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M Röyttä

Publications and source records attributed to M Röyttä.

At least 19 recordsLinked to original sources
PubMed2004

Distinct expression of TGF-beta1 mRNA in the endo- and epineurium after nerve injury.

TGF-beta is a multifunctional regulatory protein with important effects on cell proliferation and differentiation, immune reactivity and extracellular matrix (ECM). During peripheral regeneration it can have growth promoting effects for axonal sprouting, but on the other hand, it may be involved in epineurial scarring and neuroma formation. We studied the expression of TGF-beta1 mRNA in the rat peripheral nerve with real time-PCR at 1, 3, 5, 7, 14, 21, 28, 35, and 42 days after transection. The sciatic nerve was sutured after transection to prevent axonal regeneration. Samples from both proximal and distal stumps were collected. To distinguish the possible different expression in the endo- and epineurium these two compartments were studied separately. The most significant finding was observed in the epineurium of the proximal stump 35 days after the operation. The expression of TGF-beta1 mRNA was over 700 times higher than that found in the non-operated controls. At the same time the expression of TGF-beta1 mRNA in the endoneurium was only twice as high as the values measured from the non-operated controls. Distally the TGF-beta1 mRNA expression in the endoneurium reached its peak after 2 weeks, and at weeks 3-6, the expression was two to four times higher than in the controls. This study supports the concept that TGF-beta1 can affect epineurial scarring.

Animals↗
PubMed2002

Unbiased morphological measurements show no neuronal loss in the substantia nigra in Alzheimer's disease.

This is the first study to use the unbiased stereological method, the disector, to estimate the total number of pigmented neurons in the pars compacta of the substantia nigra (SNpc) in Alzheimer's disease (AD) patients as compared to healthy controls. The right half of the SNpc of 11 AD patients and 24 controls was studied. We also used single sections to determine the neuronal number and area in different subregions of the SNpc. The results showed that there was no significant difference in the total number of pigmented neurons in the SNpc (154,415+/-13,593 for AD and 160,163+/-8027 for controls) or in the volume of the SNpc between the patients with AD and controls. Studies on single sections revealed that even subregionally there was no significant difference in the neuronal number or area in the SNpc between AD patients and controls.

Adolescent↗
PubMed2002

Semliki Forest virus infection is enhanced in Th1-prone SJL mice but not in Th2-prone BALB/c mice during Linomide-induced immunomodulation.

Linomide (quinoline-3-carboxamide) is an immunomodulator with diverse effects on the immune system. Its beneficial effects on experimental autoimmune disease models have been linked to downregulation of Th1 cytokines and altered macrophage functions. We studied this effect of downregulation of Th1-type of immune response on Semliki Forest A7 virus infection in experimental autoimmune encephalomyelitis (EAE) susceptible Th1-prone SJL mice and in EAE-resistant Th2-prone BALB/c mice. We aimed at addressing the target-cell population of Linomide responsible for this Th1 downregulation. Treatment with Linomide led to increased virus infection in brain and this effect coincided with decreased production of IL-12 and IFN-gamma from stimulated spleen cells in SJL mice. In contrast, IL-12 and IFN-gamma expression were increased in Linomide-treated BALB/c mice. Treatment of infected SJL mice resulted in decreased percentage of CD11b+ and CD11c+ cells. Thus, the target cell population of Linomide may be antigen-presenting cells (APC) which are considered as candidates for regulatory cells of Th1/Th2 balance.

Adjuvants, Immunologic↗
PubMed2002

Lack of association between an estrogen receptor 1 gene polymorphism and Parkinson's disease with dementia.

OBJECTIVE: To test for an association between an estrogen receptor 1 (ESR1) gene polymorphism and Parkinson's disease with dementia (PDD) in Finnish subjects. SUBJECTS AND METHODS: Forty-one clinically demented and pathologically confirmed PDD patients and 59 cognitively intact aged individuals with normal neuropathology were genotyped for the ESR1 PvuII polymorphism. RESULTS: We found no significant differences in the genotype or allele frequencies when the PDD patients were compared with the controls. Nor were there any significant differences in these frequencies when the PDD patients with coexisting Alzheimer's disease pathology were compared with the control group. CONCLUSION: We failed to demonstrate an association between dementia-associated PD and the ESR1 PvuII polymorphism in Finnish subjects.

