Evaluation of the efficacy and economics of irrigation management, plant resistance and Brassica(spot)(TM) models for management of white blister on Brassica crops

Options for the integrated management of white blister (caused by Albugo candida) of Brassica crops include the use of well timed overhead irrigation, resistant cultivars, programs of weekly fungicide sprays or strategic fungicide applications based on the disease risk prediction model, Brassica(spot)(TM). Initial systematic surveys of radish producers near Melbourne, Victoria, indicated that crops irrigated overhead in the morning (0800-1200 h) had a lower incidence of white blister than those irrigated overhead in the evening (2000-2400 h). A field trial was conducted from July to November 2008 on a broccoli crop located west of Melbourne to determine the efficacy and economics of different practices used for white blister control, modifying irrigation timing, growing a resistant cultivar and timing spray applications based on Brassica(spot)(TM). Growing the resistant cultivar, 'Tyson', instead of the susceptible cultivar, 'Ironman', reduced disease incidence on broccoli heads by 99 %. Overhead irrigation at 0400 h instead of 2000 h reduced disease incidence by 58 %. A weekly spray program or a spray regime based on either of two versions of the Brassica(spot)(TM) model provided similar disease control and reduced disease incidence by 72 to 83 %. However, use of the Brassica(spot)(TM) models greatly reduced the number of sprays required for control from 14 to one or two. An economic analysis showed that growing the more resistant cultivar increased farm profit per ha by 12 %, choosing morning irrigation by 3 % and using the disease risk predictive models compared with weekly sprays by 15 %. The disease risk predictive models were 4 % more profitable than the unsprayed control.

Luke, The Friend of Sinners

I examine the portrayal of Jesus as a friend of toll collectors and sinners in the Third Gospel. I aim at a comprehensive view on the Lukan sinner texts, combining questions of the origin and development of these texts with the questions of Luke s theological message, of how the text functions as literature, and of the social-historical setting(s) behind the texts. Within New Testament scholarship researchers on the historical Jesus mostly still hold that a special mission to toll collectors and sinners was central in Jesus public activity. Within Lukan studies, M. Goulder, J. Kiilunen and D. Neale have claimed that this picture is due to Luke s theological vision and the liberties he took as an author. Their view is disputed by other Lukan scholars. I discuss methods which scholars have used to isolate the typical language of Luke s alleged written sources, or to argue for the source-free creation by Luke himself. I claim that the analysis of Luke s language does not help us to the origin of the Lukan pericopes. I examine the possibility of free creativity on Luke s part in the light of the invention technique used in ancient historiography. Invention was an essential part of all ancient historical writing and therefore quite probably Luke used it, too. Possibly Luke had access to special traditions, but the nature of oral tradition does not allow reconstruction. I analyze Luke 5:1-11; 5:27-32; 7:36-50; 15:1-32; 18:9-14; 19:1-10; 23:39-43. In most of these some underlying special tradition is possible though far from certain. It becomes evident that Luke s reshaping was so thorough that the pericopes as they now stand are decidedly Lukan creations. This is indicated by the characteristic Lukan story-telling style as well as by the strongly unified Lukan theology of the pericopes. Luke s sinners and Pharisees do not fit in the social-historical context of Jesus day. The story-world is one of polarized right and wrong. That Jesus is the Christ, representative of God, is an intrinsic part of the story-world. Luke wrote a theological drama inspired by tradition. He persuaded his audience to identify as (repenting) sinners. Luke's motive was that he saw the sinners in Jesus' company as forerunners of Gentile Christianity.

Communities of wood-inhabiting fungi : Ecological requirements and responses to forest management and fragmentation

Despite much research on forest biodiversity in Fennoscandia, the exact mechanisms of species declines in dead-wood dependent fungi are still poorly understood. In particular, there is only limited information on why certain fungal species have responded negatively to habitat loss and fragmentation, while others have not. Understanding the mechanisms behind species declines would be essential for the design and development of ecologically effective and scientifically informed conservation measures, and management practices that would promote biodiversity in production forests. In this thesis I study the ecology of polypores and their responses to forest management, with a particular focus on why some species have declined more than others. The data considered in the thesis comprise altogether 98,318 dead-wood objects, with 43,085 observations of 174 fungal species. Out of these, 1,964 observations represent 58 red-listed species. The data were collected from 496 sites, including woodland key habitats, clear-cuts with retention trees, mature managed forests, and natural or natural-like forests in southern Finland and Russian Karelia. I show that the most relevant way of measuring resource availability can differ to a great extent between species seemingly sharing the same resources. It is thus critical to measure the availability of resources in a way that takes into account the ecological requirements of the species. The results show that connectivity at the local, landscape and regional scales is important especially for the highly specialized species, many of which are also red-listed. Habitat loss and fragmentation affect not only species diversity but also the relative abundances of the species and, consequently, species interactions and fungal successional pathways. Changes in species distributions and abundances are likely to affect the food chains in which wood-inhabiting fungi are involved, and thus the functioning of the whole forest ecosystem. The findings of my thesis highlight the importance of protecting well-connected, large and high-quality forest areas to maintain forest biodiversity. Small habitat patches distributed across the landscape are likely to contribute only marginally to protection of red-listed species, especially if habitat quality is not substantially higher than in ordinary managed forest, as is the case with woodland key habitats. Key habitats might supplement the forest protection network if they were delineated larger and if harvesting of individual trees was prohibited in them. Taking the landscape perspective into account in the design and development of conservation measures is critical while striving to halt the decline of forest biodiversity in an ecologically effective manner.

