Increasing incidence of multiple sclerosis in women in Northern Finland.

BACKGROUND: The geographical distribution of multiple sclerosis (MS) means that prevalence rates increase with latitude north or south of the equator. Temporally, a tendency for increased incidences of MS has been observed over the past two decades. OBJECTIVES: Since epidemiological studies of MS in areas close to the Arctic Circle are rare, we evaluated the incidence and prevalence of MS in Northern Ostrobothnia by means of a retrospective cohort study covering the period 1992-2007. METHODS: Patients with a definite clinical diagnosis of MS based on the Poser criteria and the early McDonald criteria of 2001 were identified in the region of Northern Ostrobothnia (population 386,972) and the incidence was calculated at 1-year time intervals, both overall and by gender. RESULTS: The overall prevalence was 103/100,000 (95% CI, 93-113), with a female/male ratio of 2.17. The mean overall incidence was 6.3/100,000 (95% CI, 5.2-7.2). The incidence shows a tendency to increase over the 16-year period due to a pronounced rise in the female incidence. CONCLUSIONS: Our results show a high prevalence of MS in Northern Ostrobothnia and a disproportional increase in the female MS incidence. These recent epidemiological features may be associated with environmental risk factors such as a vitamin D deficit, low life-long UV radiation and the high-latitude geographical location.

DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis.

BACKGROUND: Leucoencephalopathy with brain stem and spinal cord involvement and high brain lactate (LBSL) was first defined by characteristic magnetic resonance imaging and spectroscopic findings. The clinical features include childhood or juvenile onset slowly progressive ataxia, spasticity, and dorsal column dysfunction, occasionally accompanied by learning difficulties. Mutations in DARS2, encoding mitochondrial aspartyl-tRNA synthetase, were recently shown to cause LBSL. The signs and symptoms show some overlap with the most common leucoencephalopathy of young adults, multiple sclerosis (MS). OBJECTIVE: To clarify the molecular background of LBSL patients in Finland, and to look for DARS2 mutations in a group of MS patients. METHODS: Clinical evaluation of LBSL patients, DARS2 sequencing and haplotype analysis, and carrier frequency determination in Finland. RESULTS: All eight LBSL patients were compound heterozygotes for DARS2 mutations: all carried R76SfsX5 change, seven had M134_K165del, and one had C152F change. Axonal neuropathy was found in five of the eight patients. The carrier frequencies of the R76SfsX5 and M134_K165del mutations were 1:95 and 1:380, respectively. All patients shared common European haplotypes, suggestive of common European LBSL ancestors. No enrichment of the two common DARS2 mutations was found in 321 MS patients. CONCLUSION: All LBSL patients were compound heterozygotes, which suggests that DARS2 mutation homozygosity may be lethal or manifest as a different phenotype. The authors show here that despite identical mutations the clinical picture was quite variable in the patients. Axonal neuropathy was an important feature of LBSL. DARS2 mutations cause childhood-to-adolescence onset leucoencephalopathy, but they do not seem to be associated with MS.

Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations.

BACKGROUND: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). METHODS: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. RESULTS: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. CONCLUSION: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.

Characterisation of volatile organic compounds in stemwood using solid-phase microextraction.

Solid-phase microextraction (SPME), hydrodistillation and dynamic headspace combined with GC and GC-MS were applied and compared for the analysis of volatile organic compounds (VOCs) from coniferous wood. The SPME conditions (type of fibre, size of wood sample, temperature and exposure time) were optimised, and more than 100 VOCs and semi-volatile compounds extracted and identified from the sapwood and heartwood of Norway spruce (Picea abies). The total number of mono- and sesquiterpenes eluted and identified was similar for the SPME and hydrodistillation methods, but more semi-volatile compounds were released by hydrodistillation. By applying dynamic headspace at room temperature, it was possible to analyse only the most volatile compounds. The qualitative composition of VOCs was similar in spruce sapwood and heartwood, although Z-beta-ocimene occurred only in sapwood while fenchol was present only in heartwood. SPME sampling coupled with GC, applied here to the analysis of VOCs released from stemwood of firs for the first time, is a convenient, sensitive, fast, solvent-free and simple method for the determination of wood volatiles. The technique requires much smaller sample amounts compared with hydrodistillation, and the total amount of VOCs extracted and identified is higher than that obtained by hydrodistillation or dynamic headspace. The relative ratios of the main mono- and sesquiterpenes and -terpenoids were similar using the SPME-GC and hydrodistillation methods.

Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries.

BACKGROUND: Several investigators have shown striking differences in semen quality and testicular cancer rate between Denmark and Finland. Since maldescent of the testis is a shared risk factor for these conditions we undertook a joint prospective study for the prevalence of congenital cryptorchidism. METHODS: 1068 Danish (1997-2001) and 1494 Finnish boys (1997-99) were consecutively recruited prenatally. We also established prevalence data for all newborns at Turku University Central Hospital, Finland (1997-99, n=5798). Testicular position was assessed by a standardised technique. All subtypes of congenital cryptorchidism were included, but retractile testes were considered normal. FINDINGS: Prevalence of cryptorchidism at birth was 9.0% (95% CI 7.3-10.8) in Denmark and 2.4% (1.7-3.3) in Finland. At 3 months of age, prevalence rates were 1.9% (1.2-3.0) and 1.0% (0.5-1.7), respectively. Significant geographic differences were still present after adjustment for confounding factors (birthweight, gestational age, being small for gestational age, maternal age, parity, mode of delivery); odds ratio (Denmark vs Finland) was 4.4 (2.9-6.7, p<0.0001) at birth and 2.2 (1.0-4.5, p=0.039) at three months. The rate in Denmark was significantly higher than that reported 40 years ago. INTERPRETATION: Our findings of increasing and much higher prevalence of congenital cryptorchidism in Denmark than in Finland contribute evidence to the pattern of high frequency of reproductive problems such as testicular cancer and impaired semen quality in Danish men. Although genetic factors could account for the geographic difference, the increase in reproductive health problems in Denmark is more likely explained by environmental factors, including endocrine disrupters and lifestyle.

A two-stage study on multiple sclerosis susceptibility and chromosome 2q33.

We have performed a two-stage study to analyse the association of polymorphism on chromosome 2q33 with multiple sclerosis (MS). In all, 17 markers were analysed in stage-1 in 134 Finnish MS families and the observed associations were tested in stage-2 in 186 MS families. We did not find previously reported allelic or haplotype associations with CTLA4. We obtained a weak signal of two distinct predisposing genes, one proximal the other distal of CTLA4. The putative proximal gene was associated with the marker rs3977 in families lacking HLA-DR2 (P=0.02 and 0.02) and the other distal gene was associated with D2S1271 in families from a high-risk region in western Finland (P=0.02 and 0.01). Based on the >3 cM distance and the lack of linkage disequilibrium between these loci, we conclude that the two association signals are independent. Our results provide preliminary evidence for two distinct MS susceptibility genes on 2q33 outside of CTLA4.

Linkage disequilibrium between the MBP tetranucleotide repeat and multiple sclerosis is restricted to a geographically defined subpopulation in Finland.

We have previously found evidence for linkage as well as allelic and haplotype association between the myelin basic protein (MBP) gene and multiple sclerosis (MS). These findings have, however, not been reproduced in other populations. Here, we have analyzed association between MBP and MS in a new set of 349 Finnish triad families. Families with a parent born in the Southern Ostrobothnian region in western Finland (Bothnia families, n=98) were analyzed as a separate group since our previous studies included a high proportion of patients and families from this high-incidence region. Other families (n=251) were collected at five hospitals in southern, eastern, and northern Finland. The MBP short tandem repeat was genotyped, and haplotype patterns were verified by sequencing. In the Bothnia families, the previously detected associations with the 1.27 kb allele and haplotype 1.27-B10 were confirmed (P=0.01 and 0.02, respectively), whereas in the other families there was not even a trend toward association. These results demonstrate a geographic/genealogical restriction in the association between MS and the MBP short tandem repeat, highlight the importance of genealogical information in genetic studies of complex traits, and may provide an explanation why the association has not been found in many other populations.

