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PubMed2003

'MAD'ly phasing the extracellular domain of the LDL receptor: a medium-sized protein, large tungsten clusters and multiple non-isomorphous crystals.

The crystal structure of the extracellular domain of the LDL receptor (LDL-R) was determined in a MAD experiment using 12-tungstophosphate clusters as anomalous scatterers. While useful for phasing, the tungsten clusters rendered the crystals radiation-sensitive and non-isomorphous and profoundly altered the diffraction data, causing complications. The work is presented as a case study for phasing a medium-sized protein (700 residues) at low resolution (4 A) with multiple non-isomorphous crystals containing 31 W atoms in the asymmetric unit.

Animals↗
PubMed1998

Space-time clustering of multiple sclerosis cases around birth.

OBJECTIVES: To investigate whether infectious events around birth and during early infancy are likely to be of relevance in MS pathogenesis. SUBJECTS AND METHODS: Data are available from two regions in The Netherlands: Groningen (n=320) and Rotterdam (n=226). Simultaneous clustering in birth date and birth location of MS cases is tested by the methods of Mantel, Knox and Jacquez. RESULTS: No evidence was found for a space-time interaction between place and time of birth. CONCLUSION: Perinatal infectious events are unlikely to be a major factor in determining MS susceptibility.

Age Distribution↗
PubMed1991

A unique pattern of astrocytosis in the primary motor area in amyotrophic lateral sclerosis.

We examined the primary motor area (PMA, Brodmann area 4) from 23 cases of adult-onset sporadic amyotrophic lateral sclerosis (ALS) with immunocytochemistry using anti-glial fibrillary acidic protein antibody. There was astrocytosis in the middle of the pyramidal cell layer in all cases except for one that did not present any upper motor neuron signs clinically. The astrocytosis was characterized by multiple clusters of astrocytes, some of which showed a close association with macrophages. In about a half of the cases, these multiple clusters of astrocytes became confluent and presented as a laminar astrocytosis in the middle of the pyramidal cell layer. Our studies demonstrate a unique pattern of astrocytosis in the PMA in ALS. This pattern of astrocytosis may be useful not only for diagnostic purposes, but also for a better understanding of the pathological process involving the PMA in ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1994

Familial clustering of multiple sclerosis in a northern Swedish rural district.

A small rural district in the most northerly province of Sweden was found to have a very high occurrence of multiple sclerosis. A total of 12 patients with multiple sclerosis among 4744 inhabitants were identified (five females, seven males), corresponding to a prevalence of 253/100,000. Many of the patients were related and a further 21 cases with multiple sclerosis (14 females, seven males), mostly living in the neighbouring area, have family ties to the district. A genealogical investigation showed that 22 of the 33 patients identified had ties of kinship and thus, to our knowledge, the largest aggregation of multiple sclerosis in a family is presented.

Adolescent↗
PubMed1976

Studies on the clustering of multiple sclerosis in Finland.

The epidemiological investigation of multiple sclerosis (MS) in Finland revealed a prevalence rate of 40.3 per 100.000 inhabitants. The geographic distribution of MS was uneven in the country. MS seemed to occur more often in the western and southwestern parts of the country, where the prevalences varied between 51.7 and 62.1 This phenomenon became even more pronounced when the distribution of the disease was investigated in small geographic units. Optic neuritis showed a geographic distribution similar to that of MS, with clustering in the same parts of the country and even in the same narrow districts. The correlation between the birthplaces of MS and optic neuritis patients was very significant (p less than 0.001), which suggest that they share a common aetiology. The possible aetiological role of genetic and exogenous factors was discussed in the western cluster of MS, where the percentage of familial cases was 13 and an accumulation of muscular dystrophy of cattle was observed.

Finland↗
PubMedDate not supplied

Challenges in addressing community concerns regarding clusters of multiple sclerosis and potential environmental exposures.

Citizens living around hazardous waste sites in the USA have expressed concern to public health officials at the local, state and federal level about a perceived high prevalence of multiple sclerosis (MS) in their communities. Many believe the occurrence of the disease is directly linked to exposure to chemical agents from the nearby hazardous waste site. Although the public's concern regarding these clusters should be addressed, epidemiologists have long known that evaluating perceived clusters is rarely fruitful for identifying an etiologic agent. In order to adequately address concerns regarding clusters of MS, as well as examining the role of environmental exposures and genetic susceptibility in the causal mechanism of disease, several activities need to be conducted including characterizing the occurrence of disease, developing a standardized case definition and establishing partnerships to develop innovative research techniques. Only with collaboration across disciplines and lessons learned from past research will we be able to effectively guide research efforts directed at determining the etiology of this disease.