Methicillin-resistant Staphylococcus aureus in Finland: recent changes in the epidemiology, long-term facility aspects, and phenotypic and molecular detection of isolates

Staphylococcus aureus is one of the most important bacteria that cause disease in humans, and methicillin-resistant S. aureus (MRSA) has become the most commonly identified antibiotic-resistant pathogen in many parts of the world. MRSA rates have been stable for many years in the Nordic countries and the Netherlands with a low MRSA prevalence in Europe, but in the recent decades, MRSA rates have increased in those low-prevalence countries as well. MRSA has been established as a major hospital pathogen, but has also been found increasingly in long-term facilities (LTF) and in communities of persons with no connections to the health-care setting. In Finland, the annual number of MRSA isolates reported to the National Infectious Disease Register (NIDR) has constantly increased, especially outside the Helsinki metropolitan area. Molecular typing has revealed numerous outbreak strains of MRSA, some of which have previously been associated with community acquisition. In this work, data on MRSA cases notified to the NIDR and on MRSA strain types identified with pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and staphylococcal cassette chromosome mec (SCCmec) typing at the National Reference Laboratory (NRL) in Finland from 1997 to 2004 were analyzed. An increasing trend in MRSA incidence in Finland from 1997 to 2004 was shown. In addition, non-multi-drug resistant (NMDR) MRSA isolates, especially those resistant only to methicillin/oxacillin, showed an emerging trend. The predominant MRSA strains changed over time and place, but two internationally spread epidemic strains of MRSA, FIN-16 and FIN-21, were related to the increase detected most recently. Those strains were also one cause of the strikingly increasing invasive MRSA findings. The rise of MRSA strains with SCCmec types IV or V, possible community-acquired MRSA was also detected. With questionnaires, the diagnostic methods used for MRSA identification in Finnish microbiology laboratories and the number of MRSA screening specimens studied were reviewed. Surveys, which focused on the MRSA situation in long-term facilities in 2001 and on the background information of MRSA-positive persons in 2001-2003, were also carried out. The rates of MRSA and screening practices varied widely across geographic regions. Part of the NMDR MRSA strains could remain undetected in some laboratories because of insufficient diagnostic techniques used. The increasing proportion of elderly population carrying MRSA suggests that MRSA is an emerging problem in Finnish long-term facilities. Among the patients, 50% of the specimens were taken on a clinical basis, 43% on a screening basis after exposure to MRSA, 3% on a screening basis because of hospital contact abroad, and 4% for other reasons. In response to an outbreak of MRSA possessing a new genotype that occurred in a health care ward and in an associated nursing home of a small municipality in Northern Finland in autumn 2003, a point-prevalence survey was performed six months later. In the same study, the molecular epidemiology of MRSA and methicillin-sensitive S. aureus (MSSA) strains were also assessed, the results to the national strain collection compared, and the difficulties of MRSA screening with low-level oxacillin-resistant isolates encountered. The original MRSA outbreak in LTF, which consisted of isolates possessing a nationally new PFGE profile (FIN-22) and internationally rare MLST type (ST-27), was confined. Another previously unrecognized MRSA strain was found with additional screening, possibly indicating that current routine MRSA screening methods may be insufficiently sensitive for strains possessing low-level oxacillin resistance. Most of the MSSA strains found were genotypically related to the epidemic MRSA strains, but only a few of them had received the SCCmec element, and all those strains possessed the new SCCmec type V. In the second largest nursing home in Finland, the colonization of S. aureus and MRSA, and the role of screening sites along with broth enrichment culture on the sensitivity to detect S. aureus were studied. Combining the use of enrichment broth and perineal swabbing, in addition to nostrils and skin lesions swabbing, may be an alternative for throat swabs in the nursing home setting, especially when residents are uncooperative. Finally, in order to evaluate adequate phenotypic and genotypic methods needed for reliable laboratory diagnostics of MRSA, oxacillin disk diffusion and MIC tests to the cefoxitin disk diffusion method at both +35°C and +30°C, both with or without an addition of sodium chloride (NaCl) to the Müller Hinton test medium, and in-house PCR to two commercial molecular methods (the GenoType® MRSA test and the EVIGENETM MRSA Detection test) with different bacterial species in addition to S. aureus were compared. The cefoxitin disk diffusion method was superior to that of oxacillin disk diffusion and to the MIC tests in predicting mecA-mediated resistance in S. aureus when incubating at +35°C with or without the addition of NaCl to the test medium. Both the Geno Type® MRSA and EVIGENETM MRSA Detection tests are usable, accurate, cost-effective, and sufficiently fast methods for rapid MRSA confirmation from a pure culture.

