Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer's disease: the OmegAD study.

OBJECTIVE: Little is known about the transfer of essential fatty acids (FAs) across the human blood-brain barrier (BBB) in adulthood. In this study, we investigated whether oral supplementation with omega-3 (n-3) FAs would change the FA profile of the cerebrospinal fluid (CSF). METHODS: A total of 33 patients (18 receiving the n-3 FA supplement and 15 receiving placebo) were included in the study. These patients were participants in the double-blind, placebo-controlled randomized OmegAD study in which 204 patients with mild Alzheimer's disease (AD) received 2.3 g n-3 FA [high in docosahexaenoic acid (DHA)] or placebo daily for 6 months. CSF FA levels were related to changes in plasma FA and to CSF biomarkers of AD and inflammation. RESULTS: At 6 months, the n-3 FA supplement group displayed significant increases in CSF (and plasma) eicosapentaenoic acid (EPA), DHA and total n-3 FA levels (P < 0.01), whereas no changes were observed in the placebo group. Changes in CSF and plasma levels of EPA and n-3 docosapentaenoic acid were strongly correlated, in contrast to those of DHA. Changes in DHA levels in CSF were inversely correlated with CSF levels of total and phosphorylated tau, and directly correlated with soluble interleukin-1 receptor type II. Thus, the more DHA increased in CSF, the greater the change in CSF AD/inflammatory biomarkers. CONCLUSIONS: Oral supplementation with n-3 FAs conferred changes in the n-3 FA profile in CSF, suggesting transfer of these FAs across the BBB in adults.

IL-1/IL-1ra balance in the brain revisited - evidence from transgenic mouse models.

The interleukin-1 (IL-1) family is unique in its including an endogenous antagonist of the IL-1 receptor (IL-1ra). IL-1ra has been shown to antagonise IL-1 signalling so effectively, that it came into clinical use within a few years from its discovery. Although barely detectable in the normal brain, IL-1 is dramatically upregulated during neuroinflammation, and also displays peaks of expression in the brain during development, as well as following the induction of long-term potentiation. IL-1 has been ascribed a central role in neuroinflammation accompanying ageing and age-related neurodegenerative conditions. Several experimental models based on genetically modified mice have been used in order to address the role of IL-1 in neurodegeneration and neuroprotection. Most of the findings here are based on the experiments involving a transgenic mouse strain with brain-directed overexpression of human IL-1ra, in which the balance between IL-1 and IL-1ra is permanently tipped towards inhibiting IL-1 signalling. The developmental effects of IL-1 are evident in the altered brain morphology in adult transgenic mice. In addition, IL-1 appears to be central in regulating the elasticity of the brain response to injury. Thus, a number of lines of evidence support the essential role played by IL-1 in development, plasticity, and physiological brain function.

Studies on brain volume, Alzheimer-related proteins and cytokines in mice with chronic overexpression of IL-1 receptor antagonist.

Inflammation is associated with both acute and chronic neurological disorders, including stroke and Alzheimer's disease (AD). Cytokines such as interleukin (IL)-1 have several activities in the brain both under physiological and pathophysiological conditions. The objective of this study was to evaluate consequences of the central blockade of IL-1 transmission in a previously developed transgenic mouse strain with brain-directed overexpression of human soluble IL-1 receptor antagonist (Tg hsIL-1ra). Effects on brain morphology and brain levels of the AD-related proteins beta-amyloid precursor protein (APP) and presenilin 1(PS1), as well as the levels of IL-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha) were analysed in homozygotic and heterozygotic mice and wild type (WT) controls, of both genders and of young (30-40 days) and adult (13-14 months) age. A marked reduction in brain volume was observed in transgenic mice as determined by volumetry. Western blot analysis showed higher levels of APP, but lower levels of PS1, in adult animals than in young ones. In the cerebellum, heterozygotic (Tg hsIL-1ra(+/-)) mice had lower levels of APP and PS1 than WT mice. With one exception, there were no genotypic differences in the levels of IL-1beta, IL-6 and TNF-alpha. The cytokine levels were generally higher in adult than in young mice. In conclusion, the chronic blockade of IL-1 signalling in the brain was associated with an atrophic phenotype of the brain, and with modified levels of APP and PS1. Brain-directed overexpression of hsIL-1ra was not followed by major compensatory changes in the levels of pro-inflammatory cytokines.

High cholesterol diet results in increased expression of interleukin-6 and caspase-1 in the brain of apolipoprotein E knockout and wild type mice.