Vipera berus adder bite in the water, complicated by rapid shock. A case history.

A case of a child who presented with severe and rapid shock after receiving a common adder (vipera berus berus) bite in sea water is presented. Although most poisonous snakebites in Europe tend to be relatively minor and uncomplicated, the present case highlights the need to regard all viper bites as life-threatening accidents, before proved otherwise by a medical professional.

Hyaluronic acid in incision wound fluid: a clinical study with the Cellstick device in children.

When inserted into a human incision wound, the Cellstick device harvests inflammatory cells and collects wound fluid, reflecting time-related changes in cell populations and in wound fluid composition. Hyaluronic acid has been postulated to be an important factor in scar reduction in wound healing and in scarless fetal wound healing. The aim of this work was to determine the concentration and variation of hyaluronic acid and proportions of wound cells in closed surgical wounds in children at two time points. The Cellstick device was inserted subcutaneously into the wound at the end of an elective inguinal hernia operation on 37 healthy boys, and the devices were removed 3+/-1 or 24+/-3 hours after surgery. Haluronic acid concentration was measured from the wound fluid and a differential count of the wound cells was performed. There was a significant decrease in hyaluronic acid concentration from 3+/-1 to 24+/-3 hours after surgery (p<0.001, Kruskal-Wallis anova). The variance of hyaluronic acid concentration in wound fluid differed between the wounds at the two time points (p<0.01, Levene test for homogeneity of variance). A positive correlation between hyaluronic acid concentration and patient age (r=0.91, p<0.05, Spearman) at 3+/-1 hours post surgery and between HA and wound lymphocytes (r=0.38, p<0.05, Spearman) was also found. We conclude that the hyaluronic acid concentration in wound fluid peaks early in children and decreases significantly by 3 to 24 hours after surgery, and the concentrations in the wound fluid of healthy boys are more variable 3 hours than at 24 hours after surgery.

Duration of surgery and patient age affect wound healing in children.

The migration of inflammatory cells into a wound and their subsequent changes during wound healing are essential for the complex processes of tissue repair to occur. The aim of this work was to investigate the number of wound leukocytes during early wound healing at different time periods in children. Wound cells of 184 children aged 0-15 years, operated on for a benign disease in the lower abdominal region, were harvested with the Cellstick(R) device. The device was removed from the wound at 3, 6, or 24 hours after surgery and differential cell counts were performed. The cellular patterns were significantly influenced by the age of the patient and by the duration of the surgery. The proportions of neutrophils, lymphocytes, and monocytes changed significantly from 3-24 hours. Our results suggest that there is a distinct time-related change in the pattern of inflammatory cells in the early phase of wound healing in children. This pattern is affected by the age of the child and by the duration of the surgery.

Hydroxymatairesinol, a novel enterolactone precursor with antitumor properties from coniferous tree (Picea abies).

The potential for the extraction of the plant lignan hydroxymatairesinol (HMR) in large scale from Norway spruce (Picea abies) has given us the opportunity to study the metabolism and biological actions of HMR in animals. HMR, the most abundant single component of spruce lignans, was metabolized to enterolactone (ENL) as the major metabolite in rats after oral administration. The amounts of urinary ENL increased with the dose of HMR (from 3 to 50 mg/kg), and only minor amounts of unmetabolized HMR isomers and other lignans were found in urine. HMR (15 mg/kg body wt po) given for 51 days decreased the number of growing tumors and increased the proportion of regressing and stabilized tumors in the rat dimethylbenz[a]anthracene-induced mammary tumor model. HMR (50 mg/kg body wt) did not exert estrogenic or antiestrogenic activity in the uterine growth test in immature rats. HMR also showed no antiandrogenic responses in the growth of accessory sex glands in adult male rats. Neither ENL nor enterodiol showed estrogenic or antiestrogenic activity via a classical alpha- or beta-type estrogen receptor-mediated pathway in vitro at < 1.0 microM. HMR was an effective antioxidant in vitro.