Outcomes of ruptured abdominal aortic aneurysm

Ruptured abdominal aortic aneurysm (RAAA) is a life-threatening event, and without operative treatment the patient will die. The overall mortality can be as high as 80-90%; thus repair of RAAA should be attempted whenever feasible. The quality of life (QoL) has become an increasingly important outcome measure in vascular surgery. Aim of the study was to evaluate outcomes of RAAA and to find out predictors of mortality. In Helsinki and Uusimaa district 626 patients were identified to have RAAA in 1996-2004. Altogether 352 of them were admitted to Helsinki University Central Hospital (HUCH). Based on Finnvasc Registry, 836 RAAA patients underwent repair of RAAA in 1991-1999. The 30-day operative mortality, hospital and population-based mortality were assessed, and the effect of regional centralisation and improving in-hospital quality on the outcome of RAAA. QoL was evaluated by a RAND-36 questionnaire of survivors of RAAA. Quality-adjusted life years (QALYs), which measure length and QoL, were calculated using the EQ-5D index and estimation of life expectancy. The predictors of outcome after RAAA were assessed at admission and 48 hours after repair of RAAA. The 30-day operative mortality rate was 38% in HUCH and 44% nationwide, whereas the hospital mortality was 45% in HUCH. Population-based mortality was 69% in 1996-2004 and 56% in 2003-2004. After organisational changes were undertaken, the mortality decreased significantly at all levels. Among the survivors, the QoL was almost equal when compared with norms of age- and sex-matched controls; only physical functioning was slightly impaired. Successful repair of RAAA gave a mean of 4.1 (0-30.9) QALYs for all RAAA patients, although non-survivors were included. The preoperative Glasgow Aneurysm Score was an independent predictor of 30-day operative mortality after RAAA, and it also predicted the outcome at 48- hours for initial survivors of repair of RAAA. A high Glasgow Aneurysm Score and high age were associated with low numbers of QALYs to be achieved. Organ dysfunction measured by the Sequential Organ Failure Assessment (SOFA) score at 48 hours after repair of RAAA was the strongest predictor of death. In conclusion surgery of RAAA is a life-saving and cost-effective procedure. The centralisation of vascular emergencies improved the outcome of RAAA patients. The survivors had a good QoL after RAAA. Predictive models can be used on individual level only to provide supplementary information for clinical decision-making due to their moderate discriminatory value. These results support an active operation policy, as there is no reliable measure to predict the outcome after RAAA.

Leukoencephalopathies in childhood : Delineation of phenotypes

Within the last 15 years, several new leukoencephalopathies have been recognized. However, more than half of children with cerebral white matter abnormalities still have no specific diagnosis. Our aim was to classify unknown leukoencephalopathies and to identify new diseases among them. During the study, three subgroups of patients were delineated and examined further. First, we evaluated 38 patients with unknown leukoencephalopathy. Brain MRI findings were grouped into seven categories according to the predominant location of the abnormalities. The largest subgroups were myelination abnormalities (n=20) and periventricular white matter abnormalities (n=12). Six patients had uniform MRI findings with signal abnormalities in hemispheric white matter and in selective brain stem and spinal cord tracts. Magnetic resonance spectroscopy (MRS) showed elevated lactate and decreased N-acetylaspartate in the abnormal white matter. The patients presented with ataxia, tremor, distal spasticity, and signs of dorsal column dysfunction. This phenotype - leukoencephalopathy with brain stem and spinal cord involvement and elevated white matter lactate (LBSL) - was first published elsewhere in 2003. A new finding was development of a mild axonal neuropathy. The etiopathogenesis of this disease is unknown, but elevated white matter lactate in MRS suggests a mitochondrial disorder. Secondly, we studied 22 patients with 18q deletions. Clinical and MRI findings were correlated with molecularly defined size of the deletion. All patients with deletions between markers D18S469 and D18S1141 (n=18) had abnormal myelination in brain MRI, while four patients with interstitial deletions sparing that region, had normal myelination pattern. Haploinsufficiency of myelin basic protein is suggested to be responsible for this dysmyelination. Congenital aural atresia/stenosis was found in 50% of the cases and was associated with deletions between markers D18S812 (at 18q22.3) and D18S1141 (at q23). Last part of the study comprised 13 patients with leukoencephalopathy and extensive cerebral calcifications. They showed a spectrum of findings, including progressive cerebral cysts, retinal telangiectasias and angiomas, intrauterine growth retardation, skeletal and hematologic abnormalities, and severe intestinal bleeding, which overlap with features of the previously reported patients with "Coats plus" syndrome and "leukoencephalopathy with calcifications and cysts", suggesting that these disorders are related. All autopsied patients had similar neuropathologic findings showing calcifying obliterative microangiopathy. Our patients may represent an autosomally recessively inherited disorder because there were affected siblings and patients of both sexes. We have started genealogic and molecular genetic studies of this disorder.