Inflammation in the central nervous system is an early hallmark of many neurodegenerative diseases including Alzheimer's disease (AD). Recently, increasing evidence suggests that hypercholesterolemia during midlife and abnormalities in the cholesterol metabolism could have an important role in the pathogenesis of AD. In the present study, we have evaluated the effect of high cholesterol (HC) diet on the expression of interleukin-6 (IL-6), a cytokine involved in neurodegeneration, and caspase-1, that is responsible for the cleavage of the precursors of interleukin-1 beta (IL-1 beta) and interleukin-18 (IL-18) in the brain of apolipoprotein E (Apo E) knock-out (KO) and wild type (WT) mice. The density of IL-6-positive cells was increased in the hippocampus (p<0.0001) and the dorsal part of the cortex (p<0.001) of KO and WT mice on HC diet (KOHC and WTHC mice, respectively) compared to KO and WT mice on ND (KOND and WTND mice, respectively). KOHC mice had increased caspase-1 positive cells and staining intensity in the hippocampus in comparison with WTHC mice (p<0.01). In the hippocampus, the density of caspase-1 positive cells was also higher in KOHC compared to KOND mice (p<0.05) and KOHC compared with WTHC mice (p<0.01). There was a major increase in caspase-1 immunoreactivity and cell density in both the dosal part of the cortex (p<0.001) and the lateral part of the cortex (p<0.005) in KO and WT mice on HC diet compared to ND. The findings of the present study indicate that chronic exposure to HC diet increases the expression of the two important inflammatory mediators IL-6 and caspase-1 in the brain of KO and WT mice. In the case of caspase-1, we report a major difference in the effect of HC diet on the KO mice compared to WT mice in the hippocampus. Increased expression of inflammatory mediators involved in neurodegeneration could be a potential mechanism by which hypercholesterolemia and HC diet increase the risk of AD.

Effects of high cholesterol diet on gliosis in apolipoprotein E knockout mice. Implications for Alzheimer's disease and stroke.

Hypercholesterolemia has been suggested as a risk factor for Alzheimer's disease (AD). A genetic risk factor for AD is the E4 allele of apolipoprotein E (apoE). ApoE is the major lipoprotein transporter in the brain, and is mainly produced by glial cells. The present study is focussed on analysing the effects of high cholesterol (HC) diet, duration 9 months, on glial activation in the brain, both in wild type (WT) mice and in mice with a null mutation in the apoE gene (knock-out, KO) mice. The activation of astrocytes and microglia was analysed after immunohistochemical labelling of glial fibrillary acidic protein (GFAP), and F4/80, respectively. In addition, the expression of the antioxidant enzyme NAD(P)H:quinone oxidoreductase (NQO1) was analysed. There was a marked stimulation of astrocyte and microglial activation as well as induced expression of NQO1 in the hippocampus and cerebral cortex upon HC diet. Furthermore, there was significant astrocyte activation in the apoE KO mice, as compared to the WT mice, on ND. The long time exposure to HC diet combined with apoE deficiency resulted in a synergistic effect on the expression of NQO1 in the brain.

Inflammatory mechanisms associated with brain damage induced by kainic acid with special reference to the interleukin-1 system.

The evidence of inflammatory processes in the clinical manifestations and neuropathological sequelae of epilepsy have accumulated in the last decade. Administration of kainic acid, an analogue of the excitatory amino acid glutamate, induces a characteristic behavioural syndrome and a reproducible pattern of neurodegeneration in several brain areas, closely resembling human temporal lobe epilepsy. Results from studies using the kainic acid model indicate that manipulation of pro- and anti-inflammatory cytokines can modify the outcome with regard to the behavioural syndrome as well as the neuropathological consequences. Interleukin-1 is one of the most important cytokines and has several actions in the brain that are critical for the host defense against injury and infection, and it is involved in the initiation of early stages of inflammation. It is believed that interleukin-1 plays a pivotal role in the neuroinflammation associated with certain forms of neurodegeneration, including cerebral ischemia, trauma and excitotoxic brain injury. In this review, we have summarized the experimental data available with regard to the involvement of the interleukin-1 system in kainic acid-induced changes in the brain and emphasized the modulatory role of interleukin-1beta in this model of epilepsy

Effects of kainic acid on rat body temperature: unmasking by dizocilpine.

