The multiple sclerosis risk gene IL22RA2 contributes to a more severe murine autoimmune neuroinflammation.

Single-nucleotide polymorphisms close to IL22RA2, coding for the soluble interleukin (IL)-22-binding protein (IL-22BP), are strongly and reproducibly associated with multiple sclerosis (MS), but there is little data on how this molecule may affect neuroinflammation. Here, we have studied the mouse ortholog in C57BL/6 wild-type and Il22ra2-deficient mice in the context of experimental autoimmune encephalomyelitis (myelin oligodendrocyte glycoprotein-EAE). In wild-type mice, we demonstrated changes in the levels of transcripts for IL-22, the signaling IL-22 receptor and IL-22BP in lymphoid tissues at the time of T-cell priming and in the inflamed central nervous system (CNS). Because IL-22BP is known to antagonize IL-22 signaling, a primarily pro-inflammatory cytokine, we hypothesized that the Il22ra2-deficient mice would have more severe EAE. Paradoxically, the knockout mice displayed a less severe disease course, less demyelination and less infiltration of immune cells in the CNS. The most straightforward interpretation of our findings is that lack of IL-22BP leads to a higher availability of IL-22, which in the case of CNS inflammation, surprisingly acts in a protective fashion. Thus, deletion of the ortholog of the MS risk gene Il22ra2 in mice has beneficial effects on EAE, which may be considered in new therapeutic strategies for treating neuroinflammation.

Preparation and complex characterization of silica holmium sol-gel monoliths.

Amorphous, sol-gel derived SiO(2) are known to biocompatible and bioresorbable materials. Biodegradable and inert materials containing radioactive isotopes have potential application as delivery vehicles of the beta radiation to the cancer tumors inside the body. Incorporation of holmium in the sol-gel derived SiO(2) could lead to the formation of a biodegradable material which could be used as carrier biomaterial for the radiation of radioactive holmium to the various cancer sites. The homogeneity of the prepared sol-gel silica holmium monoliths was investigated by Back Scattered Electron Imaging of Scanning Electron Microscope equipped with Energy Dispersive X-ray Analysis, X-ray Induced Photoelectron Spectroscopy and Nuclear Magnetic Resonance Spectroscopy. The biodegradation of the monoliths was investigated in Simulated Body Fluid and TRIS (Trizma pre-set Crystals) solution. The results show that by suitable tailoring of the sol-gel processing parameters holmium can be homogeneously incorporated in the silica matrix with a controlled biodegradation rate.

A method for spatiotemporal mapping of event-related modulation of cortical rhythmic activity.

Cortical rhythmic activity can be systematically modulated by stimuli or tasks and may thus provide relevant information about brain function. Meaningful use of those phenomena requires characterization of both locations and time courses of event-related suppressions and increases of oscillatory activity. However, localization of the neural sources of cortical rhythms during intervals of very low levels of activity, and within short time intervals, is not a trivial matter. Hence, event-related modulation of rhythmic activity has typically been described at the level of magnetoencephalography (MEG) sensors or electroencephalography (EEG) electrodes, without reaching into the brain. Here, we introduce erDICS, an event-related version of Dynamic Imaging of Coherent Sources that allows spatial mapping of the level of oscillatory activity in the brain as a function of time, with respect to stimulus or task timing. By utilizing a time-resolved frequency-domain beamformer, erDICS yields the spatial distribution of both power suppressions and power increases. Permutation tests further reveal areas and time windows in which the modulations of oscillatory power are statistically significant, in individual subjects. We demonstrate the usability of erDICS on simulated and real MEG data. From the erDICS maps we identify areas showing salient event-related changes of rhythmic activity, represent them with equivalent current dipoles and calculate their contribution to the measured signal. Comparison of this multidipole model with the original signal yields a quantitative measure of goodness for the identified source areas and the analysis approach in general.

Histopathological findings of cardiac conduction system of 150 Finns.