Preoperative visual acuity of cataract patients. Repeatability of visual acuity and refractive error measurements in clinical settings

Visual acuities at the time of referral and on the day before surgery were compared in 124 patients operated on for cataract in Vaasa Central Hospital, Finland. Preoperative visual acuity and the occurrence of ocular and general disease were compared in samples of consecutive cataract extractions performed in 1982, 1985, 1990, 1995 and 2000 in two hospitals in the Vaasa region in Finland. The repeatability and standard deviation of random measurement error in visual acuity and refractive error determination in a clinical environment in cataractous, pseudophakic and healthy eyes were estimated by re-examining visual acuity and refractive error of patients referred to cataract surgery or consultation by ophthalmic professionals. Altogether 99 eyes of 99 persons (41 cataractous, 36 pseudophakic and 22 healthy eyes) with a visual acuity range of Snellen 0.3 to 1.3 (0.52 to -0.11 logMAR) were examined. During an average waiting time of 13 months, visual acuity in the study eye decreased from 0.68 logMAR to 0.96 logMAR (from 0.2 to 0.1 in Snellen decimal values). The average decrease in vision was 0.27 logMAR per year. In the fastest quartile, visual acuity change per year was 0.75 logMAR, and in the second fastest 0.29 logMAR, the third and fourth quartiles were virtually unaffected. From 1982 to 2000, the incidence of cataract surgery increased from 1.0 to 7.2 operations per 1000 inhabitants per year in the Vaasa region. The average preoperative visual acuity in the operated eye increased by 0.85 logMAR (in decimal values from 0.03to 0.2) and in the better eye 0.27 logMAR (in decimal values from 0.23 to 0.43) over this period. The proportion of patients profoundly visually handicapped (VA in the better eye <0.1) before the operation fell from 15% to 4%, and that of patients less profoundly visually handicapped (VA in the better eye 0.1 to <0.3) from 47% to 15%. The repeatability visual acuity measurement estimated as a coefficient of repeatability for all 99 eyes was ±0.18 logMAR, and the standard deviation of measurement error was 0.06 logMAR. Eyes with the lowest visual acuity (0.3-0.45) had the largest variability, the coefficient of repeatability values being ±0.24 logMAR and eyes with a visual acuity of 0.7 or better had the smallest, ±0.12 logMAR. The repeatability of refractive error measurement was studied in the same patient material as the repeatability of visual acuity. Differences between measurements 1 and 2 were calculated as three-dimensional vector values and spherical equivalents and expressed by coefficients of repeatability. Coefficients of repeatability for all eyes for vertical, torsional and horisontal vectors were ±0.74D, ±0.34D and ±0.93D, respectively, and for spherical equivalent for all eyes ±0.74D. Eyes with lower visual acuity (0.3-0.45) had larger variability in vector and spherical equivalent values (±1.14), but the difference between visual acuity groups was not statistically significant. The difference in the mean defocus equivalent between measurements 1 and 2 was, however, significantly greater in the lower visual acuity group. If a change of ±0.5D (measured in defocus equivalents) is accepted as a basis for change of spectacles for eyes with good vision, the basis for eyes in the visual acuity range of 0.3 - 0.65 would be ±1D. Differences in repeated visual acuity measurements are partly explained by errors in refractive error measurements.

Children and adolescents in full-time special education : an epidemiological and magnetic resonance imaging study

The need for special education (SE) is increasing. The majority of those whose problems are due to neurodevelopmental disorders have no specific aetiology. The aim of this study was to evaluate the contribution of prenatal and perinatal factors and factors associated with growth and development to later need for full-time SE and to assess joint structural and volumetric brain alterations among subjects with unexplained, familial need for SE. A random sample of 900 subjects in full-time SE allocated into three levels of neurodevelopmental problems and 301 controls in mainstream education (ME) provided data on socioeconomic factors, pregnancy, delivery, growth, and development. Of those, 119 subjects belonging to a sibling-pair in full-time SE with unexplained aetiology and 43 controls in ME underwent brain magnetic resonance imaging (MRI). Analyses of structural brain alterations and midsagittal area and diameter measurements were made. Voxel-based morphometry (VBM) analysis provided detailed information on regional grey matter, white matter, and cerebrospinal fluid (CSF) volume differences. Father’s age ≥ 40 years, low birth weight, male sex, and lower socio-economic status all increased the probability of SE placement. At age 1 year, one standard deviation score decrease in height raised the probability of SE placement by 40% and in head circumference by 28%. At infancy, the gross motor milestones differentiated the children. From age 18 months, the fine motor milestones and those related to speech and social skills became more important. Brain MRI revealed no specific aetiology for subjects in SE. However, they had more often ≥ 3 abnormal findings in MRIs (thin corpus callosum and enlarged cerebral and cerebellar CSF spaces). In VBM, subjects in full-time SE had smaller global white matter, CSF, and total brain volumes than controls. Compared with controls, subjects with intellectual disabilities had regional volume alterations (greater grey matter volumes in the anterior cingulate cortex bilaterally, smaller grey matter volume in left thalamus and left cerebellar hemisphere, greater white matter volume in the left fronto-parietal region, and smaller white matter volumes bilaterally in the posterior limbs of the internal capsules). In conclusion, the epidemiological studies emphasized several factors that increased the probability of SE placement, useful as a framework for interventional studies. The global and regional brain MRI findings provide an interesting basis for future investigations of learning-related brain structures in young subjects with cognitive impairments or intellectual disabilities of unexplained, familial aetiology.