The effects of intraperitoneal (i.p.) administration of kainic acid (KA) and dizocilpine, alone or in combination, on body temperature of freely moving rats were examined. Injection of saline or dizocilpine (3.0 or 5.0 mg/kg) was followed after an hour by injection of saline or KA (10 mg/kg) and the body temperature was measured at different time points during the first 5 h. KA alone produced an initial short-lasting hypothermia followed by a longer-lasting hyperthermic effect. Administration of dizocilpine alone produced an early increase in core temperature. Pretreatment of KA-injected rats with dizocilpine potentiated the KA-induced hypothermic effect at 30 min and dose-dependently reduced the temperature measured at 1 h after KA-injection without influencing the ensuing hyperthermia.These data suggest that the KA-induced changes in body temperature do not necessarily involve the activation of NMDA-receptors as opposed to KA-induced behavioural changes that are blocked by dizocilpine in a dose-dependent manner. It is unlikely, therefore, that the KA-induced hyperthermia is a result of the KA-induced seizure motor activity. Furthermore, our findings indicate that KA-induced changes in core temperature may be used as a criterion of drug-responsiveness when the behavioural changes are blocked, e.g. with dizocilpine.

Effects of alpha-MSH on kainic acid induced changes in core temperature in rats.

The effects of intraperitoneal (i.p.) administration of kainic acid (KA) and alpha-melanocyte-stimulating hormone (alpha-MSH) alone or in combination, on core temperature of freely moving rats were examined. KA or saline was administered once (10 mg/kg) and alpha-MSH or saline was given repeatedly i.e. 10 min before and 10, 30 and 60 min after the administration of saline or KA. Two doses of alpha-MSH were used: 0.5 and 2.5 mg/kg. KA alone produced a biphasic effect on core temperature, i.e. an initial short-lasting hypothermia followed by hyperthermia that lasted about 6 h. The higher dose of alpha-MSH had a potentiating effect on KA-induced hypothermia, while the lower dose of alpha-MSH increased the hyperthermia produced by KA. alpha-MSH administered alone produced a late (3 h), dose-dependent increase in core temperature. It is conceivable that repeated administration of alpha-MSH in the doses used in our study may cause a cumulative effect in raising body temperature for a limited period of time. The previously described interactions between KA and alpha-MSH, respectively, with dopaminergic and serotoninergic systems may account for the effects on core temperature in rats observed in our study.

Early induction of interleukin-6 mRNA in the hippocampus and cortex of APPsw transgenic mice Tg2576.

The neuropathological changes in Alzheimer's disease (AD) include the occurrence of activated microglia and astrocytes. Activated microglia expressing interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) immunoreactivity have been observed in close vicinity of the amyloid plaques in post-mortem tissue from AD patients. In order to further analyze the inflammatory process in relation to amyloidosis, we have studied the levels of markers for inflammation in the brain of Tg(HuAPP695K670N/M671L)2576 transgenic mice (Tg2576) that express high levels of human beta-amyloid precursor protein with the Swedish double mutation and develop prominent AD type neuropathology. The mRNA levels for IL-1beta, IL-1beta-converting enzyme (ICE/caspase-1) and IL-6 were analyzed by semi-quantitative reverse transcription-polymerase chain reaction in the cerebral cortex, hippocampus and cerebellum from Tg2576 and wild type (wt) mice. The levels of mRNA for IL-1beta and caspase-1 were not significantly increased in either young (4 months) or aged (18 months) Tg2576 mice as compared to the age-matched wt mice. However, we observed an increase in IL-6 mRNA levels in the hippocampus and cortex of both 4- and 18-month-old transgenic mice as compared to wt mice. The increase in IL-6 mRNA levels in Tg2576 animals thus occurs before amyloid plaques can be detected (9-10 months). This would indicate that IL-6 mRNA induction is an early event in a beta-amyloid-induced immune response cascade or that it may be involved in the amyloidosis.

Expression and distribution of tartrate-resistant purple acid phosphatase in the rat nervous system.

