Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1.

Narcolepsy type 1 (NT1) is a chronic neurological disorder having a strong association with HLA-DQB1*0602, thereby suggesting an immunological origin. Increased risk of NT1 has been reported among children or adolescents vaccinated with AS03 adjuvant-supplemented pandemic H1N1 influenza A vaccine, Pandemrix. Here we show that pediatric Pandemrix-associated NT1 patients have enhanced T-cell immunity against the viral epitopes, neuraminidase 175-189 (NA175-189) and nucleoprotein 214-228 (NP214-228), but also respond to a NA175-189-mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1675-689). A pathogenic role of influenza virus-specific T-cells and T-cell cross-reactivity in NT1 are supported by the up-regulation of IFN-γ, perforin 1 and granzyme B, and by the converging selection of T-cell receptor TRAV10/TRAJ17 and TRAV10/TRAJ24 clonotypes, in response to stimulation either with peptide NA175-189 or POMT1675-689. Moreover, anti-POMT1 serum autoantibodies are increased in Pandemrix-vaccinated children or adolescents. These results thus identify POMT1 as a potential autoantigen recognized by T- and B-cells in NT1.

The significance of supportive and undermining elements in the maternal representations of an unborn baby.

OBJECTIVE: The maternal representations of an unborn baby begin to develop during pregnancy. However, the factors that moderate them are not well identified. The objective of this study was to jointly explore supportive and undermining factors in the maternal representations of an unborn baby and motherhood. METHODS: Cross-sectional data comprising 1646 women studied during the third trimester of pregnancy. Maternal expectations were measured using a 12-item self-report questionnaire, Mother's Representations about an Unborn Baby. Depression, anxiety, family atmosphere and adult attachment were measured using standardised questionnaires. Statistical analysis is based on multivariate linear regression analysis. RESULTS: The most powerful predictors of a mother's prenatal expectations were the mother's educational status, age, closeness in adult relationships, higher levels of depressive symptoms and family atmosphere. In accordance with our hypothesis, depression was related to the mother's more negative expectations on their relationship with the unborn baby and on regularity in the baby's sleeping and eating patterns. A positive family atmosphere and the mother's ability for closeness and dependence (i.e. confidence) in adult relationships were related to more positive expectations of the mother-unborn baby relationship. On the other hand, stress, anxiety and adverse life events were not related to the mother's expectations of her unborn baby. CONCLUSIONS: The results may be helpful in identifying families who need early professional support and call for studies where the prenatal phase is explored as a proactive phase for the development of the child-parent relationship.

ImatraNMR: novel software for batch integration and analysis of quantitative NMR spectra.

Quantitative NMR spectroscopy is a useful and important tool for analysis of various mixtures. Recently, in addition of traditional quantitative 1D (1)H and (13)C NMR methods, a variety of pulse sequences aimed for quantitative or semiquantitative analysis have been developed. To obtain actual usable results from quantitative spectra, they must be processed and analyzed with suitable software. Currently, there are many processing packages available from spectrometer manufacturers and third party developers, and most of them are capable of analyzing and integration of quantitative spectra. However, they are mainly aimed for processing single or few spectra, and are slow and difficult to use when large numbers of spectra and signals are being analyzed, even when using pre-saved integration areas or custom scripting features. In this article, we present a novel software, ImatraNMR, designed for batch analysis of quantitative spectra. In addition to capability of analyzing large number of spectra, it provides results in text and CSV formats, allowing further data-analysis using spreadsheet programs or general analysis programs, such as Matlab. The software is written with Java, and thus it should run in any platform capable of providing Java Runtime Environment version 1.6 or newer, however, currently it has only been tested with Windows and Linux (Ubuntu 10.04). The software is free for non-commercial use, and is provided with source code upon request.

Crystal structures of the CBS and DRTGG domains of the regulatory region of Clostridiumperfringens pyrophosphatase complexed with the inhibitor, AMP, and activator, diadenosine tetraphosphate.