One hundred and fifty heart specimens were collected from the cases submitted for autopsy in the Department of Forensic Medicine in the University of Turku in March-May 1995 and May-July 1996, respectively. The cardiac conduction system (CCS) of these hearts were examined in order to find out the histopathological changes in the CCS of Finnish persons and their forensic pathological significance. There were 94 males and 56 females. Almost all age groups were included. The results revealed that in most of the persons the fibrous tissue and fatty tissue in the CCS increased with aging. In about half of the persons, there was deposition of calcium in the central fibrous body, pars membranacea, and the top of the musculature in the interventricular septum. In seven cases, the atrioventricular node (AVN), His bundle (HB) or bundle branches (RBB, LBB) were compressed by the calcium deposition. Hemorrhage, inflammation, amyloidosis, tumor, fatty infiltration and developmental malformations were observed in 31 cases. Twenty-eight cases died of myocardial infarct, among them, no involvement of the CCS could be observed. The authors concluded that routine examination of the CCS is helpful for revealing diseases of the CCS and improving the quality of forensic pathological diagnosis.

Importance of storing emergency serum samples for uncovering murder with insulin.

A case of a previously healthy 48-year-old man murdered by exogenous insulin administration is reported. The patient was delivered unconscious to the emergency unit. Initially, treatment with hyperbaric oxygen was commenced because decompression sickness was suspected. However, the treatment was aborted as the patient was found to be hypoglycaemic (nadir serum glucose 0.3 mmol/l) and treatment and diagnostics of hypoglycaemia commenced. Brain damage due to hypoglycaemia was severe, and the patient remained in a vegetative state for 2 months before he died of multiorgan failure. Serum samples drawn at admittance were stored frozen, whereby it was possible to show retrospectively, that while the concentration of insulin in serum was high (75 mU/l, increasing further to over 240 mU/l in the next few hours) concentration of C-peptide was low (below detection limit of 0.1 nmol/l) at the hypoglycaemic stage. It was concluded that the patient had received exogenous insulin somehow, and the police was informed. Circumstantial evidence obtained during ensuing criminal investigation was considered by the court to prove the patient's wife (a nurse) guilty of murder. The availability of stored frozen serum samples drawn at the early stage of hospitalization helped to uncover the crime involved in our case.

Expression of the myc-family proto-oncogenes and related genes max and mad in synovial tissue.

OBJECTIVE: To examine the expression of myc proto-oncogenes; c-myc, L-myc, and N-myc, and their related genes max and mad, in the arthritic synovium. METHODS: Using reverse transcription-polymerase chain reaction (RT-PCR), Northern and Southern hybridizations, the expression of these genes in the synovial tissue from rheumatoid arthritis (RA) and osteoarthritis (OA) was analyzed. Synovial specimens from cadavers without any joint disease and peripheral blood mononuclear cells (PBMC) from healthy individuals served as controls. RESULTS: As a novel finding, synovial cells were observed to express L-myc, N-myc as well as their related genes max and mad, in addition to the previously described presence of c-myc proto-oncogene in synovium. c-myc, L-myc, N-myc, and mad were expressed in all patient samples studied, including the controls. Instead, max was detected in only 10/12 of RA patients, in 11/13 of OA patients, and in all controls (4/4 cadavers, 5/5 blood donors). Six patients with RA revealed positive signals for max only after hybridization. The same was also true of two patients with OA and of one healthy individual donating blood. CONCLUSIONS: The L-myc, N-myc, max, and mad genes are expressed in synovial cells, in addition to c-myc proto-oncogene. However, expression of these genes is not disease-specific, since they were equally expressed in synovial samples from patients with RA or OA as well as from cadavers representing controls without any joint disease.

[The amyloidosis in cardiac conduction system].

OBJECTIVE: To investigate the relationship between arrhythmia, cardiac failure and amyloidosis of cardiac conduction system (CCS). METHODS: CCS from 6 cases with cardiac amyloidosis were sampled using technique designed by the authors. The CCS were studied by Congo red staining and polarization microscopy. RESULTS: Pathological changes could be found in the CCS of these 6 cases. It was serious in sino-atrial node while slight in atrio-ventricular conduction system. The changes in atrio-ventricular conduction system were exacerbated from proximal part (atrio-ventricular node) to distal part (left bundle branch). In the 3 cases with sinus bradycardia and conduction blocking manifested by electrocardiogram, the pathological changes in CCS were more extensive and serious than that of other cases. CONCLUSION: The amyloidosis in CCS is one of the pathological bases of arrhythmia.