Pancreatic injuries in children.

AIMS: There are several different philosophies in the diagnostics of blunt abdominal trauma (BAT), yet none of them has been shown to be superior, although enhanced computed tomography (CT) and diagnostic ultrasonography (US) seem to be the most used methods today. Treatment of pancreatic injury (PI) in children is a matter of controversy, whether operative treatment is needed and to what extent. MATERIAL AND METHODS: Seventeen pancreatic injuries were found in a retrospective analysis of 111 paediatric patients, aged 2-14 years, who underwent a laparotomy because of BAT, between 1968 and 1995 in Turku University Central Hospital. The number of non-operated BAT patients was calculated as 287. RESULTS: During the past two decades, the number of BATs and operations diminished by more than two thirds, but the number of PIs remained the same. Twelve acute operations led to four pancreatic resections, two external drainages and two explorations. PI was present but not the main reason for operation in four cases. Five PIs were operated on later due to postraumatic pseudocyst of the pancreas. CONCLUSIONS: PI was rare (15%) in laparotomies done because of BAT, operations which have diminished by 74% during the last twenty years. When PI was found, a variety of operative procedures was needed.

Correlation between interleukin-6 and matrix metalloproteinase-9 in early wound healing in children.

Interleukin-6 and matrix metalloproteinase-9 concentrations in the wound fluid and their associations to cellular changes were determined in early wound healing. Wound healing of 75 children who underwent elective operations was studied with the Cellstick(R) device, which was inserted into the wound at the end of the operation and removed 3 or 24 hours post-wounding. Differential counts of the wound cells and interleukin-6 and matrix metalloproteinase-9 concentrations in the wound fluid were analyzed. Interleukin-6 and the matrix metalloproteinase-9 concentrations increased in parallel (r = 0.81). The proportion of wound neutrophils increased (p < 0.0001) and lymphocytes decreased (p < 0. 0001) between the observation times. The number of wound neutrophils had a strong correlation with both interleukin-6 (adjusted R2 = 0.41, p < 0.0001) and matrix metalloproteinase-9 concentrations (adjusted R2 = 0.37, p < 0.0001). The extracellular matrix degradation process of the early wound healing seems to be closely linked to the inflammatory response. Both of these measured markers are associated significantly with the neutrophil proportion in the wound.

A double-blind placebo-controlled study assessing the efficacy and tolerability of 50 mg sumatriptan tablets in the acute treatment of migraine. Sumatriptan Tablets S2CM07 Study Group.

BACKGROUND: Oral sumatriptan 50 mg has been found to have good efficacy and tolerability in the acute treatment of migraine but has been less well studied than the 100 mg dose. METHODS: This was a double-blind, parallel-group study (Glaxo Wellcome protocol number S2CM07) comparing the efficacy and safety of sumatriptan 50 mg tablets with placebo in the acute treatment of migraine. Patients treated three migraine attacks with study medication; a second, optional dose was available for treating recurrent headache. Of the 560 patients randomized, 485 treated at least one attack, 411 at least two attacks, and 362 three attacks. The primary efficacy measure was the proportion of patients who had obtained complete or almost complete headache relief at 4 h after dosing. RESULTS: For all attacks, a significantly greater proportion of patients experienced headache relief at 4 h with sumatriptan 50 mg tablets than with placebo (59% to 62% versus 32% to 42%; P = 0.005). The same was true at 3 h across all attacks, and at 2 h for attacks 1 and 2 (49% versus 23% and 45% versus 29%, respectively). Although sumatriptan and placebo were associated with similar incidences of recurrence, sumatriptan was associated with a longer time to recurrence. The incidence of adverse events with sumatriptan was similar to that with placebo, and there was no increase in adverse events associated with use of a second dose to treat recurrence. CONCLUSIONS: Sumatriptan 50 mg tablets are well tolerated and efficacious in relieving migraine headache.