Nucleotide-binding cystathionine beta-synthase (CBS) domains serve as regulatory units in numerous proteins distributed in all kingdoms of life. However, the underlying regulatory mechanisms remain to be established. Recently, we described a subfamily of CBS domain-containing pyrophosphatases (PPases) within family II PPases. Here, we express a novel CBS-PPase from Clostridium perfringens (CPE2055) and show that the enzyme is inhibited by AMP and activated by a novel effector, diadenosine 5',5-P1,P4-tetraphosphate (AP(4)A). The structures of the AMP and AP(4)A complexes of the regulatory region of C. perfringens PPase (cpCBS), comprising a pair of CBS domains interlinked by a DRTGG domain, were determined at 2.3 A resolution using X-ray crystallography. The structures obtained are the first structures of a DRTGG domain as part of a larger protein structure. The AMP complex contains two AMP molecules per cpCBS dimer, each bound to a single monomer, whereas in the activator-bound complex, one AP(4)A molecule bridges two monomers. In the nucleotide-bound structures, activator binding induces significant opening of the CBS domain interface, compared with the inhibitor complex. These results provide structural insight into the mechanism of CBS-PPase regulation by nucleotides.

Hyperglycaemia is associated with changes in the regional concentrations of glucose and myo-inositol within the brain.

AIMS/HYPOTHESIS: The aim of the study was to assess the effect of hyperglycaemia on regional concentrations of glucose and other substrates within the brain in non-diabetic individuals and in patients with type 1 diabetes. METHODS: The brain metabolites of 17 men with type 1 diabetes and 12 age-matched non-diabetic men (22-43 years old) were studied after an overnight fast (plasma glucose 9.2 +/- 3.0 vs 4.8 +/- 0.5 mmol/l, respectively). N-Acetylaspartate (NAA), creatine, choline, myo-inositol (mI) and glucose in the frontal cortex, frontal white matter and thalamus were quantified with proton magnetic resonance spectroscopy. RESULTS: In the non-diabetic participants, the glucose level was 47% higher (p < 0.01) in the frontal cortex than in the frontal white matter. In contrast, this regional variation was not observed in the diabetic participants, in whom the glucose level in the frontal white matter was 64% higher (p < 0.001) and in the frontal cortex 25% higher (p = 0.033) than that of the non-diabetic participants. In the diabetic participants, the glucose level in each of the three regions studied correlated with fasting plasma glucose (r = 0.88-0.67, p < 0.01). In addition, in the diabetic participants, mI was 20% higher (p < 0.001) and NAA 6% lower (p = 0.037) in the frontal white matter, and mI was 8% higher (p = 0.042) in the frontal cortex, than in the non-diabetic participants. CONCLUSIONS/INTERPRETATION: In type 1 diabetes, hyperglycaemia is associated with accumulation of glucose and mI in the cortex and in the white matter.

Relationship between lipid profiles and kidney function in patients with type 1 diabetes.

AIMS/HYPOTHESIS: We studied the relationship between the lipid profile, estimated GFR (eGFR) and AER in patients with type 1 diabetes. We also assessed the association between the lipid profile and glycaemic control, obesity and hypertension in an environment free of manifest renal disease, as well as exploring how well the patients would have achieved the targets set in international guidelines. METHODS: A total of 2,927 adult patients who had type 1 diabetes and for whom lipid profiles were available were included from people participating in the nationwide, multicentre Finnish Diabetic Nephropathy Study (FinnDiane). eGFR was determined using the Cockcroft-Gault formula adjusted for body surface area. RESULTS: Patients with impaired renal function (eGFR <60 ml min(-1) 1.73 m(-2)) had higher total cholesterol, triacylglycerol and apolipoprotein B, and lower HDL-cholesterol concentrations than patients with normal renal function (eGFR >90 ml min(-1) 1.73 m(-2)) or mildly impaired renal function (eGFR 60-90 ml min(-1) 1.73 m(-2)) (p < 0.001 for all associations). In type 1 diabetic patients without manifest renal disease, similar adverse lipid profiles could be observed in those who were overweight or obese and in those who had intermediate or poor glycaemic control or hypertension. In all the different patient groups 14 to 43% would have achieved the recommended target of <2.6 mmol/l for LDL-cholesterol. CONCLUSIONS/INTERPRETATION: Multiple lipid abnormalities are not only present in type 1 diabetic patients with an abnormal AER, but also in those with impaired renal function. In patients without manifest renal disease, obesity, glycaemic control or hypertension were associated with an adverse lipid profile. A substantial number of patients studied would have exceeded the targets set by international guidelines, particularly the targets for LDL-cholesterol.

