Terttu Särkioja

Gene expression in macrophage-rich human atherosclerotic lesions. 15-lipoxygenase and acetyl low density lipoprotein receptor messenger RNA colocalize with oxidation specific lipid-protein adducts.

Oxidatively modified low density lipoprotein (LDL) exhibits several potentially atherogenic properties, and inhibition of LDL oxidation in rabbits decreases the rate of the development of atherosclerotic lesions. In vitro studies have suggested that cellular lipoxygenases may be involved in LDL oxidation, and we have shown previously that 15-lipoxygenase and oxidized LDL are present in rabbit atherosclerotic lesions. We now report that epitopes of oxidized LDL are also found in macrophage-rich areas of human fatty streaks as well as in more advanced human atherosclerotic lesions. Using in situ hybridization and immunostaining techniques, we also report that 15-lipoxygenase mRNA and protein colocalize to the same macrophage-rich areas. Moreover, these same lesions express abundant mRNA for the acetyl LDL receptor but no detectable mRNA for the LDL receptor. We suggest that atherogenesis in human arteries may be linked to macrophage-induced oxidative modification of LDL mediated by 15-lipoxygenase, leading to subsequent enhanced macrophage uptake, partly by way of the acetyl LDL receptor.

Expression of extracellular SOD and iNOS in macrophages and smooth muscle cells in human and rabbit atherosclerotic lesions : Colocalization with epitopes characteristic of oxidized LDL and peroxynitrite-modified proteins

Oxidative processes play an important role in atherogenesis. Because superoxide anion and nitric oxide (NO) are important mediators in vascular pathology, we studied the expression of extracellular superoxide dismutase (EC-SOD) and inducible nitric oxide synthase (iNOS) in human and rabbit atherosclerotic lesions by using simultaneous in situ hybridization and immunocytochemistry and EC-SOD enzyme activity measurements. We also analyzed the presence in the arterial wall of oxidized lipoproteins and peroxynitrite-modified proteins as indicators of oxidative damage and possible mediators in vascular pathology. EC-SOD and iNOS mRNA and protein were expressed in smooth muscle cells and macrophages in early and advanced lesions. The expression of both enzymes was especially prominent in macrophages. As measured by enzyme activity, EC-SOD was the major SOD isoenzyme in the arterial wall. EC-SOD activity was higher in highly cellular rabbit lesions but lower in advanced, connective tissue-rich human lesions. Despite the abundant expression of EC-SOD, malondialdehyde-lysine and hydroxynonenal-lysine epitopes characteristic of oxidized lipoproteins and nitrotyrosine residues characteristic of peroxynitrite-modified proteins were detected in iNOS-positive, macrophage-rich lesions, thus implying that malondialdehyde, hydroxynonenal, and peroxynitrite are important mediators of oxidative damage. We conclude that EC-SOD, iNOS, and the balance between NO and superoxide anion play important roles in atherogenesis. EC-SOD and iNOS are highly expressed in lesion macrophages. High EC-SOD expression in the arterial wall may be required not only to prevent deleterious effects of superoxide anion but also to preserve NO activity and prevent peroxynitrite formation. Modulation of arterial EC-SOD and iNOS activities could provide means to protect arteries against atherosclerotic vascular disease.

Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions.

Macrophage- and smooth muscle cell (SMC)-derived foam cells are typical constituents of human atherosclerotic lesions. At least three receptor systems have been characterized that could be involved in the development of foam cells: alpha 2-macroglobulin receptor/LDL receptor-related protein (alpha 2 MR/LRP), scavenger receptor, and LDL receptor. We studied the expression of these receptors in human atherosclerotic lesions with in situ hybridization and immunocytochemistry. An abundant expression of alpha 2MR/LRP mRNA and protein was found in SMC and macrophages in both early and advanced lesions in human aortas. alpha 2MR/LRP was also present in SMC in normal aortas. Scavenger receptor mRNA and protein were expressed in lesion macrophages but no expression was found in lesion SMC. LDL receptor was absent from the lesion area but was expressed in some aortas in medial SMC located near the adventitial border. The results demonstrate that (a) alpha 2MR/LRP is, so far, the only lipoprotein receptor expressed in lesions SMC in vivo; (b) scavenger receptors are expressed only in lesion macrophages; and (c) both receptors may play important roles in the development of human atherosclerotic lesions.

Dopamine D(2)/D(3)-receptor and transporter densities in nucleus accumbens and amygdala of type 1 and 2 alcoholics.

Alcohol acts through mechanisms involving the brain neurotransmitter dopamine (DA) with the nucleus accumbens as the key zone for mediating these effects. We evaluated the densities of DA D2/D3 receptors and transporters in the nucleus accumbens and amygdala of post-mortem human brains by using [125l]epidepride and [125I]PE2I as radioligands in whole hemispheric autoradiography of Cloninger type 1 and 2 alcoholics and healthy controls. When compared with controls, the mean binding of [125I]epidepride to DA D2/D3 receptors was 20% lower in the nucleus accumbens and 41% lower in the amygdala, and [125I]PE2I binding to DA transporters in the nucleus accumbens was 39% lower in type 1 alcoholics. These data indicate that dopaminergic functions in these limbic areas may be impaired among type 1 alcoholics, due to the substantially lower number of receptor sites. Our results suggest that such a reduction may result in the chronic overuse of alcohol as an attempt to stimulate DA function.

Hypophyseal hemorrhage and panhypopituitarism during Puumala Virus Infection: Magnetic Resonance Imaging and detection of viral antigen in the hypophysis.