Alzheimer changes are common in aged drivers killed in single car crashes and at intersections.

With increasing age, diseases affecting the cognitive functions are more frequent. These diseases may increase the risk for fatal car crashes. We analyzed the frequency of neuropathological alterations characteristic of Alzheimer's disease (i.e. neuritic and diffuse plaques, and neurofibrillary tangles) in two association areas of the brain, parietal and frontal cerebral cortex, from 98 fatally injured aged drivers. In the age groups of 65-75 and over 75 years of age, 50% and 72% of the drivers, respectively, had neuritic plaques in either parietal and/or frontal cortex. In 14% of all killed drivers the number of neuritic plaques reached the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) age-related histologic score C, which indicates the diagnosis of Alzheimer's disease (AD), and an additional 33% had score B, which suggests the diagnosis of AD. Neuropathological AD changes were most common in the brains of drivers killed in single vehicle crashes, followed by multivehicle crashes at intersections and least common in multivehicle crashes elsewhere, but the differences did not reach statistical significance. In a great majority (80-85%) of cases the killed aged driver was the guilty party of the crash. The results imply, that incipient AD may contribute to fatal crashes of aged drivers, and therefore the forensic autopsy of these victims should include neuropathological examination.

A modified method for examining the cardiac conduction system.

A revised technique is described in which the sino-atrial node, the atrio-ventricular node and the distal part of the His bundle and the bundle brances of the cardiac conduction system are demonstrated in longitudinal sections through cutting of 4-5 blocks. The longitudinal sectioning allows observation of continuity between different components of the cardiac conduction tissue. This method reduces the workload and hopefully encourages the pathologist to make the examination of the cardiac conduction system a part of the routine procedure.

Self-reported hostility and suicidal acts, accidents, and accidental deaths: a prospective study of 21,443 adults aged 25 to 59.

The association of self-reported hostility with morbidity and mortality due to external causes, including suicidal acts, was analyzed in 10,586 Finnish men and 10,857 Finnish women aged 24 to 59 years. Hostility was assessed from self-ratings on irritability, ease of anger-arousal, and argumentativeness. Three groups, low (33.6% of subjects), intermediate (50.6%), and extreme (15.9%), were formed from the self-reported hostility scores. A 6-year mortality follow-up yielded 76 violent deaths among men and 11 among women. A 4-year morbidity follow-up found 399 hospitalizations due to external causes among men and 169 among women. Among men, the risk ratio between the highest and lowest hostility groups was 1.51 (95% confidence interval, 1.16-1.96) for all events due to external causes and 3.6 (95% confidence interval, 1.63-7.89) for suicidal behavior, when effects of age, marital status, social status, and self-reported alcohol use were controlled in a multivariate model. No association was observed between traffic-related injuries and hostility. Hostility did not predict accidents or accidental deaths or suicidal behavior among women.

Surveillance of human immunodeficiency virus (HIV) antibodies in medicolegal autopsies in Finland--monitoring early changes in HIV-seropositivity among risk groups and average population.

In order to cooperate with voluntary screening programs aimed at the surveillance of the HIV epidemic in Finland, we have studied medicolegal autopsies for HIV antibodies since 1986 using an enzyme immunoassay on postmortem sera. The investigation covered 47.4% and 39.2%, respectively, of all deaths under the age of 65 years in the metropolitan areas of Helsinki and Turku--two cities on the densely populated southern coast of Finland from which most HIV infections have thus far been detected. Nine HIV-positive cases (0.12%) were detected among the 7305 medicolegal autopsies tested in 1986 to 1990. This figure is higher than the prevalence of 0.01 to 0.03% in voluntary screening programs for the general population would suggest. Seven of our cases had previously tested positive, and two were previously unknown cases, indicating that people at high risk are clustered in the medicolegal autopsy series. Of the six cases in an early stage of infection, three committed suicide suggesting the importance of HIV-screening in suicide cases in tracing symptomless HIV carriers. Five of the cases were detected in 1990, a year when the number of new HIV infections had more than doubled compared to the previous two years. This suggests that testing of medicolegal autopsies as surrogate tests for the population gives useful information even in low-prevalence areas like Finland. Such testing has none of the ethical problems of many other back-up surveys, and may be particularly sensitive to early changes in epidemiology.