Acute hyperglycaemia rapidly increases arterial stiffness in young patients with type 1 diabetes.

AIMS/HYPOTHESIS: Augmentation index (AIx) and pulse wave velocity (PWV), both measures of arterial stiffness, constitute risk factors for cardiovascular disease. Notably, hyperglycaemia during an acute cardiovascular event is associated with poor prognosis. The objective of this study was to investigate whether acute hyperglycaemia increases arterial stiffness in patients with type 1 diabetes and in healthy subjects. METHODS: Twenty-two male patients with type 1 diabetes and thirteen healthy men, who were age-matched non-smokers and without any diabetic complications, underwent a 120 min hyperglycaemic clamp (15 mmol/l). AIx was calculated to assess arterial stiffness. Before and during the clamp, carotid-radial (brachial) and carotid-femoral (aortic) PWV was measured. RESULTS: At baseline there was a difference in the AIx between patients with type 1 diabetes and healthy volunteers (-5 +/- 2.7 vs -20 +/- 2.8%, p < 0.05). Acute hyperglycaemia rapidly increased AIx in patients with type 1 diabetes (-5 +/- 2.7 vs 8 +/- 2.5%, p < 0.001) and healthy volunteers (-20 +/- 2.8 vs 6 +/- 8.8%, p < 0.001). Brachial PWV increased during acute hyperglycaemia in patients with type 1 diabetes (7.1 +/- 1.2 vs 8.0 +/- 1.0 m/s, p < 0.001), but not in healthy men (7.4 +/- 1.7 vs 7.3 +/- 1.4 m/s, NS). CONCLUSIONS/INTERPRETATION: Acute hyperglycaemia increases the stiffness of intermediate-sized arteries and resistance arteries in young patients with type 1 diabetes and consequently emphasises the importance of strict daily glycaemic control. No change was observed in aortic PWV during the clamp, indicating that acute hyperglycaemia does not affect the large vessels.

Subjective daytime sleepiness and its predictors in Finnish adolescents in an interview study.

UNLABELLED: The purpose of this study is to evaluate the predictors of subjective daytime sleepiness (SDS) and its chronicity in adolescents. Two groups of adolescents (107 with SDS and 107 without SDS) from our first questionnaire study were invited to an interview after 3 y. A follow-up questionnaire had been sent to them one year earlier. The interview included questions about sleep, daytime sleepiness, living habits, physical and mental health, and progress at school. The adolescents were also examined clinically. Interviews were conducted with 66 out of 107 subjects with SDS and 64 out of 107 without SDS (age range 12 to 19 y). In this interview 42 out of the 130 adolescents had SDS. A total of 20 adolescents reported SDS in both questionnaire studies and in the interview (chronic SDS). In a multivariate analysis (logistic regression) sleep disorders, frequent medication and depressive emotions were significantly associated with SDS. Chronic SDS was connected in a bivariate analysis (Pearson's chi-square) with excessive night waking, difficulty in falling asleep, dreaming, frequent medication, frequent alcohol drinking, and irregular breakfast eating, and in our previous studies also with delayed sleep rhythm. CONCLUSION: Sleep disorders and health problems were more common causes of SDS than undesirable living habits. However, alcohol drinking and delayed sleep rhythm were associated with chronic SDS in addition to sleep disorders and medication.

Subjective daytime sleepiness in schoolchildren.

