Huntington disease in Finland: a molecular and genealogical study

Summary Huntington disease (HD) is found at exceptionally low frequency in the Finnish population. In this population, linkage disequilibrium was earlier established with markers from the D4S10 and D4S43 loci. We now report a continuation to the restriction fragment length polymorphism haplotype analysis, in combination with a genealogical study of all the Finnish HD families. When the HD pedigrees were systematically traced to the 18th century, only one consanguinity was found, and a high percentage (28%) of the families had foreign ancestors. The majority of the Finnish ancestors were localized to border regions or trade centers of the country following the old postal routes. The observed high risk haplotypes formed with markers from the D4S10 and D4S43 loci were evenly distributed among the HD families in different geographical locations. Consequently, the HD gene(s) has most probably arrived in Finland on several occasions via foreign immigrants during the last few centuries.     

Long-term microtine dynamics in north Fennoscandian tundra: the vole cycle and the lemming chaos

Densities of microtine rodents in two habitat complexes in the tundra of Finnmarks-vidda, Norwegian Lapland, were studied during 1977-89 by means of snap trapping (Small Quadrat Method) Predator populations were studied by mapping breeding raptors and by snow-tracking small mustelids During 1977-85, snow-trackmg was conducted only during peak and decline years, whereas during 1986-89, snow-tracking was conducted every winter (November-December) and live-trapping (in August) was used as an additional method
Lowland vole populations had regular density fluctuations with peaks in 1978-79. 1982-84 and 1987-88 Highland vole populations fluctuated less regularly and at lower over-all densities Highland lemming populations had two outbreaks, in 1978 and 1988, ending in abrupt winter crashes In the lowland, outbreak levels were reached only in 1978 All microtine declines in relatively productive lowland habitats were accompanied by intense activity of small mustelids. whereas avian predators were common only in 1983 Lowland declines also showed clear between-habitat asynchrony they started in areas with an exceptional abundance of productive habitats and then spread to more barren areas These lowland data are consistent with the hypothesis of a mustelid-microtine limit cycle, although also several other hypotheses remain unrefuted The highland lemming data suggest a simple exploiter-victim interaction between lemmings and the vegetation     

Habitat use of small mustelids in north Fennoscandian tundra: a test of the hypothesis of patchy exploitation ecosystems

The habitat use of small mustelids in a tundra area in Norwegian Lapland was studied chiefly by means of snow-tracking 1986-89 Stoats showed strong peference to a habitat complex immediately beneath the thrust line of the Scandes, with exceptional abundance of luxuriant habitats, whereas weasel activity was more evenly spread over the lowland tundra Mustelid activity on the high tundra above the thrust line was consistently low Within each subarea. stoat activity was concentrated to the most luxuriant habitats Similar preferences were shown by weasels on the lowland but not in the vicinity of the thurst cliff Daily movements of both species varied from local (c 200 m) to extensive (up to 4 km), no consistent interspecific differences in travel distances could be observed
The results largely conform to the hypothesis of patchy exploitation ecosystems (T Oksanen 1990a), according to which predator activity tends to "spill over' from luxuriant habitats, capable of supporting predator populations, to adjacent barren ones, due to despotic behavior within and between species and due to opportunistic predation by transient predators However, predator activity in barren habitats during the crash winter could not be explained by these mechanisms alone A third mechanism - breakdown of habitat preferences of predators during crash phases of a cyclic prey population - was thus introduced     

High prevalence of aspartylglycosaminuria among school-age children in eastern Finland

Summary A high prevalence of the lysosomal storage disease aspartylglycosaminuria was found in a study of four birth cohorts of 12882 children in eastern Finland. Using school achievement tests and registers of mentally retarded individuals, 178 mentally retarded children were identified. Randomized urine samples from 151 of the 178 retarded children and from 101 healthy children were analyzed quantitatively for aspartylglucosamine by high-performance liquid chromatography. The results identified three affected individuals in the retarded group indicating an exceptionally high prevalence of aspartylglycosaminuria (1:3643) in the study population, consistent with a carrier frequency of 1:30. The 95% confidence limits for the prevalence are 1:4 352-1:16389. This is the highest prevalence described for any glycoproteinosis in any population and comparable to the incidence figures of the most common lysosomal storage diseases, Gaucher disease type I and Tay-Sachs disease among Ashkenazi Jews. In the study group, aspartylglycosaminuria was, after trisomy 21 (n = 19) and the fragile X syndrome (n = 6), the most common genetic cause for mental retardation.     