Genistein and 17β-estradiol fatty acid esters in blood and adipose tissue and the structure-related antioxidant activity of estrogens on lipoproteins

Soy-derived phytoestrogen genistein and 17β-estradiol (E2), the principal endogenous estrogen in women, are also potent antioxidants protecting LDL and HDL lipoproteins against oxidation. This protection is enhanced by esterification with fatty acids, resulting in lipophilic molecules that accumulate in lipoproteins or fatty tissues. The aims were to investigate, whether genistein becomes esterified with fatty acids in human plasma accumulating in lipoproteins, and to develop a method for their quantitation; to study the antioxidant activity of different natural and synthetic estrogens in LDL and HDL; and to determine the E2 esters in visceral and subcutaneous fat in late pregnancy and in pre- and postmenopause. Human plasma was incubated with [3H]genistein and its esters were analyzed from lipoprotein fractions. Time-resolved fluoroimmunoassay (TR-FIA) was used to quantitate genistein esters in monkey plasma after subcutaneous and oral administration. The E2 esters in women s serum and adipose tissue were also quantitated using TR-FIA. The antioxidant activity of estrogen derivatives (n=43) on LDL and HDL was assessed by monitoring the copper induced formation of conjugated dienes. Human plasma was shown to produce lipoprotein-bound genistein fatty acid esters, providing a possible explanation for the previously reported increased oxidation resistance of LDL particles during intake of soybean phytoestrogens. Genistein esters were introduced into blood by subcutaneous administration. The antioxidant effect of estrogens on lipoproteins is highly structure-dependent. LDL and HDL were protected against oxidation by many unesterified, yet lipophilic derivatives. The strongest antioxidants had an unsubstituted A-ring phenolic hydroxyl group with one or two adjacent methoxy groups. E2 ester levels were high during late pregnancy. The median concentration of E2 esters in pregnancy serum was 0.42 nmol/l (n=13) and in pre- (n=8) and postmenopause (n=6) 0.07 and 0.06 nmol/l, respectively. In pregnancy visceral fat the concentration of E2 esters was 4.24 nmol/l and in pre- and postmenopause 0.82 and 0.74 nmol/l. The results from subcutaneous fat were similar. In serum and fat during pregnancy, E2 esters constituted about 0.5 and 10% of the free E2. In non-pregnant women most of the E2 in fat was esterified (the ester/free ratio 150 - 490%). In postmenopause, E2 levels in fat highly exceeded those in serum, the majority being esterified. The pathways for fatty acid esterification of steroid hormones are found in organisms ranging from invertebrates to vertebrates. The evolutionary preservation and relative abundance of E2 esters, especially in fat tissue, suggest a biological function, most likely in providing a readily available source of E2. The body s own estrogen reservoir could be used as a source of E2 by pharmacologically regulating the E2 esterification or hydrolysis.

Anti-TNF treatment in juvenile idiopathic arthritis and associated uveitis : Clinical perspectives on growth, uveitis, and drug survival

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of childhood chronic arthritides, associated with chronic uveitis in 20% of cases. For JIA patients responding inadequately to conventional disease-modifying anti-rheumatic drugs (DMARDs), biologic therapies, anti-tumor necrosis factor (anti-TNF) agents are available. In this retrospective multicenter study, 258 JIA-patients refractory to DMARDs and receiving biologic agents during 1999-2007 were included. Prior to initiation of anti-TNFs, growth velocity of 71 patients was delayed in 75% and normal in 25%. Those with delayed growth demonstrated a significant increase in growth velocity after initiation of anti-TNFs. Increase in growth rate was unrelated to pubertal growth spurt. No change was observed in skeletal maturation before and after anti-TNFs. The strongest predictor of change in growth velocity was growth rate prior to anti-TNFs. Change in inflammatory activity remained a significant predictor even after decrease in glucocorticoids was taken into account. In JIA-associated uveitis, impact of two first-line biologic agents, etanercept and infliximab, and second-line or third-line anti-TNF agent, adalimumab, was evaluated. In 108 refractory JIA patients receiving etanercept or infliximab, uveitis occurred in 45 (42%). Uveitis improved in 14 (31%), no change was observed in 14 (31%), and in 17 (38%) uveitis worsened. Uveitis improved more frequently (p=0.047) and frequency of annual uveitis flares was lower (p=0.015) in those on infliximab than in those on etanercept. In 20 patients taking adalimumab, 19 (95%) had previously failed etanercept and/or infliximab. In 7 patients (35%) uveitis improved, in one (5%) worsened, and in 12 (60%) no change occurred. Those with improved uveitis were younger and had shorter disease duration. Serious adverse events (AEs) or side-effects were not observed. Adalimumab was effective also in arthritis. Long-term drug survival (i.e. continuation rate on drug) with etanercept (n=105) vs. infliximab (n=104) was at 24 months 68% vs. 68%, and at 48 months 61% vs. 48% (p=0.194 in log-rank analysis). First-line anti-TNF agent was discontinued either due to inefficacy (etanercept 28% vs. infliximab 20%, p=0.445), AEs (7% vs. 22%, p=0.002), or inactive disease (10% vs. 16%, p=0.068). Females, patients with systemic JIA (sJIA), and those taking infliximab as the first therapy were at higher risk for treatment discontinuation. One-third switched to the second anti-TNF agent, which was discontinued less often than the first. In conclusion, in refractory JIA anti-TNFs induced enhanced growth velocity. Four-year treatment survival was comparable between etanercept and infliximab, and switching from first-line to second-line agent a reasonable therapeutic option. During anti-TNF treatment, one-third with JIA-associated anterior uveitis improved.