OBJECTIVES: The aim of this study was to find out how the occurrence of subjective daytime sleepiness (SDS) in schoolchildren had changed after 2 years follow-up and which were the predictors associated with persistence and appearance of SDS. METHODS: A total of 107 schoolchildren with SDS (Group 1) and an equal number without SDS (Group 2) were chosen to take part in the questionnaire study (age range 12-20 years). The questions concerned sleeping habits, sleep disorders and daytime sleepiness of the child and the family, progress at school and TV/video watching of the child, and social background of the family. A bivariate method (Pearson's chi-square) was used as a statistical tool. RESULTS: We received 68 replies (64%) from Group 1 and 75 (70%) from Group 2. Fifty-four schoolchildren were still sleepy in Group 1 and 28% had become sleepy in Group 2. The persistence of SDS in Group 1 was related to older age, irregular sleeping habits, frequent night waking and the fathers' sleep difficulties. The appearance of SDS in Group 2 was related to a high average grade at school. CONCLUSION: A delayed sleep phase rhythm and problems staying asleep are obvious causes of persistent SDS, but the stress of schoolwork can also cause daytime sleepiness in schoolchildren.

A new visual performance test offers new variables for assessing daytime vigilance: short pauses in performance.

A new visual performance test, VigiMouse, was evaluated with the aid of 6 volunteering pediatry residents. The results were compared with a visual analogue scale in differentiating four different states: mild sleep deprivation, low blood alcohol level, a combination of both, and the normal state. A normal night shift at a busy pediatric ward was chosen to represent sleep deprivation. A new set of parameters based on short pauses in performance proved to be more sensitive in detecting small changes in performance than parameters based on reaction times.

Duplex ultrasound in the subclavian steal syndrome.

PURPOSE: The effect of subclavian steal on the contralateral vertebral flow and its possible effect on carotid flow were studied and the US results were compared to the angiographic findings. MATERIAL AND METHODS: The study consisted of the records of 74 patients with a duplex Doppler finding of subclavian steal syndrome. Of these, 48 patients had had both angiography and US of the neck arteries and were selected for comparison. For a comparison of the US flow values, a control series of 48 was selected from our carotid archive and consisted of patients without subclavian steal who had also been examined with both US and angiography. RESULTS: Of the 48 patients, 44 had a subclavian steal syndrome at angiography, 31 on the left side and 13 on the right. Of the 44, 21 patients had subclavian occlusion, and 23 stenosis. In 84% of the subclavian occlusions, US showed a complete systodiastolic steal and in 16% a partial systolic steal, while the corresponding findings for subclavian stenoses were 17% and 83%. Of the 48 cases, 4 were not real subclavian steals: 2 had vertebral occlusion (1 with a 90% subclavian diameter stenosis) on the side of retrograde flow at US and a steal through the vertebral and collateral arteries to the spinal arteries; and 2 had a 70% diameter stenosis of the subclavian artery and to-and-fro flow in the vertebral artery at angiography. In the 21 cases of complete steals, the subclavian diameter stenosis was 97 +/- 8% at angiography, and in the 23 partial steals, it was 85 +/- 10%. There was a significant increase in contralateral vertebral and common carotid flow in the cases with retrograde vertebral flow compared to the vertebral and common carotid flow of the control subjects. The retrograde flow values, the ipsilateral vertebral lumen diameter, and the flow values in the common carotid arteries were higher in complete steals and subclavian occlusions than in partial steals. CONCLUSION: A complete vertebral steal at US correlated well with subclavian occlusion and a partial steal suggested stenosis of the subclavian artery. There were also flow changes in the contralateral vertebral artery and the common carotid arteries that compensated for the steal. Retrograde vertebral flow at US was sometimes associated with vertebral occlusion in subclavian stenosis without a true subclavian steal.

Preoperative embolization in the management of neck paragangliomas.