Carbonic anhydrase II in the cerebrospinal fluid: its value as a disease marker.

Carbonic anhydrase (CA) II is the predominant CA isoenzyme in the brain of mammals. We have recently developed a dual-label time-resolved immunofluorometric assay to quantify minute amounts of CA I and II in the cerebrospinal fluid (CSF). The present study was aimed at elucidating the clinical value of such measurements in the case of neurological disorders. Lumbar CSF samples were obtained from 111 patients suffering from various neurological diseases and from 97 control patients with no specific signs of central nervous system diseases. The highest CA II concentrations were found in patients with brain infarction (median 66.5 micrograms L-1, n = 20), whereas the control patients had markedly lower values (median 7.8 micrograms L-1, n = 97). Relative to a reference range calculated from the control material (10.2 +/- 17.2 micrograms L-1), the sensitivity of CA II measurement in differentiating brain infarction was 100%. Patients with transient ischaemic attack (median 11.2 micrograms L-1, n = 9), multiple sclerosis (median 14.7 micrograms L-1, n = 18) or epilepsy (median 20.3 micrograms L-1, n = 17) usually had CA II concentrations within the normal range, but those with central nervous system infection (n = 14), dementia (n = 19) or trigeminal neuralgia (n = 6) tended to have higher CA II levels in their CSF, the median values being 39.1 micrograms L-1, 45.5 micrograms L-1 and 44.0 micrograms L-1 respectively. The findings indicate that the concentration of CA II in the CSF marks disease activity in patients with brain damage. This finding could provide a basis for further studies estimating the value of CA II measurement as a new laboratory marker of diseases affecting the brain.

Endoscopic collagen injection: its limits in correcting vesico-ureteral reflux in duplicated ureters.

OBJECTIVE: The aim of this prospective study was to investigate whether it is possible, by endoscopic collagen injection, to treat vesicoureteral reflux in children with reflux into a totally duplicated ureter system. METHODS: For more than 7 years a prospective study has been in progress on children with grade III or IV reflux (international grading). Injections were made through a pediatric cytoscope, submucosally beneath the refluxing ureteral orifice. 0.2-1.5 ml collagen was injected. Reflux was controlled with direct radionuclide cystography 1 month later. Injections were repeated once or twice (within 3 months from the first injection) if reflux persisted. Additional controls with direct radionuclide cystography were made 6 months and 2 and 4 years later. RESULTS: Up to now, 24 children (27 ureter units) with reflux to a totally duplicated ureter have been treated. After 1 month, 11 out of 24 children were free from reflux; after 6 months only 6 out of 24, after 2 years only 5 out of 23, and after 4 years only 3 out of 13 children were free from the disorder. There was no statistical difference between 1-month, 6-month, 2-year, and 4-year follow-up results. The differences among children with duplicated and single ureters at each control visit were statistically highly significant. There was no significant difference between results in grade III and IV reflux. We had to treat the reflux operatively (Cohen) in 20 of these 24 children (83%). CONCLUSIONS: Most of the children with reflux into a duplicated ureter system cannot be cured by endoscopic collagen injection.

T-cell subpopulations in the cerebrospinal fluid and peripheral blood of patients with multiple sclerosis: a follow-up study.