The beta-amyloid domain is essential for axonal sorting of amyloid precursor protein.

We have analysed the axonal sorting signals of amyloid precursor protein (APP). Wild-type and mutant versions of human APP were expressed in hippocampal neurons using the Semliki forest virus system. We show that wild-type APP and mutations implicated in Alzheimer's disease and another brain beta-amyloidosis are sorted to the axon. By analysis of deletion mutants we found that the membrane-inserted APP ectodomain but not the cytoplasmic tail is required for axonal sorting. Systematic deletions of the APP ectodomain identified two regions required for axonal delivery: one encoded by exons 11-15 in the carbohydrate domain, the other encoded by exons 16-17 in the juxtamembraneous beta-amyloid domain. Treatment of the cells with the N-glycosylation inhibitor tunicamycin induced missorting of wild-type APP, supporting the importance of glycosylation in axonal sorting of APP. The data revealed a hierarchy of sorting signals on APP: the beta-amyloid-dependent membrane proximal signal was the major contributor to axonal sorting, while N-glycosylation had a weaker effect. Furthermore, recessive somatodendritic signals, most likely in the cytoplasmic tail, directed the protein to the dendrites when the ectodomain was deleted. Analysis of detergent solubility of APP and another axonally delivered protein, hemagglutinin, demonstrated that only hemagglutinin formed CHAPS-insoluble complexes, suggesting distinct mechanisms of axonal sorting for these two proteins. This study is the first delineation of sorting requirements of an axonally targeted protein in polarized neurons and indicates that the beta-amyloid domain plays a major role in axonal delivery of APP.     

Cholinergic signaling in the rat pineal gland

Summary 1. Innervation of the mammalian pineal gland is mainly sympathetic. Pineal synthesis of melatonin and its levels in the circulation are thought to be under strict adrenergic control of serotoninN-acetyltransferase (NAT). In addition, several putative pineal neurotransmitters modulate melatonin synthesis and secretion.2. In this review, we summarize what is currently known on the pineal cholinergic system. Cholinergic signaling in the rat pineal gland is suggested based on the localization of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), as well as muscarinic and nicotinic ACh binding sites in the gland.3. A functional role of ACh may be regulation of pineal synaptic ribbon numbers and modulation of melatonin secretion, events possibly mediated by phosphoinositide (PI) hydrolysis and activation of protein kinase C via muscarinic ACh receptors (mAChRs).4. We also present previously unpublished data obtained using primary cultures of rat pinealocytes in an attempt to get more direct information on the effects of cholinergic stimulus on pinealocyte melatonin secretion. These studies revealed that the cholinergic effects on melatonin release are restricted mainly to intact pineal glands since they were not readily detected in primary pinealocyte cultures.     

Aging aggravates ischemic stroke‐induced brain damage in mice with chronic peripheral infection

Ischemic stroke is confounded by conditions such as atherosclerosis, diabetes, and infection, all of which alter peripheral inflammatory processes with concomitant impact on stroke outcome. The majority of the stroke patients are elderly, but the impact of interactions between aging and inflammation on stroke remains unknown. We thus investigated the influence of age on the outcome of stroke in animals predisposed to systemic chronic infection. Th1‐polarized chronic systemic infection was induced in 18–22 month and 4‐month‐old C57BL/6j mice by administration of Trichuris muris (gut parasite). One month after infection, mice underwent permanent middle cerebral artery occlusion and infarct size, brain gliosis, and brain and plasma cytokine profiles were analyzed. Chronic infection increased the infarct size in aged but not in young mice at 24 h. Aged, ischemic mice showed altered plasma and brain cytokine responses, while the lesion size correlated with plasma prestroke levels of RANTES. Moreover, the old, infected mice exhibited significantly increased neutrophil recruitment and upregulation of both plasma interleukin‐17α and tumor necrosis factor‐α levels. Neither age nor infection status alone or in combination altered the ischemia‐induced brain microgliosis. Our results show that chronic peripheral infection in aged animals renders the brain more vulnerable to ischemic insults, possibly by increasing the invasion of neutrophils and altering the inflammation status in the blood and brain. Understanding the interactions between age and infections is crucial for developing a better therapeutic regimen for ischemic stroke and when modeling it as a disease of the elderly.