Relationships between myocardial macrominerals and trace elements and luminal narrowing of coronary arteries in Finnish children.

In addition to the traditional risk factors for cardiovascular diseases it has been hypothesized that a suboptimal intake of macrominerals and trace elements plays a role in the etiology of such diseases. We studied the possible correlation between preatherosclerotic changes in the coronary arteries and the myocardial concentration of K, Ca, Mg, Fe, Zn, Cu and Se in an autopsy series of children who had died mainly from accidental causes (n = 58). The concentrations of myocardial elements were comparable to values published elsewhere except for a slightly higher Cu concentration. The myocardial Se concentration indicated an adequate Se status. Narrowing of the coronary artery lumen was not correlated with myocardial element concentration except in the case of Se, for which a positive correlation was found (r = 0.23, p less than 0.04). Myocardial K was positively correlated with myocardial Mg (r = 0.65, p less than 0.001) and inversely correlated with Ca (r = -0.50, p less than 0.001). The intake of saturated vs. unsaturated fats was associated with myocardial Cu and Ca concentrations. Our results suggest that myocardial macrominerals and trace elements do not play a role in juvenile preatherosclerotic changes of the arteries.

Use of orthopantomographs in forensic identification.

Radiographs of the head region were used for identification of 17 victims during an 11-year period in the Department of Forensic Medicine, University of Turku, Finland. Examinations resulted in positive identification of 10 victims. Proof of identity of four people was based on exclusion identifications. In one case, comparable information supporting the identity was achieved. Due to insufficient ante- and postmortem material, two individuals remained unidentified by radiological methods. The use of orthopantomography in identification is recommended because it enables visualization of the structures of the jaws and related areas on a single radiograph.

Dimensions of the coronary arteries in children.

The extent of narrowing of the coronary arteries was measured in a series of 106 children who died accidentally. The outer radius of left main stem coronary artery increases from 1.06 mm at the age of 1 to 1.67 mm at 15. The left anterior descending branch increased with age from 0.70 to 1.35 mm and the inner radius from 0.55 to 1.10 mm. The mean thickness of the media and intima also increased with age; the correlation between thickness and weight was less pronounced. The coronary arteries thickened concomitantly with the size of the artery but that was due mainly to thickening of the intima. Substantial narrowing was found in the youngest age groups and the extent did not correlate with age but with the size of the vessel. The greatest narrowing was 57% of the arterial lumen. The measured dimensions will serve as normal values for the coronary arteries in Finnish children at autopsy.

Intimal thickening in the coronary arteries of infants and children as an indicator of risk factors for coronary heart disease.

Narrowings of the coronary arteries were measured in 94 infants aged less than 1 year who died in hospital and 102 1- to 16-year-old children who died accidentally. The arteries were transformed mathematically to circles. The degree of narrowing caused by intimal thickening was determined as the ratio of intimal area to the original luminal area. This ratio was further transformed to percentage. The degree of narrowing varied between 0 and 58% (mean 20%). The mean degree of narrowing in the left coronary artery during the first year of life was 17% and, between 12 and 15 years, 34%. Narrowing was greater in males (P = 0.02), when all the 333 coronary samples were included in the analysis. The birthplaces of the subjects' grandparents were traced from population registers and it was found that narrowing in the left coronary artery of infants was greater in those descended from grandparents from eastern Finland, an area of high mortality from coronary heart disease (CHD). Intimal thickening in infants and children seems to be a morphological manifestation of hereditary predisposition to CHD.

Histological and histochemical studies on local coronary wall thickenings (cushions) in Finnish children who died violently. Cardiovascular risk in young Finns?