Aged↗
PubMed2002

Increased brain histamine levels in Parkinson's disease but not in multiple system atrophy.

We investigated histamine concentration in post-mortem brain samples of patients with Parkinson's disease (PD, n = 24), multiple system atrophy (MSA, n = 8) and age-matched controls (n = 27). Histamine concentrations were significantly increased in the putamen (to 159% of the control mean), substantia nigra pars compacta (to 201%), internal globus pallidus (to 234%) and external globus pallidus (to 200%), i.e. in areas which play a crucial role in the motor behaviour and which show typical functional alterations in PD. In MSA no significant differences were seen. Tele-methylhistamine (histamine metabolite) concentrations were unchanged in PD. These results indicate that histamine concentration, but not its metabolism is increased in PD, but not in MSA. This finding may have implications in developing new drug therapies for PD and in differential diagnosis between PD and MSA.

Aged↗
PubMed2001

Same axonal regeneration rate after different endoneurial response to intraneural glycerol and phenol injection.

Glycerol (an atoxic alcohol) and phenol (a toxic monohydroxybenzene) are currently used as neurolytic blocking agents to relieve pain or spasticity. In the present study we compared the endoneurial response of anhydrous glycerol and 7% phenol-aqua after intraneural injection into rat sciatic nerve, using electron microscopy and immunohistochemical stainings. Despite the wide use of these drugs, a systematic morphological study of their action has not been done. Electron microscope studies showed different patterns of nerve damage for glycerol and phenol. Glycerol injection resulted in gross sciatic nerve injury, with myelin fragments widely dispersed in the endoneurium 1-2 weeks after the injury. Phenol-aqua injection resulted in gross sciatic nerve injury with focal haemorrhagic necrosis; nerve fibres were segmentally dissolved 1-2 weeks after the injury. In both groups the first axonal sprouts appeared in the area of the lesion 2 weeks after the injury and the sprouts became myelinated in both groups by 4 weeks. Immunohistochemical staining showed that in the glycerol-treated nerves macrophages were widely scattered in the endoneurium by day 3; the number of macrophages proximal to the lesion site and at the lesion site was significantly higher in the glycerol-treated nerves than in the phenol-treated nerves both at days 3 and 7. In the phenol-treated nerves, macrophages appeared after 1 week and they exceeded the number of macrophages in the glycerol-treated nerves at 2 weeks. The number of Schwann cells remained low until 4 weeks in both groups. The results show that glycerol-induced nerve fibre damage with breaching of myelin fragments is followed by invasion of macrophages into the endoneurium after 3 days. The delayed invasion of macrophages after phenol injection may be due to occluded vessels or may be related to the denaturing effect of phenol on the proteins needed for macrophage attraction. Despite the rapid invasion of macrophages after glycerol injection axonal regeneration was delayed when compared to that seen after traumatic axotomy, but the axonal regeneration occurred at the same time in both experimental groups. Thus, the results suggest that after chemical axonotmesis the axonal regeneration rate is not dependent on the macrophage invasion rate alone and that other endoneurial changes also play a role.

Animals↗
PubMed2001

Choline acetytransferase activity and striatal dopamine receptors in Parkinson's disease in relation to cognitive impairment.