Surgery of neck paragangliomas carries inherent risks of excessive blood loss and cranial nerve injury. Preoperative embolization has been used to lessen the morbidity of surgery. We sought to characterize our experience with preoperative embolization by evaluating safety, efficacy, and surgical data. During a period of 22 years (1974 to 1996), 19 consecutive patients with 27 histopathologically confirmed neck paragangliomas were surgically treated at the Oulu University Hospital. All patients underwent preoperative arteriography and 17 patients had cervical ultrasonography (US). Eleven patients with 15 tumors were operated on without embolization and nine patients with 12 tumors were preoperatively embolized with 150- to 250-microm polyvinyl alcohol (PVA) particles. The mean blood loss during surgery in the nonembolized group was 1374 mL (range, 100 to 4500 mL) and the mean operation time was 4 hours and 48 minutes (range, 1.5 to 9 hours). In the embolized group the mean blood loss was significantly less (588 mL; range, 100 to 1800 mL; P = 0.04) and the mean operation time shorter (3 hours 24 minutes; range, 2 to 5 hours; P = 0.05). No embolic complications were recorded after the embolization. We conclude that preoperative embolization of neck paragangliomas 3 cm or greater in diameter with PVA particles is safe. Embolization to minimize operative bleeding facilitates surgery, shortens the operation time, and lessens the surgical risks.

Accidental astemizole overdose in young children.

6 cases of accidental astemizole poisoning in children have been reported to the Finnish Poison Information Center. The children were aged 1 year 7 months to 3 years 4 months and had taken doses of 2.5 to 16.7 mg/kg, at least twelve times that recommended. In 2 children the overdose was verified by measurement of drug concentrations. Despite measures to prevent drug absorption prolonged QTc-interval, a sign of cardiac toxicity, was found in all 5 children on whom an electrocardiogram was available for analysis, and severe ventricular arrhythmias developed in 1. Young children with accidental astemizole overdose should be carefully monitored in hospital. Similar precautions may be justified in cases of overdose with other selective H1-histamine receptor antagonists.

Screening a family for hereditary chronic pancreatitis.

Chronic "idiopathic" pancreatitis (CP) in a 7 year-old-boy, whose father has suffered from CP, and whose former grandfather had suffered from pains possibly of pancreatic origin, led us suspect a hereditary etiology. An analysis, extended in a control fashion to the relatives of the healthy spouse of the affected grandfather, surprisingly revealed 2 more proven and 3 more suspected CP, giving the overall number of 8 affected members in this 35-member 3 generation kindred and revealed a maternal heredity instead of paternal heredity (which was first thought to be apparent). We therefore recommend that in a family suspected to suffer from hereditary CP (HCP), a screening should be extended to cover even the unaffected spouse's family--the present extended study revealed for 23 new members them to belong in an affected family. Without an extensive screening advises for family planning, alcohol consumption etc. can not be given. Plain abdominal X-ray accompanied with epigastric ultrasonographic are suitable for screening, which might be extended to every individual in smaller families, but may be safely restricted to the members ever suffered from epigastric pains in the case of a huge family. Pancreatic duct anomalies, hyperlipidaemia, hypercalcaemia, aminoaciduria or hyperimmunoglobulinaemia, all of which have been seen to accompany HCP, were not present in this family. Neither was any linkage found between the penetrance of HCP and ABO/Rh blood groups or HLA haplotypes.

Antihypertensive effects of urapidil and clonidine: a double-blind cross-over study.

The antihypertensive effects of urapidil and clonidine have been studied in a double-blind cross-over trial in 11 hypertensive outpatients with mild to moderate hypertension, at rest and during isometric exercise. Urapidil 30 mg b.i.d. significantly decreased the standing diastolic blood pressure (p less than 0.05) and the systolic blood pressure at the end of isometric exercise (p less than 0.05). Clonidine 0.075-0.15 mg b.i.d. was more effective in decreasing both systolic and diastolic blood pressure in the supine and standing positions as well as during isometric work (p less than 0.05-0.001). Urapidil caused fewer side-effects than clonidine. Overall, in the doses used urapidil had a weaker antihypertensive effect and caused fewer side-effects than clonidine.