br J Ophthalmol 2009 Oct 23;93(10):1401-6. Epub 2009 Jul 23.

Department of Internal Medicine, Clinical Research Center, Oulu University Hospital and Biocenter Oulu, University of Oulu, Oulu, Finland.

Background: In diabetic retinopathy, the vascular endothelium is damaged due to oxidative stress and inflammation, and vitreous VEGF concentration becomes elevated. The association of diabetic retinopathy with single nucleotide polymorphisms (SNPs) was studied on two genes: VEGF, an important mediator of neovascularisation, and MnSOD, a major antioxidant enzyme.

Methods: The study population was 755 individuals consisting of 131 diabetic (type 1 or type 2) patients with diabetic retinopathy (DR group), 98 diabetic controls without retinopathy (DC group) and 526 non-diabetic controls. VEGF SNPs rs699947, rs2010963, rs2146232, rs3025033, rs3025039 and Ala16Val polymorphism of the MnSOD gene were genotyped.

Results: The frequencies of allele and genotype of the single genotyped VEGF SNPs or reconstructed haplotypes of these single SNPs did not differ between DR and DC groups. A higher frequency of the AlaAla genotype (p = 0.03) and Ala16 allele (p = 0.04) of the MnSOD gene in the DR group was found when compared with the DC group.

Conclusions: In conclusion, the studied VEGF SNPs were not associated with the risk of diabetic retinopathy, and so it is unlikely that the VEGF gene is a major locus determining the risk of diabetic retinopathy. A statistically significant association of MnSOD Ala16Val polymorphism with diabetic retinopathy was found.
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http://dx.doi.org/10.1136/bjo.2009.159012DOI Listing
October 2009

Efficacy and safety levels of preserved and preservative-free tafluprost are equivalent in patients with glaucoma or ocular hypertension: results from a pharmacodynamics analysis.

Acta Ophthalmol Suppl (Oxf ) 2008 ;242:14-9

Augenzentrum Dr. Hamacher Praxis, Maximilianstrasse 2B, Starnberg, Germany.

Purpose: Tafluprost is a new prostaglandin F(2alpha) (PGF(2alpha)) derivative in development for the treatment of glaucoma. Tafluprost is the first PGF(2alpha) analogue with a preservative-free formulation.

Methods: This randomized, investigator-masked, multicentre, crossover phase III study evaluated the pharmacodynamics and safety of preserved and preservative-free tafluprost 0.0015% eyedrops administered for 4 weeks in 43 patients with open-angle glaucoma or ocular hypertension. The primary variable was change from baseline in overall diurnal intraocular pressure (IOP) at 4 weeks. Adverse events and other safety parameters were also analysed.

Results: Decreased IOP was clearly observed with both formulations at week 1 and was sustained until week 4. The overall treatment difference (preservative-free versus preserved formulations) at week 4 was 0.01 mmHg (95% confidence interval - 0.46 to 0.49; p = 0.96). There were no unexpected safety-related findings. Both formulations were well tolerated and most adverse events were ocular and mild in severity.

Conclusions: THE reduction in IOP achieved by preservative-free tafluprost is equivalent to that obtained with the preserved formulation. The preservative-free formulation was generally well tolerated.
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http://dx.doi.org/10.1111/j.1755-3768.2008.01381.xDOI Listing
November 2008

High vitreous concentration of vascular endothelial growth factor in diabetic patients with proliferative retinopathy using statins.

Ann Med 2008 ;40(3):209-14

Department of Internal Medicine and Clinical Research Center, University of Oulu, Oulu, Finland.

Background: Vascular endothelial growth factor (VEGF) plays an important role in the development of diabetic retinopathy. Previous studies have suggested that angiotensin-converting enzyme (ACE) inhibitor therapy may reduce vitreous VEGF concentration in diabetic retinopathy. Also HMG CoA reductase inhibitors (statins), known for their beneficial effects on vascular endothelium, might influence vitreous VEGF concentration in diabetic retinopathy.

Aim: Vitreous VEGF concentration of diabetic patients with proliferative retinopathy using statin therapy and/or ACE inhibitor therapy was studied.

Methods: Fifty diabetic patients with proliferative diabetic retinopathy, 21 diabetic control patients without proliferative retinopathy, and 43 non-diabetic control subjects underwent vitrectomy. Vitreous samples were collected at the beginning of surgery, and VEGF concentration was assessed using a chemiluminescent VEGF immunoassay.

Results: Vitreous VEGF concentration was significantly higher in diabetic patients with proliferative retinopathy using statins than in those not using statins. The diabetic patients with proliferative retinopathy were divided into subgroups according to use of ACE inhibitor and/or statin medication. These groups did not differ significantly in concentration of vitreous VEGF.

Conclusions: Statin therapy is associated with high vitreous VEGF concentration in diabetic patients with proliferative retinopathy. In contrast to previous reports, ACE inhibitor use did not significantly influence vitreous VEGF concentration in these patients.
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http://dx.doi.org/10.1080/07853890701749209DOI Listing
June 2008

Defective glycosylation of cholesteryl ester transfer protein in plasma from alcohol abusers.

Alcohol Alcohol 2006 Jan-Feb;41(1):18-23. Epub 2005 Oct 3.

Department of Internal Medicine, University of Oulu, PO Box 5000, 90014 Oulu, Finland.

Aims: Alcohol consumption reduces the carbohydrate content of some glycoproteins, e.g. carbohydrate-deficient transferrin. The aim of this study was to investigate if there is such an alcohol-induced glycosylation defect in plasma cholesteryl ester transfer protein (CETP). A defect in the posttranslational glycosylation of CETP may affect its structure and electrical charge and may therefore affect its function. CETP activity is low in alcohol abusers.

Methods: We studied the effect of alcohol consumption on CETP properties in 10 alcohol abusers and 10 control subjects. CETP was partially purified from lipoprotein-free plasma by FPLC using a Phenyl-Sepharose column. Isoelectric focusing, polyacrylamide gel electrophoresis, and western blotting were performed for partially purified CETP.

Results: CETP had a lower molecular weight in the alcohol abusers than in the controls (range 50.6-84.0 kDa in the alcohol abusers vs 51.3-85.0 kDa in the controls). CETP purified from alcohol abusers had a higher isoelectric point, indicating a lower negative charge on the surface of the protein than in the controls' CETP. A similar effect was observed when control CETP was incubated with neuraminidase, an enzyme which is known to remove sialic acid from glycoproteins.

Conclusions: We conclude that CETP from alcohol abusers may have a glycosylation defect due to defective sialylation caused posttranslationally by alcohol itself or its metabolite acetaldehyde. The defective glycosylation of CETP associated with altered binding to lipoproteins may lead to the low CETP activity observed previously in alcoholic subjects.
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http://dx.doi.org/10.1093/alcalc/agh216DOI Listing
April 2006