Brain tissue from 44 patients with Parkinson's disease (PD) and 36 age-matched controls was examined for choline acetyltransferase (ChAT) activity, and for densities of D1 and D2 dopamine receptors. Brain samples were examined for Alzheimer' disease (AD) type changes and for Lewy bodies (LBs), and for apolipoprotein E genotype. Patients were evaluated for the stage of cognitive impairment using Reisberg's global deterioration scale. ChAT activity in PD was reduced in all brain areas examined, being 51% of the control mean in the hippocampus (P<0.001), 57% in the prefrontal cortex (P< 0.001) and 64% in the temporal cortex (P<0.001). The number of LBs had a significant negative correlation with ChAT activity in both prefrontal (r=-0.33, P<0.05) and temporal cortex (r=-0.32, P<0.05). The reduction in ChAT activity in the prefrontal cortex had a significant negative correlation (r=-0.38, P=0.012) with the extent of cognitive impairment. When the CERAD class 'C' was excluded, cognitive impairment correlated significantly with both prefrontal ChAT activity (r=-0.52, P=0.0051) and the density of D1 dopamine receptors in the caudate nucleus (r=-0.40, P=0.037). The number of D1 and D2 dopamine receptors was reduced in both caudate nucleus and putamen in PD patients without neuroleptics as compared to controls. An increased D2 receptor number was found in the caudate nucleus and putamen in PD patients treated with neuroleptics. The present study showed that cognitive decline in PD is associated with reduced ChAT activity in the prefrontal cortex and the D1 dopamine receptor number in the caudate nucleus, even in the absence of AD-type pathology.

Aged↗
PubMed2001

Different pattern of reduction of striatal dopamine reuptake sites in Alzheimer's disease and ageing.

Striatal dopamine reuptake sites were studied in brain samples from 14 Alzheimer's disease (AD) patients. A cocaine analogue, [3H]CFT (WIN 35,428, 2beta-carbomethoxy-3beta-(4-fluorophenyl)-tropane) was used as a radioligand to determine the number of [3H]CFT binding sites (Bmax) and their dissociation constant (Kd). In patients with AD the reduction in [3H]CFT binding in the putamen was about 50% compared to age-matched controls. In the caudate nucleus the reduction was about 33%. Thus, the putamen was more severely affected. No change was observed in Kd values between AD patients and controls. Brain samples from 37 healthy controls (aged from 8 to 91 years) were used to study the changes in striatal [3H]CFT binding with increasing age. The Bmax of [3H]CFT uptake was reduced both in the putamen and in the caudate nucleus. The average decline per decade was greater in the caudate nucleus (7.3%) than in the putamen (5.5%). In conclusion, the pattern of changes in AD is different from that seen during normal ageing, which seems to affect more severely the caudate nucleus than the putamen.

Adolescent↗
PubMed2001

Expression of interleukin-4 but not of interleukin-10 from a replicative herpes simplex virus type 1 viral vector precludes experimental allergic encephalomyelitis.

We have used interleukin (IL)-4 and -10-producing HSV-1 gamma(1)34.5 deletion viruses in gene therapy of a BALB/c model of experimental allergic encephalomyelitis (EAE), a T cell-mediated demyelinating disease of the central nervous system. It is known that in EAE of mice the Th2-type cytokines are down-regulated and the Th1-type cytokines up-regulated during the onset and relapse of the disease. Therefore, we tested two HSV-1 recombinants expressing the Th2-type cytokines IL-4 and IL-10. The recombinant viruses were injected intracranially (i.c.) in BALB/c mice 6 days after induction of EAE. As control groups we used mice without any infection, mice infected with backbone virus R3659 and mock-infected mice. Weights and symptoms of the mice were recorded daily and the tissue specimens were collected at specific time-points. The results indicate that the intracranial infection with IL-4-producing virus (1) precludes EAE symptoms, (2) protects the spinal cord from massive leukocyte infiltrations and (3) prevents demyelination and axonal loss. The IL-10-expressing virus R8308 did not have a similar favorable effect on the recovery of the mice as did the IL-4 virus R8306.

Animals↗
PubMed2000

Interaction between estrogen receptor 1 and the epsilon4 allele of apolipoprotein E increases the risk of familial Alzheimer's disease in women.