Coronary arteries of 93 clinically healthy Finnish children of both sexes were collected from successive, medicolegal autopsies of victims of violent death. In the histological and histochemical study, local, cushion-type thickenings of the coronary walls were demonstrable in 47, i.e. 50 per cent, of the children, the occurrence increasing with age. The most prominent change was the splitting of the internal elastic membrane and the accumulation of smooth muscle cells, forming a new, musculo-elastic layer. Glycosaminoglycans appeared in the luminal parts of the thickenings. There was an average decrease in the succinate dehydrogenase reaction in the cushion area, implying a degenerative process. The increase in the reaction of "injury markers", acid phosphatase and esterase based on the increase of cells rich in these enzymes, indicated pathologic process. It was concluded that change of this kind, demonstrable early in childhood, may dispose coronary arteries to atherosclerosis.

Effect of lifelong selenium and vitamin E deficiency or supplementation on pigment accumulation in rat peripheral tissues.

The accumulation of lipopigments during aging in several peripheral organs and in the nervous system is considered to be related to the peroxidation of unsaturated fatty acids. In this study the effect of lifelong (until to 18 months) dietary antioxidants selenium and vitamin-E on pigment accumulation in some peripheral tissues was estimated using fluorescence and electron microscopy. In the vitamin E deficiency group, there was increased pigment accumulation in all peripheral tissues studied except the hypogastric ganglion, where no change was observed. The vitamin E supplementation degreased the pigment accumulation in older animals in some of the tissues studied. At the electron microscopical level the accumulated pigment in the adrenal cortex showed a lipofuscin-like structure. Lifelong selenium supplementation or deficiency did not significantly alter pigment accumulation in any of the tissues studied. It is possible that in many organs dietary selenium may not play a critical role in lipofuscin formation.

Glycosaminoglycans and apolipoproteins B and A-I in human aortas. Chemical and immunological analysis of lesion-free aortas from children and adults.

To study changes in the contents of plasma lipoproteins in human arteries with age and the relationship of lipoproteins with other arterial constituents, we analyzed the contents of apolipoproteins B (apo B) and A-I (apo A-I), free and esterified cholesterol, and glycosaminoglycans (GAG) in lesion-free aortic intimas of 30 children and adults. The content of apo B increased significantly with age, whereas that of apo A-I remained relatively constant. Apo B and apo A-I had significant positive correlations with the content of chondroitin sulphates A + C (CS A + C), which comprised 35% to 47% of the aortic GAG. The correlations remained significant after correction for the effect of age. Aortic apo B, but not apo A-I, also showed significant positive correlations with the contents of intimal free and esterified cholesterol. The results indicate that: considerable amounts of apo B and apo A-I can be found in lesion-free aortic intimas; there is an age-related rise in the content of apo B and a fall in the ratio of apo A-I to apo B, which are unfavorable developments in the light of current views on atherogenesis; the contents of the apolipoproteins are proportional to that of CS A + C, which might have a role in the retention of lipoproteins in the arteries.

Biochemical composition of coronary arteries in Finnish children.

To study the early features of atherosclerosis, we analyzed coronary artery intima medias from 63 boys and 30 girls who were newborn to 15 years old at the time of accidental death. Fatty streaks were found in five boys and one girl and, with one exception, were not present until the second decade of life. From birth there was a continuous increase in esterified cholesterol (EC) and a two- to threefold rise in free cholesterol and phospholipid. DNA, total protein, and collagen tended to rise after the first decade. The content of hyaluronic acid remained fairly constant, but sulphated glycosaminoglycans (GAGs) rose during the second decade; the highest increases were in dermatan and chondroitin sulphates. The content of arterial EC showed significant positive correlations with those of GAGs, but associations with the contents of DNA, total protein, and collagen were not significant. As judged by the observed gradual increase in arterial EC and a change in its fatty acid composition, there is a continuous increase with age in LDL-derived EC in the arterial wall. The mechanism of this accumulation is unknown, but the findings provide circumstantial evidence to support the concept that arterial GAGs may cause retention of plasma-derived lipids, which may subsequently be altered and internalized by the intimal cells.