Individualized immunosuppression after renal transplantation in childhood

Pediatric renal transplantation (TX) has evolved greatly during the past few decades, and today TX is considered the standard care for children with end-stage renal disease. In Finland, 191 children had received renal transplants by October 2007, and 42% of them have already reached adulthood. Improvements in treatment of end-stage renal disease, surgical techniques, intensive care medicine, and in immunosuppressive therapy have paved the way to the current highly successful outcomes of pediatric transplantation. In children, the transplanted graft should last for decades, and normal growth and development should be guaranteed. These objectives set considerable requirements in optimizing and fine-tuning the post-operative therapy. Careful optimization of immunosuppressive therapy is crucial in protecting the graft against rejection, but also in protecting the patient against adverse effects of the medication. In the present study, the results of a retrospective investigation into individualized dosing of immunosuppresive medication, based on pharmacokinetic profiles, therapeutic drug monitoring, graft function and histology studies, and glucocorticoid biological activity determinations, are reported. Subgroups of a total of 178 patients, who received renal transplants in 1988 2006 were included in the study. The mean age at TX was 6.5 years, and approximately 26% of the patients were <2 years of age. The most common diagnosis leading to renal TX was congenital nephrosis of the Finnish type (NPHS1). Pediatric patients in Finland receive standard triple immunosuppression consisting of cyclosporine A (CsA), methylprednisolone (MP) and azathioprine (AZA) after renal TX. Optimal dosing of these agents is important to prevent rejections and preserve graft function in one hand, and to avoid the potentially serious adverse effects on the other hand. CsA has a narrow therapeutic window and individually variable pharmacokinetics. Therapeutic monitoring of CsA is, therefore, mandatory. Traditionally, CsA monitoring has been based on pre-dose trough levels (C0), but recent pharmacokinetic and clinical studies have revealed that the immunosuppressive effect may be related to diurnal CsA exposure and blood CsA concentration 0-4 hours after dosing. The two-hour post-dose concentration (C2) has proved a reliable surrogate marker of CsA exposure. Individual starting doses of CsA were analyzed in 65 patients. A recommended dose based on a pre-TX pharmacokinetic study was calculated for each patient by the pre-TX protocol. The predicted dose was clearly higher in the youngest children than in the older ones (22.9±10.4 and 10.5±5.1 mg/kg/d in patients <2 and >8 years of age, respectively). The actually administered oral doses of CsA were collected for three weeks after TX and compared to the pharmacokinetically predicted dose. After the TX, dosing of CsA was adjusted according to clinical parameters and blood CsA trough concentration. The pharmacokinetically predicted dose and patient age were the two significant parameters explaining post-TX doses of CsA. Accordingly, young children received significantly higher oral doses of CsA than the older ones. The correlation to the actually administered doses after TX was best in those patients, who had a predicted dose clearly higher or lower (> ±25%) than the average in their age-group. Due to the great individual variation in pharmacokinetics standardized dosing of CsA (based on body mass or surface area) may not be adequate. Pre-Tx profiles are helpful in determining suitable initial CsA doses. CsA monitoring based on trough and C2 concentrations was analyzed in 47 patients, who received renal transplants in 2001 2006. C0, C2 and experienced acute rejections were collected during the post-TX hospitalization, and also three months after TX when the first protocol core biopsy was obtained. The patients who remained rejection free had slightly higher C2 concentrations, especially very early after TX. However, after the first two weeks also the trough level was higher in the rejection-free patients than in those with acute rejections. Three months after TX the trough level was higher in patients with normal histology than in those with rejection changes in the routine biopsy. Monitoring of both the trough level and C2 may thus be warranted to guarantee sufficient peak concentration and baseline immunosuppression on one hand and to avoid over-exposure on the other hand. Controlling of rejection in the early months after transplantation is crucial as it may contribute to the development of long-term allograft nephropathy. Recently, it has become evident that immunoactivation fulfilling the histological criteria of acute rejection is possible in a well functioning graft with no clinical sings or laboratory perturbations. The influence of treatment of subclinical rejection, diagnosed in 3-month protocol biopsy, to graft function and histology 18 months after TX was analyzed in 22 patients and compared to 35 historical control patients. The incidence of subclinical rejection at three months was 43%, and the patients received a standard rejection treatment (a course of increased MP) and/or increased baseline immunosuppression, depending on the severity of rejection and graft function. Glomerular filtration rate (GFR) at 18 months was significantly better in the patients who were screened and treated for subclinical rejection in comparison to the historical patients (86.7±22.5 vs. 67.9±31.9 ml/min/1.73m2, respectively). The improvement was most remarkable in the youngest (<2 years) age group (94.1±11.0 vs. 67.9±26.8 ml/min/1.73m2). Histological findings of chronic allograft nephropathy were also more common in the historical patients in the 18-month protocol biopsy. All pediatric renal TX patients receive MP as a part of the baseline immunosuppression. Although the maintenance dose of MP is very low in the majority of the patients, the well-known steroid-related adverse affects are not uncommon. It has been shown in a previous study in Finnish pediatric TX patients that steroid exposure, measured as area under concentration-time curve (AUC), rather than the dose correlates with the adverse effects. In the present study, MP AUC was measured in sixteen stable maintenance patients, and a correlation with excess weight gain during 12 months after TX as well as with height deficit was found. A novel bioassay measuring the activation of glucocorticoid receptor dependent transcription cascade was also employed to assess the biological effect of MP. Glucocorticoid bioactivity was found to be related to the adverse effects, although the relationship was not as apparent as that with serum MP concentration. The findings in this study support individualized monitoring and adjustment of immunosuppression based on pharmacokinetics, graft function and histology. Pharmacokinetic profiles are helpful in estimating drug exposure and thus identifying the patients who might be at risk for excessive or insufficient immunosuppression. Individualized doses and monitoring of blood concentrations should definitely be employed with CsA, but possibly also with steroids. As an alternative to complete steroid withdrawal, individualized dosing based on drug exposure monitoring might help in avoiding the adverse effects. Early screening and treatment of subclinical immunoactivation is beneficial as it improves the prospects of good long-term graft function.