Cluster Analysis↗
PubMed2004

A cluster of multiple sclerosis cases in Lysvik in the Swedish county of Värmland.

OBJECTIVES: When surveying the county of Värmland in Sweden in order to determine the prevalence of multiple sclerosis (MS), we observed an aggregation of MS cases originating from the parish of Lysvik in the local region called Fryksdalen. Our intention was to analyse this cluster thoroughly, confirming the MS diagnosis and seeing if a hereditary or environmental background was plausible. METHODS: The medical files were studied and the cases were classified by a neurologist according to Poser's criteria. Hereditary factors were analysed. RESULTS: Sixteen living cases of MS were found, either living in the parish (n = 6) or born or raised there and had later moved to another place (n = 10). All patients had clinically definite MS. Eleven patients had relatives with MS, all of these being descendants of the Suhoinen family. Another two cases were Suhoinen descendants who did not have relatives with MS. Other common ancestors were also identified. Two cases were adopted. Eleven deceased MS patients from Lysvik were found, 10 of them had Suhoinen ancestry. CONCLUSION: We report a cluster of MS cases with a common ancestry indicating heredity for MS in 85% of the cases. Lysvik is a parish where Finnish immigration was pronounced in the 17th century and there has been inbreeding to a certain extent through marriage between cousins. Thus, we interpret this aggregation as possibly being genetically based, and neurogenetic studies are now being performed. However, as two of the cases were adopted environmental factors must also be considered.

Cluster Analysis↗
PubMed2001

Phylogenetic analysis of Japanese encephalitis virus: envelope gene based analysis reveals a fifth genotype, geographic clustering, and multiple introductions of the virus into the Indian subcontinent.

We report the analysis of the complete nucleotide sequence for the Indian isolate (P20778; Genbank Accession number AF080251) of Japanese encephalitis virus (JEV). The phylogenetic tree topology obtained using thirteen complete genome sequences of JEV was reproduced with the envelope, NS1, NS3, and NS5 genes and revealed extensive divergence between the two Indian strains included. A more exhaustive analysis of JEV evolution using 107 envelope sequences available for isolates from different geographic locations worldwide revealed five distinct genotypes of JEV, displaying a minimum nucleotide divergence of 7% with high bootstrap support values. The tree also revealed overall clustering of strains based on geographic location, as well as multiple introductions of JEV into the Indian subcontinent. Nonsynonymous nucleotide divergence rates of the envelope gene estimated that the ancestor common to all JEV genotypes arose within the last three hundred years.

Aedes↗
PubMed1985

Clustering of multiple sclerosis in the county of Hordaland, Western Norway.

We studied the distribution of MS cases in the county of Hordaland, Western Norway. The total MS population comprised 426 patients. The prevalence on January 1st, 1963, and on January 1st, 1983, and the average annual incidence in the period 1963-1982 were all lower in the coastal area compared to the inland area. An increase in incidence started in the urban area and was followed some 10 years later in the rural area. The Knox method revealed no statistically significant evidence of clustering either for time/place of onset or for time/place of birth. Indications of clustering according to year of onset were, however, observed in the rural area.

Humans↗
PubMed1989

In vitro clustering and multiple fusion among macrophage endosomes.

Early steps of receptor-mediated endocytosis appear to require the fusion of endosomes with each other. Recently, these fusion events have been reconstituted in vitro using vesicle preparations from J774 macrophages which have internalized ligands via the mannose receptor (Diaz, R., Mayorga, L., and Stahl, P. (1988) J. Biol. Chem. 263, 6093-6100). The present studies indicate that endosomes first form clusters when incubated under fusogenic conditions. Aggregation state was determined by electron microscopy using vesicles containing ligand-coated colloidal gold of different sizes previously internalized via the mannose receptor. Aggregation required cytosol and ATP. Afterwards, the limiting membranes of the vesicles composing these aggregates undergo multiple fusion and bring about the formation of large diameter vesicles that maintained the same density as endosomes when analyzed by Percoll gradient sedimentation. These large diameter vesicles were no longer fusogenic in the fusion assay. Multiple fusion was determined morphologically by the co-localization of three different size colloidal gold vesicles inside endocytic vesicles and biochemically by the fusion-dependent formation of triple immune complexes between three endocytic ligands internalized by receptor-mediated endocytosis: anti-dinitrophenol mouse IgG and dinitrophenol-derivatized beta-glucuronidase, ligands for the mannose receptor, and aggregated rabbit anti-mouse IgG, a ligand for the macrophage Fc receptor.

Animals↗
PubMed1991

Human monoclonal antibodies specific for capsular polysaccharides of Klebsiella recognize clusters of multiple serotypes.