We analyzed the relative and absolute numbers of CD4+ cells positive and negative for CD45RA marker as well as the numbers of CD8+ cells positive and negative for CD11b in the cerebrospinal fluid (CSF) and peripheral blood (PB) of 17 patients with multiple sclerosis (MS) during and 60 days after an exacerbation. We also studied samples from 27 control patients, 17 of whom had a noninflammatory neurologic disease and 10 of whom had an inflammatory neurologic disease other than MS. The results confirmed the small number of CD45RA-positive (naive or suppressor inducer) CD4+ cells as well as CD11b-positive (suppressor) CD8+ cells in the CSF compared with the PB for all paired CSF-blood comparisons. The relative numbers of these cells did not significantly differ between samples taken during an exacerbation and those taken 2 months later. In PB, the percentage of CD8+ CD11b-positive lymphocytes was lower in patients with MS or in patients with an inflammatory neurologic disease than in patients with a noninflammatory neurologic disease. The results indicate that there are fewer cells responsible for suppression-related phenomena in CSF than in PB but that this phenomenon is not specific to MS.

A randomised open multicentre comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy.

The efficacy and safety of lamotrigine and carbamazepine as monotherapy in patients with untreated, newly diagnosed or recurrent partial and/or generalised tonic-clonic seizures, were compared in a randomised, open, multicentre study. Patients received 24 weeks' treatment with oral lamotrigine 100 mg (LTG 100, n = 115) or 200 mg (LTG 200, n = 111) or carbamazepine 600 mg (CBZ 600, n = 117). Efficacy measurements were comparable between the three treatment groups, although the higher lamotrigine dose was possibly most effective, with 60.4% completing seizure free compared with 51.3% (LTG 100) and 54.7% (CBZ 600). Both dosage regimens of lamotrigine were well tolerated. More patients on CBZ 600 reported adverse experiences, 66% versus 53% (LTG 100) and 58% (LTG 200), and of these a greater proportion were attributed to CBZ 600 treatment, 53% versus 23% (LTG 100) and 28% (LTG 200). Similarly, a greater proportion of the CBZ 600 group required a change in dose, 47% versus 20% (LTG 100) and 17% (LTG 200) or withdrew completely due to adverse experiences, 10.3% versus 4.3% (LTG 100) and 4.5% (LTG 200). The most common adverse experience leading to withdrawal was rash, with approximately double the proportion of reports occurring in patients on CBZ 600 (5.1%) compared with lamotrigine (1.7% on LTG 100 and 2.7% on LTG 200). Overall lamotrigine appeared equally effective but better tolerated compared with carbamazepine.

Correction of vesicoureteral reflux in children by endoscopic collagen injection: a prospective study.

PURPOSE: The aim of our prospective study was to evaluate the long-term results of correction of vesicoureteral reflux in children by subureteral submucosal endoscopic collagen injection. MATERIALS AND METHODS: Between May 1988 and June 1994, 197 refluxing ureters in 148 children (grade III or IV, international grading system) were treated by collagen injection. Injection was done using general anesthesia and repeated 1 or 2 times if reflux persisted on the 1-month followup radionuclide cystogram. Cystography was repeated at 6 months, 2 years and 4 years. RESULTS: After 1 month, 6 months, 2 years and 4 years grades III and IV reflux were cured in 93.9%, 91.7%, 85.3% and 81.8%, respectively, of 132 simple ureters. For the 27 duplex ureters success rates were 44.4%, 25.9%, 23.1% and 21.4%, respectively, after 1 month, 6 months, 2 years and 4 years. After failed injections neo-implantation was performed with no difficulty. CONCLUSIONS: Our results show that in simple ureters reflux, especially grade III, can be corrected by collagen injection. Results seem to be stable after 2 years of followup.

Influx of nonactivated T lymphocytes into the cerebrospinal fluid during relapse of multiple sclerosis.

T lymphocytes were analyzed in the cerebrospinal fluid of 17 patients with multiple sclerosis during and 2 months after an exacerbation. The percentage of activated (HLA-DR+) T lymphocytes was decreased in the cerebrospinal fluid during the relapse but returned thereafter to the level comparable to that in patients with noninflammatory neurological diseases, whereas no fluctuation in the total number of these cells was found. This suggests an influx of nonactivated T lymphocytes into the cerebrospinal fluid at the beginning of the relapse.