Snow characteristics in Dronning Maud Land, Antarctica

Snow cover is very sensitive to climate change and has a large feedback effect on the climate system due to the high albedo. Snow covers almost all surfaces in Antarctica and small changes in snow properties can mean large changes in absorbed radiation. In the ongoing discussion of climatic change, the mass balance of Antarctica has received increasing focus during recent decades, since its reaction to global warming strongly influences sea-level change. The aim of the present work was to examine the spatial and temporal variations in the physical and chemical characteristics of surface snow and annual accumulation rates in western Dronning Maud Land, Antarctica. The data were collected along a 350-km-long transect from the coast to the plateau during the years 1999-2004 as a part of the Finnish Antarctic Research Programme (FINNARP). The research focused on the most recent annual accumulation in the coastal area. The results show that the distance from the sea, and the moisture source, was the most predominant factor controlling the variations in both physical (conductivity, grain size, oxygen isotope ratio and accumulation) and chemical snow properties. The sea-salt and sulphur-containing components predominated in the coastal region. The local influences of nunataks and topographic highs were also visible on snow. The variations in all measured properties were wide within single sites mostly due to redistribution by winds and sastrugi topography, which reveals the importance of the spatially representative measurements. The mean accumulations occurred on the ice shelf, in the coastal region and on the plateau: 312 ± 28, 215 ± 43 and 92 ± 25 mm w.e., respectively. Depth hoar layers were usually found under the thin ice crust and were associated with a low dielectric constant and high concentrations of nitrate. Taking into account the vast size of the Antarctic ice sheet and its geographic characteristics, it is important to extend investigation of the distribution of surface snow properties and accumulation to provide well-documented data.

R3Mn1.5CuV0.5O9 (R = Y, Ho, Er, Tm, Yb and Lu) and Lu3Mn3-3xCu2xVxO9: New noncentro symmetric oxides related to YMnO3

We report formation of new noncentrosymmetric oxides of the formula, R3Mn1.5CuV0.5O9 for R = Y, Ho, Er, Tm, Yb and Lu, possessing the hexagonal RMnO3 (space group P6(3)cm) structure. These oxides could be regarded as the x = 0.5 members of a general series R3Mn3-3xCu2xVxO9. Investigation of the Lu-Mn-Cu-V-O system reveals the existence of isostructural solid solution series, Lu3Mn3-3xCu2xVxO9 for 0 < x <= 0.75. Magnetic and dielectric properties of the oxides are consistent with a random distribution of Mn3+, Cu2+ and V5+ atoms that preserve the noncentrosymmetric RMnO3 structure. (c) 2006 Elsevier Ltd. All rights reserved.