We report the generation and the characterization of a set of human monoclonal antibodies (HmAb) specific for Gram-negative bacteria of Klebsiella pneumoniae. The eight human hybridomas secrete either IgM kappa, IgA1 kappa, or IgA2 kappa antibodies. One HmAb binds bacteria of only one serotype. Five HmAb recognize non-overlapping clusters of 2, 3, or 10 different serotypes. The remaining two HmAb both recognize three serotypes. Two serotypes are recognized by both HmAb, and in addition both HmAb bind one more nonidentical serotype. These results suggest that in man, epitopes are immunodominant, different from serotype-specific determinants detected by conventional rabbit antisera. Screening of clinical isolates revealed that the HmAb recognize not only representative typing strains but also most isolates of the corresponding serotype. In addition, most of the isolates that were non-typable by polyclonal antisera were recognized by one of the HmAb. Fine specificity analyses revealed that all HmAb are highly specific for the isolated capsular polysaccharides (CPS) of bacteria within the corresponding cluster of serotypes. However, the avidity of a HmAb for the different CPS can differ significantly. Taken together, our results suggest that the unequivocal interactions between HmAb and CPS offer the basis for an alternative, better defined classification system, and that passive immunization with a limited number of HmAb may provide a feasible strategy for the protection against the majority of fatal, nosocomial infections with multidrug-resistant strains of K. pneumoniae.

Antibodies, Bacterial↗
PubMed1975

Studies on the clustering of multiple sclerosis in Finland I: Comparison between the domiciles and places of birth in selected subpopulations.

Further studies pm yjr rofr,op;phu pg ,i;yo;r dv;rtpdod (MS) IN Finland were carried out in three different types of geographical unit: in counties, combined clerical districts, and single clerical district. For longitudinal studies, the prevalence of MS by present domicile was compared to that by place of birth, and also to the number of MS cases in relation to the number of births. The analysis was based on 1,866 living MS patients. The highest prevalence by present domicile was recorded in the southwestern county of Turku and Pori (52.3 cases per 100,000 inhabitants). It was 39.6 for the whole country. Two separate clusters were found at the level of combined and single clerical districts: one in the western county of Vaasa, and another in the southwestern county of Turku and Pori. The highest prevalences by present comicile were found in two clerical districts of Vaasa (83.5 and 79.7). They also had very high prevalences by place of birth. They lie close to each other, but are not immediate neighbours. Another high-risk focus was revealed in an area of the neighbouring districts of Turku and Pori. In fact, the two highest prevalences by place of birth were found in this region (123.1 and 95.0). The focus extended from the coastal area to the more central region of the county, and further to the western districts of the otherwise medium-risk county of Hme. Thus, two separate foci were found in Finland: one in the western and another in the southwestern part of the country. The clustering became even more pronounced when the prevalences by place of birth were analysed. Considering that the Finnish population still largely originates from genetic isolates of varying degrees, gene enrichment explains the clustering at least partly.

Adult↗
PubMed2004

Evidence for independent Hox gene duplications in the hagfish lineage: a PCR-based gene inventory of Eptatretus stoutii.

Hox genes code for transcription factors that play a major role in the development of all animal phyla. In invertebrates these genes usually occur as tightly linked cluster, with a few exceptions where the clusters have been dissolved. Only in vertebrates multiple clusters have been demonstrated which arose by duplication from a single ancestral cluster. This history of Hox cluster duplications, in particular during the early elaboration of the vertebrate body plan, is still poorly understood. In this paper we report the results of a PCR survey on genomic DNA of the pacific hagfish Eptatretus stoutii. Hagfishes are one of two clades of recent jawless fishes that are an offshoot of the early radiation of jawless vertebrates. Our data provide evidence for at least 33 distinct Hox genes in the hagfish genome, which is most compatible with the hypothesis of multiple Hox clusters. The largest number, seven, of distinct homeobox fragments could be assigned to paralog group 9, which could imply that the hagfish has more than four clusters. Quartet mapping reveals that within each paralog group the hagfish sequences are statistically more closely related to gnathostome Hox genes than with either amphioxus or lamprey genes. These results support two assumptions about the history of Hox genes: (1) The association of hagfish homeobox sequences with gnathostome sequences suggests that at least one Hox cluster duplication event happened in the stem of vertebrates, i.e., prior to the most recent common ancestor of jawed and jawless vertebrates. (2) The high number of paralog group 9 sequences in hagfish and the phylogenetic position of hagfish suggests that the hagfish lineage underwent additional independent Hox cluster/-gene duplication events.

Animals↗