Estrogens may be implicated in the development of Alzheimer's disease (AD). Most of their effects are mediated via receptors whose function and expression may be modified by DNA polymorphisms. Here the estrogen receptor 1 gene (ESR1) polymorphisms XbaI and PvuII were analyzed in 214 AD patients and 290 controls. In logistic regression analysis, a significantly increased risk of familial AD due to interaction between the ESR1 xx genotype and the apolipoprotein E epsilon4 allele was observed in women in a Swedish clinic-based sample, taking subjects who had neither the xx genotype nor epsilon4 as reference (OR 11.3, 95% CI 2.9-43.8). The risk of AD was more pronounced in early-onset (OR 22.0, 95% CI 3. 7-132.7) than in late-onset (OR 6.0, 95% CI 1.2-29.7) female patients. For women carrying the pp genotype together with epsilon4 the risk of AD was similarly elevated. Likewise in a Swedish community-based set of women, an increased risk of familial AD was observed in subjects who had either the ESR1 xx or pp genotype together with epsilon4. Furthermore, the Pp genotype frequency was found to be significantly increased in Finnish women with sporadic AD. We, thus, conclude that the ESR1 gene may have a role in the development of AD in females.

Age of Onset↗
PubMed2000

Peripheral nerve injury induces endoneurial expression of IFN-gamma, IL-10 and TNF-alpha mRNA.

Axotomy of a peripheral nerve leads to interruption of axon continuity with Wallerian degeneration in the distal segment and regenerative events in the proximal remaining neuron. Local inflammation is a consequence of trauma in general and signal molecules regulating inflammation, such as cytokines, participate in the outcome of nerve trauma. We studied a broad set of potent immunoregulatory cytokines after transection of rat sciatic nerve. The endoneurium of the transected rat sciatic nerve was taken from both proximal and distal stumps. The pooled endoneurium of 6 rats was studied using reverse transcription polymerase chain reaction (RT-PCR) after 14 h; 1, 3, 5, 7 days; 2 and 4 weeks after transection. A new observation was that TNF-alpha mRNA showed phasic expression pattern; three distinct peaks were seen, immediately (14 h), after 5 days and in the distal part also after 2 weeks. This phenomenon may be related to the breakdown of the blood-nerve barrier and to the recruitment of circulating macrophages. We further noticed that IFN-gamma mRNA was expressed between 5 days and 2 weeks. This suggests that T-cells may also take part in the regenerative processes. Furthermore, we observed that IL-10 mRNA is expressed continuously during Wallerian degeneration. The continuous expression of IL-10 mRNA may attenuate the production of inflammatory cytokines by macrophages and other cells.

Animals↗
PubMed2000

Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease.

Amygdala, hippocampus and six cortical gyri were examined for the Lewy body (LB) degeneration and Alzheimer's disease (AD) type changes in 45 patients with Parkinson's disease (PD). For detection of LBs, the brain areas were stained with an antibody against alpha-synuclein. The extent of neuropathological lesions was investigated in relation to cognitive dysfunction and apolipoprotein E (apoE) epsilon4 allele dosage. At least one cortical LB was found in 95% of cases (43/45). Furthermore, 40% of cases (18/45) had histological findings of definite AD (CERAD class C). Those PD cases with the apoE epsilon4 allele had a significantly greater number of cortical LBs than those without the apoE epsilon4 allele, but this was statistically significant only in precentral, angular and temporal gyri. The LB density correlated better with the number of plaques than with the density of tangles. The number of LBs in several cortical areas correlated significantly with the cognitive impairment. In stepwise linear regression analysis, the number of LBs in the cingulate gyrus and the amount of tangles in the temporal cortex remained statistically significant. When the CERAD class C was excluded, the correlation between cognitive decline and the number of LBs in cortical areas became even more pronounced. A stepwise linear regression analysis in these cases found the number of LBs in the frontal gyrus to be the statistically most significant predictor of cognitive impairment. This study shows, for the first time, that in PD, alpha-synuclein-positive cortical LBs are associated with cognitive impairment independent of AD-type pathology.

Aged↗
PubMed2000

Increased expression of chemokines (MCP-1, MIP-1alpha, RANTES) after peripheral nerve transection.