Tartrate-resistant purple acid phosphatase (TRAP) of osteoclasts and certain cells of the monocyte-macrophage lineage belongs to the family of purple acid phosphatases (PAPs). We provide here evidence for TRAP/PAP expression in the central and peripheral nervous systems in the rat. TRAP/PAP protein was partially purified and characterized from the trigeminal ganglion, brain, and spinal cord. The TRAP activity (U/mg tissue) in these tissues was about 10-20 times lower than in bone. Reducing agents, e.g. ascorbate and ferric iron, increased the TRAP activity from the neural tissues (nTRAP) and addition of oxidizing agents completely inactivated both bone and nTRAP. The IC(50) for three known oxyanion inhibitors of TRAP/PAP was similar for bone and nTRAP with the same rank order of potency (molybdate > tungstate > phosphate). This indicates that the redox-sensitive binuclear iron center characteristic of mammalian PAPs is present also in nTRAP. Western blots of partially purified nTRAP revealed a band with the expected size of 35 kD. The expression of TRAP in the trigeminal ganglion, brain, and spinal cord was confirmed at the mRNA level by RT-PCR. In situ hybridization histochemistry demonstrated TRAP mRNA expression in small ganglion cells of the trigeminal ganglion, in alpha-motor neurons of the ventral spinal cord, and in Purkinje cells of the cerebellum. TRAP-like immunoreactivity was encountered in the cytoplasm of neuronal cell bodies in specific areas of both the central and the peripheral nervous system. Together, the data demonstrate that active TRAP/PAP is expressed in certain parts of the rat nervous system.

Expression of interleukin 1 alpha and beta, and interleukin 1 receptor antagonist mRNA in the rat central nervous system after peripheral administration of lipopolysaccharides.

Interleukin 1alpha (IL-1alpha) and IL-1beta, and the endogenous IL-1 receptor antagonist (IL-1ra) are known members of the IL-1 family. Using in situ hybridization histochemistry we demonstrated that following endotoxin injection (lipopolysaccharides, LPS, 2.0 mg/kg, i.p.) a time dependent expression and partly different expression patterns of the cytokines occurred within the rat brain and pituitary gland. All cytokines were observed in the choroid plexus. In addition, IL-1ra mRNA expressing cells were observed scattered in the brain parenchyma, whereas scattered IL-1beta mRNA expressing cells were restricted to central thalamic nuclei, the dorsal hypothalamus, and cortical regions, such as the parietal and frontal cortex. A strong IL-1beta mRNA expression was found in the circumventricular organs. In the pituitary gland, a low IL-1alpha and a high IL-1beta mRNA expression was observed, with the highest density of cytokine-expressing cells seen in the posterior pituitary. The cell types expressing the mRNA's of IL-1alpha, IL-1beta and IL-1ra were identified as monocytes in the circumventricular organs and the pituitary gland, and as microglia in the brain parenchyma. In conclusion, the present findings revealed that cytokine production in response to a peripheral endotoxin challenge mainly occurs in peripherally derived monocytes in the circumventricular organs and the pituitary gland. IL-1beta is the predominant form expressed, whereas the expression of IL-1alpha mRNA and IL-1ra mRNA is lower. Our observations support the view that peripherally derived IL-1 may play a role in the induction of centrally mediated illness symptoms.

Provocation with stress and electricity of patients with "sensitivity to electricity".

Twenty-four patients with self-reported "sensitivity to electricity" were divided into two groups and tested in a double-blind provocation study. These patients, who reported increased skin symptoms when exposed to electromagnetic fields, were compared with 12 age- and sex-matched controls. Both groups were exposed to 30-minute periods of high or low stress situations, with and without simultaneous exposure to electromagnetic fields from a visual display unit. The matched controls were tested twice and given the same exposure as the patients but had the fields turned on every time. Stress was induced by requiring the participants to act in accordance with a random sequence of flashing lights while simultaneously solving complicated mathematical problems. Blood samples were analyzed for levels of the stress-related hormones melatonin, prolactin, adrenocorticotrophic hormone, neuropeptide Y, and growth hormone, and the expression of different peptides, cellular markers, and cytokines (somatostatin, CD1, factor XIIIa, and tumor necrosis factor-alpha). Skin biopsies were also analyzed for the occurrence of mast cells. Stress provocation resulted in feelings of more intense mental stress and elevated heart rate. The patients reported increased skin symptoms when they knew or believed that the electromagnetic field was turned on. With the blind conditions there were no differences between "on" or "off." Inflammatory mediators and mast cells in the skin were not affected by the stress exposure or by exposure to electromagnetic fields. The main conclusion was that the patients did not react to the fields.

Increased expression of mRNA encoding interleukin-1beta and caspase-1, and the secreted isoform of interleukin-1 receptor antagonist in the rat brain following systemic kainic acid administration.