We describe 3 cases of nephropathia epidemica (NE) that confirm that Puumala virus infection may cause hypophyseal injury. Autopsy revealed a hemorrhagic hypophysis positive for Puumala virus antigen in both neuroendocrine stromal and vascular endothelial cells in 1 patient, and 2 patients developed hypophyseal hemorrhage (diagnosed with magnetic resonance imaging) during or shortly after acute NE, both of whom developed panhypopituitarism.

Cyclic time patterns of death from suicide in northern Finland

BACKGROUND Time patterns of suicide have been attributed not only to social and psychological factors but also to direct geophysical effects. Seasonal variations in day length and temperature seem likely to contribute to the timing of the suicide process. METHODS We analysed all suicides (n=1658) committed in a northern province of Finland during a period of 153 months. Daily data on the number of suicides, local weather conditions and geomagnetic storms were compiled and modelled with Poisson regression using the province population as the denominator, and with the means of harmonic series for seasonal variation. Time series analysis of monthly numbers of suicides was carried out using the seasonal-trend decomposition procedure based on loess. RESULTS Marked fluctuations in the number of suicides occurred during the study period (P=0.01). There was significant seasonal variation in death from suicide (P=0.01), but analysis of the meteorological data showed no evidence of effect on the risk of suicide. LIMITATIONS Assessment of mental disorder or alcohol consumption was missing, since only data derived from death certificate was available for each case. CONCLUSIONS The seasonal effect was significant, but remained modest compared to sex and age as risk factors for suicide. Preventive measures need to be tailored according to time of the year.

Dopamine D2 receptors and transporters in type 1 and 2 alcoholics measured with human whole hemisphere autoradiography

Increasing evidence implies the involvement of the dopamine (DA) system in the pathogenesis of alcoholism. We measured striatal DA D2 receptors in Cloninger type 1 and 2 alcoholics by using [125I]epidepride in human postmortem whole hemispheric autoradiography (WHA), which provides high‐resolution images corresponding to positron emission tomographic (PET) studies. We also evaluated the correlation between transporter and receptor DA binding site densities and putative correlation of [125I]epidepride binding between the dorsal striatum and nucleus accumbens. In the type 1 alcoholics, the DA D2 receptor density was 21.4–32.6% lower in all dorsal striatal structures (caudate, putamen, globus pallidus) when compared with the controls. Type 2 alcoholics had 19.6–21.4% lower binding in other dorsal striatal structures, except medial globus pallidus, where they were not significantly different from controls. The density of DA D2 receptors and DAT had a significant positive correlation only in the putamen of type 1 alcoholics. The binding of [125I]epidepride showed also consistent and statistically significant positive correlation between nucleus accumbens and all dorsal striatal areas in type 1 alcoholics but not in the controls. In the type 2 alcoholics, the correlation was weaker than that observed in the type 1 alcoholics, and no correlation was observed between nucleus accumbens and globus pallidus. Our results show that these two subgroups of alcoholics have stark differences in their DA D2 receptor binding characteristics. Type 2 alcoholics may have selective deficiency in the dorsal striatum, whereas in limbic structures they may not differ significantly from controls. Moreover, WHA provides a useful tool for detailed mapping of neuronal receptors in healthy as well as diseased brain, and can also be used in radioligand development for PET. Hum. Brain Mapp. 20:91–102, 2003.

Dopamine-transporter density in nucleus accumbens of type-1 alcoholics

We have shown that alcoholic patients have a lower number of dopamine transporters in the nucleus accumbens, which mediates the rewarding effects of addictive drugs. Thus, certain dopaminergic agents may be beneficial in the treatment of alcohol withdrawal and in the long-term treatment of alcoholism with selective use.

Is seasonality of suicides stronger in victims with hospital-treated atopic disorders?

The aim of the present study was to test whether the seasonal distribution of suicides differed between atopic and non-atopic suicide victims. A cross-sectional comparison of the semi-annual and seasonal distribution of suicides was made by using a 13-year database of all suicides (1296 males, 289 females) committed during the years 1988-2000 in the province of Oulu in Northern Finland. During the first half of the year, the proportion of suicides among atopic patients was significantly higher than that linked with non-atopic patients. Of all atopic patients, 72% committed suicide during the first and 28% during the second half of the year. Suicides among victims without any atopic disorders followed a uniform seasonal distribution throughout the year (50 vs. 50%). The exacerbation of an atopic disorder may increase the risk of suicide in spring; something that should be taken note of in clinical work.

Traumatic brain injury, psychiatric disorders and suicide: A population-based study of suicide victims during the years 1988-2004 in Northern Finland

Background: Depression and substance abuse are common among patients with traumatic brain injury (TBI). However, previous studies have not examined the temporal association between psychiatric disorders, TBI and suicide. Objective: To study the prevalence of TBI injury among suicide victims; to determine the association of suicide, psychiatric disorders and TBI severity; and to examine the effect of pre- and post-traumatic psychiatric disorders on their remaining life-time. Methods: This study examined all suicides (n = 1877) committed during a 16-year period in the province of Oulu, Finland. The information of suicide victims was extracted from the official death certificates and the National Hospital Discharge Registers. Results: TBI was found in 5.5% (n = 103) of the victims. Compared to the victims without TBI, those with TBI had significantly more hospital-treated psychiatric and alcohol disorders. If TBI subjects had comorbid psychiatric disorders, the time period between TBI and suicide was under 3 years in ∼ 90% of victims in this suicide population. Conclusions: Seriousness of injury, male gender, older age, being unemployed and presence of psychiatric and alcohol disorders are important to identify as possible predictors for suicidal behaviour in TBI patients. Further studies are required to shed light on interventions aimed at better life management.