After nerve injury, recruitment of circulating macrophages into the endoneurium is essential for degeneration and subsequently for successful regeneration. However, the factors leading to macrophage recruitment are not known in detail. Chemokines are one of many possible factors influencing recruitment. In this study we wanted to examine, immunohistochemically, the expression of MCP-1, MIP-1alpha and RANTES from 6 hours up to 4 weeks after transection of rat sciatic nerve. An increased expression of MCP-1 was noted already 6 hours after transection, mainly in Schwann cells. Later, the MCP-1 positive staining was seen also in macrophages, fibroblast-like cells and endothelial cells. An increased number of MIP-1alpha positive cells could be noticed after 24 hours, the maximum expression in Schwann cells was noted at the 5-day timepoint. Later, part of the positive cells appeared to be macrophages. RANTES was mainly expressed in inflammatory cells. Endothelial cells in the epi- and endoneurium showed positive staining for every chemokine studied after transection. The contralateral non-operated nerves showed an increased number of positive cells for MCP-1 and MIP-1alpha. In the control nerves MCP-1 and MIP-1alpha positive cells were scattered throughout the endoneurium. This study shows that increased expression of chemokines takes place within endoneurium after peripheral nerve transection. Thus, it is probable that chemokines can take part in the recruitment of macrophages. It further shows that there is an increased expression of the studied chemokines in the non-operated contralateral nerves. Even in normal conditions chemokines are needed, probably to keep resident macrophages within endoneurium.

Animals↗
PubMed2000

Cyclosporin A affects axons and macrophages during Wallerian degeneration.

A traumatic injury of a peripheral nerve leads to Wallerian degeneration. It includes the recruitment of macrophages and the phagocytosis of myelin and the remnants of axons. We have previously studied the recruitment of macrophages and now wished to determine if the immunosuppressant cyclosporin A (CsA) affects the number of macrophages at the site of nerve injury. The primary target of CsA is T-cells, but it may also have an effect on mononuclear phagocytes which exert a key role during Wallerian degeneration. Rats were divided into two groups: CsA-treated animals and control animals. Following transection of the sciatic nerve in the treatment group, the animals received 5 mg/kg CsA subcutaneously. The groups were further subdivided into a freely regenerating nerve group and a sutured nerve group. The number of macrophages and MHC class II positive cells were counted 3 days, 7 days, 2 weeks, 4 weeks, and 8 weeks posttransection; also CD4, CD8, IL-2 receptor positive cells, B cells, and the axonal sprouting were studied. In the CsA-treated group, there were more macrophages in the distal areas under 8 weeks than in the controls (p < 0.05); thus, the clearance of macrophages is delayed in the CsA-treated rats compared to the control rats. In the proximal area, the difference in macrophage number did not gain statistical significance. Additionally, CsA retarded axonal degeneration. CsA affects number of macrophages during Wallerian degeneration, while retarding axonal degeneration and subsequent reinnervation. Its mechanism of action appears to involve either direct or indirect via T-cells-mediated responses.

Animals↗
PubMed2000

Replicase complex genes of Semliki Forest virus confer lethal neurovirulence.

Semliki Forest virus (SFV) is a mosquito-transmitted pathogen of small rodents, and infection of adult mice with SFV4, a neurovirulent strain of SFV, leads to lethal encephalitis in a few days, whereas mice infected with the avirulent A7(74) strain remain asymptomatic. In adult neurons, A7(74) is unable to form virions and hence does not reach a critical threshold of neuronal damage. To elucidate the molecular mechanisms of neurovirulence, we have cloned and sequenced the entire 11,758-nucleotide genome of A7(74) and compared it to the highly neurovirulent SFV4 virus. We found several sequence differences and sought to localize determinants conferring the neuropathogenicity by using a panel of chimeras between SFV4 and a cloned recombinant, rA774. We first localized virulence determinants in the nonstructural region by showing that rA774 structural genes combined with the SFV4 nonstructural genome produced a highly virulent virus, while a reciprocal recombinant was asymptomatic. In addition to several amino acid mutations in the nonstructural region, the nsp3 gene of rA774 displayed an opal termination codon and an in-frame 21-nucleotide deletion close to the nsp4 junction. Replacement in rA774 of the entire nsp3 gene with that of SFV4 reconstituted the virulent phenotype, whereas an arginine at the opal position significantly increased virulence, leading to clinical symptoms in mice. Completion of the nsp3 deletion in rA774 did not increase virulence. We conclude that the opal codon and amino acid mutations other than the deleted residues are mainly responsible for the attenuation of A7(74) and that the attenuating determinants reside entirely in the nonstructural region.