Kainic acid, an analogue of glutamate, injected systemically to rats evokes seizures that are accompanied by nerve cell damage primarily in the limbic system. In the present study, we have analyzed the temporal profile of the expression of the cytokines interleukin-1beta (IL-1beta) and IL-1 receptor antagonist (IL-1ra), and the related IL-1beta-converting enzyme (ICE/caspase-1), in different regions of the rat brain in response to peripheral kainic acid administration (10 mg/kg, i.p.). In situ hybridization histochemistry experiments revealed that IL-1beta mRNA-expressing cells, morphologically identified as microglial cells, were mainly localized to regions showing pronounced neuronal degeneration; hippocampus, thalamus, amygdala, and certain cortical regions. The strongest expression of IL-1beta mRNA was observed after 12 hr in these regions. A weak induction of the IL-1beta mRNA expression was observed already at 2 hr. Similar results were obtained by RT-PCR analysis, showing a significantly increased expression of IL-1beta mRNA in the hippocampus and amygdala after 12 hr. In addition, RT-PCR analysis revealed that IL-1ra mRNA, and specifically mRNA encoding the secreted isoform of IL-1ra (sIL-1ra), was strongly induced in the hippocampus and amygdala at 12 and 24 hr post-injection. RT-PCR analysis of mRNA encoding caspase-1 showed a significantly increased expression in the amygdala after 12 hr. In conclusion, in response to systemic kainic acid injection IL-1beta mRNA is rapidly induced and followed by induction of IL-1ra mRNA and caspase-1 mRNA, supporting a role of the IL-1 system in the inflammatory response during excitotoxic damage.

IL-1beta and ICE mRNA are not altered upon beta-amyloid(25-35) induced neurotoxicity in human neuroblastoma cells.

The specific beta-amyloid(25-35) fragment induced cellular degradation of the human neuroblastoma cell line SH-SY5Y, but did not elicit an effect on the levels of interleukin-1beta and interleukin-1beta converting enzyme, as determined by semiquantitative reverse transcription-polymerase chain reaction and immunocytochemical analysis. The assays revealed constitutive expression of these proteins both at mRNA and protein level. It is conceivable that in the absence of glial elements, such as in the present neuroblastoma cell line, beta-amyloid triggers the toxicity through a direct action and/or through the production of other harmful molecules.

Inhibition of kainic acid induced expression of interleukin-1 beta and interleukin-1 receptor antagonist mRNA in the rat brain by NMDA receptor antagonists.

The cytokines interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1ra) are rapidly induced in response to excitotoxic and ischemic brain damage. The aim of the present study was to investigate the influence of a non-competitive (dizocilpine maleate, MK-801) and a competitive ((R)-CPP) NMDA receptor antagonist on the transient cytokine expression in the rat brain induced by systemic kainic acid administration. Peripheral administration of kainic acid (10 mg/kg, i.p.) results in a transient expression of IL-1 beta and IL-1ra mRNA, mainly in microglia, in regions showing neurodegeneration such as the hippocampus, thalamus, amygdala, and certain cortical regions. In addition, a few neurons expressing IL-1ra mRNA were observed in the piriform cortex and amygdala following kainic acid injection. Administration of MK-801 (i.p.) 1 h prior to kainic acid injection reduced cytokine expression in all of these regions. MK-801 at 3.0 mg/kg decreased the IL-1 beta mRNA expression, blocked or decreased the IL-1ra mRNA expression, depending on the brain region. MK-801 at 5.0 mg/kg abolished IL-1ra mRNA expression in all of the regions, whereas the IL-1 beta mRNA expression was decreased or blocked, depending on the brain region, or the time point investigated. Peripheral administration of (R)-CPP (15 mg/kg, i.p.) 15 min prior to the kainic acid injection abolished the IL-1 beta mRNA expression. The IL-1ra mRNA expression was abolished in all regions except for a few neurons in the piriform cortex. The finding that NMDA receptor antagonists inhibit the IL-1 beta and IL-1ra mRNA synthesis induced by kainic acid suggests that NMDA receptor activation may be involved in triggering cytokine synthesis following excitotoxic brain damage.

Expression of presenilin 1 mRNA in rat peripheral organs and brain.

At least 50 different mutations in the presenilin 1 gene have been shown to cause early onset familial Alzheimer's disease. Although presenilin 1 has an obvious role in the pathogenesis of Alzheimer's disease, its function is still unknown. In the present study, the occurrence and distribution of presenilin 1 mRNA was examined in rat peripheral organs as well as in the brain by in situ hybridization histochemistry, using a radiolabelled oligonucleotide probe. In comparison to the brain, a high presenilin 1 mRNA expression was found in the testis, kidney, spleen, adrenal gland and thymus. It was also observed in skeletal muscle, liver, small intestine and lung, whereas no presenilin 1 could be detected in the heart, spinal cord and pancreas. Since presenilin 1 mRNA was found to be abundant in peripheral tissues which apparently are not affected in Alzheimer's disease, additional functions of presenilin 1 are suggested, unrelated to its role in the pathological processes of the disease.