Depression and Cognition in Type 2 Diabetes from a Life Course Perspective

Background: Type 2 diabetes is linked to several complications which add to both physical and mental distress. Depression is a common co-morbidity of diabetes which can occur both as a cause and a consequence of type 2 diabetes. Depression has been shown to correlate with glucose regulation and treating depression might prove beneficial for glucose regulation as well as for mental well being. Another complication which might affect diabetes management is cognitive decline. Several risk factors and complications of diabetes might modify the risk for developing cognitive impairment, which is increased 1.5 times among subjects with type 2 diabetes. Type 2 diabetes, depression and impaired cognitive performance have all been linked to low birth weight. This thesis aimed to explore the effects and interactions of birth weight, depression and cognitive ability in relation to type 2 diabetes from a life course perspective. Subjects and methods: Studies I, II and V were part of the Helsinki Birth Cohort Study. 2003 subjects participated in an extensive clinical examination at an average age of 61 years. A standard glucose tolerance test (OGTT) was performed and depressive symptoms were assessed using the Beck Depression Inventory (BDI). In addition data was obtained from child welfare clinics and national registers. A subset of the cohort (n=1247) also performed a test on cognitive performance (CogState ®) at the average age of 64. Studies III and IV were randomised clinical trials where mildly depressed diabetic subjects were treated with paroxetine or placebo and the effect on metabolic parameters and quality of life was assessed. The first trial included 14 women and lasted 10 weeks, while the second trial included 43 subjects, both men and women, and lasted 6 months. Results: Type 2 diabetes was positively associated with the occurrence of depressive symptoms. Among diabetic subjects 23.6% had depressive symptoms, compared to 16.7% of subjects with normal glucose tolerance (OR = 1.77, p<0.001). Formal mediation analysis revealed that cardiovascular disease (CVD) is likely to act as a mediator in the association. Furthermore, low birth weight was found to modify the association between type 2 diabetes, CVD and depression. The association between BDI score and having type 2 diabetes or CVD was twice as strong in the subgroup with low birth weight (≤ 2500g) compared with the group with birth weight > 2500g (p for interaction 0.058). In the six months long randomised clinical trial (study IV) paroxetine had a transient beneficial effect on glycosylated haemoglobin A1c (GHbA1c) and quality of life when compared to placebo after three months of treatment. In study V we found that subjects with known diabetes had a consistently poorer level of cognitive performance than subjects with normal glucose tolerance in most of the tested cognitive domains. This effect was further amplified among those born with a small birth weight (p for interaction 0.002). Conclusions: Type 2 diabetes is associated with a higher occurrence of depressive symptoms compared to subjects with normal glucose tolerance. This association is especially strong among subjects with CVD and those born with a low birth weight. Treating depressed diabetic subjects with paroxetine has no long term effect on glucose regulation. Physicians should be aware of depression as an important co-morbidity of type 2 diabetes. Both depression and the cognitive decline often seen among diabetic subjects are increased if the subject is born with a low birth weight. Physicians should recognise low birth weight as an additional risk factor and modifier of diabetic complications.

Breathing, swallowing and voice in laryngeal disorsers

The aim of this work was to examine how breathing, swallowing and voicing are affected in different laryngeal disorders. For this purpose, we examined four different patient groups: patients who had undergone total laryngectomy, anterior cervical decompression (ACD), or injection laryngoplasty with autologous fascia (ILAF), and patients with dyspnea during exercise. We studied the problems and benefits related to the automatic speech valve used for the rehabilitation of speech in laryngectomized patients. The device was given to 14 total laryngectomized patients who used the traditional valve especially well. The usefulness of voice and intelligibility of speech were assessed by speech pathologists. The results demonstrated better performance with the traditional valve in both dimensions. Most of the patients considered the automatic valve a helpful additional device but because of heavier breathing and the greater work needed for speech production, it was not suitable as a sole device in speech rehabilitation. Dysphonia and dysphagia are known complications of ACD. These symptoms are caused due to the stretching of tissue needed during the surgery, but the extent and the recovery from them was not well known before our study. We studied two patient groups, an early group with 50 patients who were examined immediately before and after the surgery and a late group with 64 patients who were examined 3 9 months postoperatively. Altogether, 60% reported dysphonia and 69% dysphagia immediately after the operation. Even though dysphagia and dysphonia often appeared after surgery, permanent problems seldom occurred. Six (12 %) cases of transient and two (3 %) permanent vocal cord paresis were detected. In our third study, the long-term results of ILAF in 43 patients with unilateral vocal cord paralysis were examined. The mean follow-up was 5.8 years (range 3 10). Perceptual evaluation demonstrated improved results for voice quality, and videostroboscopy revealed complete or partial glottal closure in 83% of the patients. Fascia showed to be a stable injection material with good vocal results. In our final study we developed a new diagnostic method for exertional laryngeal dyspnea by combining a cardiovascular exercise test with simultaneous fiberoptic observation of the larynx. With this method, it is possible to visualize paradoxal closure of the vocal cords during inspiration, which is a diagnostic criterion for vocal cord dysfunction (VCD). We examined 30 patients referred to our hospital because of suspicion of exercise-induced vocal cord dysfunction (EIVCD). Twenty seven out of thirty patients were able to perform the test. Dyspnea was induced in 15 patients, and of them five had EIVCD and four high suspicion of EIVCD. With our test it is possible to set an accurate diagnosis for exertional laryngeal dyspnea. Moreover, the often seen unnecessary use of asthma drugs among these patients can be avoided.