Alphavirus Infections↗
PubMed2000

Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) gene interactions with the apolipoprotein E epsilon4 allele as risk factors in Alzheimer's disease and in Parkinson's disease with coexisting Alzheimer pathology.

Alzheimer's disease (AD) and Parkinson's disease (PD) are genetically heterogeneous. Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) genes may modify the risk of these disorders. We investigated whether common polymorphisms present in these genes operate as risk factors for AD and PD in Finnish subjects, independently or in concert with the apolipoprotein E epsilon4 allele (APOE epsilon4). Eighty late onset sporadic AD patients, 53 PD patients (34 of whom had concomitant AD pathology), and 67 control subjects were genotyped for the insertion (I)/deletion (D) polymorphism of DCP1 and the K variant of BCHE. In logistic regression analysis, the DCP1 *I allele in combination with APOE epsilon4 significantly increased the risk of AD (OR 30.0, 95% CI 7.3-123.7), compared to subjects carrying neither of the alleles. Similar analysis showed that the risk of AD was significantly increased in subjects carrying both the BCHE wild type (*WT/*WT) genotype and epsilon4 (OR 9.9, 95% CI 2.9-33.8), compared to those without this BCHE genotype and epsilon4. Further, the risk of PD with AD pathology was significantly increased for carriers of DCP1 *I and epsilon4 (OR 8.0, 95% CI 2.1-31.1). We thus conclude that, in Finns, interaction between DCP1 *I and epsilon4 increases the risk of AD as well as of PD with coexisting Alzheimer pathology, which underlines the importance of the DCP1 I/D polymorphism in the development of Alzheimer neuropathology, whereas the wild type BCHE genotype in combination with epsilon4 had a combined effect with regard to the risk of AD.

Age of Onset↗
PubMed1999

Neuritic degeneration in the hippocampus and amygdala in Parkinson's disease in relation to Alzheimer pathology.

It has been suggested that dystrophic neurites in the hippocampal CA2-3 sector are characteristic of diffuse Lewy body disease (DLBD) but not of Parkinson's disease (PD). We investigated the severity of neuritic change in the CA2-3 sector of the hippocampus and in the periamygdaloid cortex (PAC) in 45 patients with clinically diagnosed and neuropathologically verified PD. Samples from amygdala, hippocampus, entorhinal cortex (ERC) and cortical gyri were examined for Alzheimer-type (AD) changes and Lewy bodies (LBs) using antibodies against ubiquitin and tau. Ubiquitin-positive but polyclonal tau-negative neurites were detected in the CA2-3 region of the hippocampus in 88% of patients and in the PAC in 91% of patients. The CA2-3 sector neurites correlated significantly only with LBs in all other brain areas, except in the amygdala. The neurites in the PAC correlated significantly with neuropathological variables in all other brain areas examined, except with tangles in the pre-central and frontal gyrus and with LBs in the amygdala and in the ERC. Unlike in the CA2-3 sector, the neuritic change in the PAC was more prominent in those PD patients with more severe cognitive impairment (P = 0.03). There was no significant correlation between the apoE4 allele load and the neuritic change in the PAC or in the CA2-3 sector. Our study revealed that cortical LBs and neuritic change in the amygdala and hippocampal CA2-3 sector co-exist in PD. Unlike hippocampal neurites, the PAC neurites are related to AD pathology. There seems to be a relationship between the PAC neurites and cognitive impairment in PD, but its significance needs further elucidation.

Aged↗