Immunohistochemical localization of interleukin-1beta, interleukin-1 receptor antagonist and interleukin-1beta converting enzyme/caspase-1 in the rat brain after peripheral administration of kainic acid.

The temporal and anatomical distribution of members of the interleukin-1 system in the rat brain following intraperitoneal kainic acid administration was studied in relation to neurodegeneration as detected with in situ end labelling. Kainic acid administration (10 mg/kg, i.p.) resulted in the induced expression of interleukin-1beta, interleukin- receptor antagonist and caspase-1p10 immunoreactivity in areas known to display neuronal and tissue damage upon excitotoxic lesions. The induction of these proteins was transient. Interleukin-1 immunoreactivity appeared at 5 h, and the interleukin-1 receptor antagonist-immunoreactive cells were first detected at 12 h, whereas the induction of caspase- 1p10 expression was first detected 24 h after kainic acid injection. Double labelling with the microglial marker Ox42 confirmed that both interleukin-1beta and interleukin-1 receptor antagonist were mainly localized in microglial cells. The regional distribution of in situ end-labelled neurons was similar to the distribution of cells expressing interleukin-1beta and interleukin-1 receptor antagonist, whereas the distribution of caspase-1 was more limited. The in situ end-labelled neurons, were, similarly to the interleukin-1beta-positive cells, first detected at 5 h, which is earlier than the induction of caspase-1. Our results show that the induction of IL-1beta and IL-1 receptor antagonist proteins after kainic acid are closely associated with the temporal as well as the anatomical distribution of in situ end-labelled neurons, whereas the induction of caspase-1 protein exhibited a delayed temporal profile and limited distribution. Since cytokine production occurs in activated microglial cells, the inflammatory component seems to be a strong mediator of this type of excitotoxic damage. The late onset of the caspase-1 expression would seem to indicate that this enzyme has no fundamental role in directly causing neuronal cell death induced by systemic kainic acid.

Soluble interleukin-1 receptor type II levels are elevated in cerebrospinal fluid in Alzheimer's disease patients.

Evidence from epidemiological, clinical and experimental studies favour the hypothesis that inflammatory events are part of the neuropathology in Alzheimer's disease. Proinflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) have been found in activated microglia in the vicinity of amyloid plaques in Alzheimer's disease brain. In the present study, the levels of soluble IL-1 receptor type II (sIL-1R type II), IL-1 receptor antagonist (IL-1ra), IL-1beta, IL-6 and TNF-alpha were analyzed in cerebrospinal fluid (CSF) samples from Alzheimer's disease patients and control subjects. The levels of sIL-1R type II were significantly higher in CSF from Alzheimer's disease patients than in CSF samples from control subjects (38.5+/-8 pg/ml (mean+/-S.E.M.) vs. 7.9+/-4 pg/ml, p<0.05). Measurements of the proinflammatory cytokines IL-6 and TNF-alpha showed no significant difference between the two groups, and the levels of IL-1beta and IL-1ra in the present material were too low to permit detection. The increased levels of sIL-1R type II may reflect a compensatory mechanism to balance an increased release of IL-1 receptor agonists in the Alzheimer's disease brain.

Somatostatin- and factor XIIIa-immunoreactive cells in psoriasis during clobetasol propionate and calciprotriol treatment.

This study describes the changes in number and distribution of somatostatin- and factor XIIIa-immunoreactive dendritic cells in the epidermis and dermis of psoriatic lesional skin during topical treatment with clobetasol propionate or calcipotriol. Immunohistochemical analysis showed that the number of each cell type was increased in lesional skin as compared to normal skin. Investigation of serial biopsies from psoriasis lesions revealed a significant reduction in the number of somatostatin- and factor XIIIa-positive dendritic cells during the treatments. The reduction rate of the somatostatin-positive cells differed between the two groups and closely paralleled the healing process induced by the two treatments. These findings and the fact that somatostatin has been used in several studies as treatment for psoriasis may indicate that the somatostatin-positive cells are specifically involved in the healing process of psoriasis. The reduction of the factor XIIIa-positive cells was associated with the healing process as a whole, but showed no relation to either treatment.