Fine-scale mapping of a novel dementia gene, PLOSL, by linkage disequilibrium.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770) is a rare hereditary cause of presenile dementia with autosomal recessive inheritance. Its unique feature is the cystic bone lesions that accompany the dementia. About 160 cases have been reported to date, mostly in Finland and Japan. The etiology and pathogenesis of PLOSL are unknown. We recently assigned the locus for PLOSL in the Finnish population to chromosome 19q13.1 (P. Pekkarinen et al., 1998, Am. J. Hum. Genet. 62, 362-272). In the present study, we restrict the critical region for PLOSL to 153 kb by linkage-disequilibrium mapping. First, three new microsatellite markers were revealed in the PLOSL critical region. These and three other markers spanning the critical region were analyzed in Finnish PLOSL families. Strong linkage disequilibrium (multipoint P value < 10(-47)) was detected between the markers and PLOSL, and for two markers, D19S1176 and D19S610, all the PLOSL chromosomes shared identical 171- and 218-bp alleles, respectively. Haplotype analysis revealed five different haplotypes in the Finnish PLOSL chromosomes. But all of them shared the region between markers D19S1175 and D19S608 that could be traced to one ancestor haplotype by single recombination events, thus defining the critical region as 153 kb. Multipoint association analysis also assigned the most likely location of the PLOSL locus within this interval to the immediate vicinity of marker D19S610. A promising positional candidate for PLOSL, an amyloid precursor-like protein, was studied by sequencing, but no mutations were detected. These results lay the basis for the cloning of this novel dementia gene and for diagnostics in the Finnish population using haplotype analysis.

Assignment of the locus for PLO-SL, a frontal-lobe dementia with bone cysts, to 19q13.

PLO-SL (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy) is a recessively inherited disorder characterized by systemic bone cysts and progressive presenile frontal-lobe dementia, resulting in death at <50 years of age. Since the 1960s, approximately 160 cases have been reported, mainly in Japan and Finland. The pathogenesis of the disease is unknown. In this article, we report the assignment of the locus for PLO-SL, by random genome screening using a modification of the haplotype-sharing method, in patients from a genetically isolated population. By screening five patient samples from 2 Finnish families, followed by linkage analysis of 12 Finnish families, 3 Swedish families, and 1 Norwegian family, we were able to assign the PLO-SL locus to a 9-cM interval between markers D19S191 and D19S420 on chromosome 19q13. The critical region was further restricted, to approximately 1.8 Mb, by linkage-disequilibrium analysis of the Finnish families. According to the haplotype analysis, one Swedish and one Norwegian PLO-SL family are not linked to the chromosome 19 locus, suggesting that PLO-SL is a heterogeneous disease. In this chromosomal region, one potential candidate gene for PLO-SL, the gene encoding amyloid precursor-like protein 1, was analyzed, but no mutations were detected in the coding region.

Vascular changes and blood-brain barrier damage in the pathogenesis of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (membranous lipodystrophy).

The histopathological, immunohistochemical and electron microscopic findings in eight patients with polycystic lipomembranous osteodysplasia and sclerosing leukoencephalopathy (PLO-SL) are described. This autosomally recessively inherited disease is first manifested by multiple bone cysts, which are later followed around the age of 30 by severe neuropsychiatric syndrome. The pathogenesis of PLO-SL has not been established, and the search for the most suspected error in lipid metabolism has been unsuccessful. The typical macroscopic features were marked hydrocephalus ex vacuo due to severe destruction of the white matter (WM) with extensive secondary astrocytic gliosis, and with relatively better preserved gray matter (GM). The basement membranes of blood vessels with plump endothelium were thickened and often multiplied, most prominently in the WM. Extravasation of plasma constituents was demonstrated immunohistochemically. On the basis of the vascular changes, also present in bone lesions, it is proposed that severe chronic vasogenic brain edema is the main pathogenetic mechanism of the severe leukoencephalopathy in this disease entity.

Adenoma residua in colorectal cancer. A study of 34 colorectal cancers detected by an immunological occult blood test.

A retrospective histological study was made searching for adenoma remnants in 34 colorectal cancer specimens detected by the quantitative and human Hb-specific immunological FECA-EIA test for occult blood in the faeces. As a control group, 34 colorectal cancer preparations from routine hospital material were studied in a similar manner. A difference was found between these materials, 12 out of 34 study cancers showing adenoma residua compared with only two in the control group. Even if a proportion of colorectal cancers is apparently not associated with adenomas, it is suggested that the existence of adenoma remnants is a sign of biologically early tumour development and consequently, it might correlate with a favourable prognosis.

Decreased incidences of intestinal and diffuse types of gastric carcinoma in Finland during a 20-year period.

The incidence of gastric carcinoma (GCA) has decreased throughout the world. This decrease is attributed to a decline in incidence of the intestinal type of GCA (IGCA), whereas the diffuse (DGCA) type of GCA is considered to be endemic in nature and more stable in incidence. In the present study we have estimated how much the incidences of IGCA and DGCA have decreased in percentage in Finland from 1952-61 to 1972-81. Our calculations are based on the Finnish Cancer Registry data of new GCA cases, on population statistics in Finland, and on the percentage distribution of GCA subtypes in three consecutive samples of GCA patients collected in the time periods 1952-61 (reference series) and 1972-81 (two separate samples: series A and B). The samples totaled 1837 GCA cases. We calculated that the incidence of IGCA had decreased from 1952-61 to 1972-81 by 62-71% (reference series versus series A - reference series versus series B) among men and by 69-70% among women. Correspondingly, the incidence of DGCA was calculated to have decreased by 30-39% among men and 37-42% among women. We conclude that not only has the incidence of IGCA decreased in percentage approximately twice as much as the incidence of DGCA but DGCA has also distinctly decreased in incidence in Finland from 1952-61 to 1972-81.

Gastric dysplasia. Significance and pathologic criteria.

In view of uncertainty regarding the criteria and significance of gastric dysplasia as a precancerous lesion, members of the Pathology Panel of the International Study Group on Gastric Cancer (ISGGC) reviewed microslides of 93 gastric lesions showing varying degrees of mucosal abnormality, and reached the following consensus: (1) immature and proliferating gastric epithelium can be divided into two categories: hyperplastic and dysplastic; (2) the term dysplasia, especially of high-grade type, should be restricted to precancerous lesions, and hyperplasia is applied to regenerative changes; (3) regenerative hyperplasia may be simple or atypical, but dysplasia includes both moderate and severe abnormalities, since they often coexist and can not be sharply separated; and (4) occasionally the possibility of malignancy can not be excluded in a severely dysplastic epithelium; in such a case rebiopsy and diligent follow-up are necessary to establish the diagnosis. Criteria for diagnosing dysplasia and hyperplasia are presented and discussed. The opinions are offered as guidelines for establishing the diagnosis of gastric dysplasia and for prospective studies.

Further studies of intestinal heterotopia in urethral caruncle.

Colonic mucosa-like intestinal heterotopia in a urethral caruncle is reported in a 2 yr 7 mth old girl and three women; 55, 71 and 78 yrs old. The occurrence of the anomaly in a child supports the first two author's earlier suggestion that the condition is congenital in nature. In princip this could also be the case in post-menopausal women, although the possibility of metaplasia must also be considered. Perhaps the condition could be a precursor of some adenocarcinomas of the distal urethra.

Canine gastric glycoprotein antigens in early carcinogenesis.

The effect of one single dose of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on the antigenic structures of gastric juice glycoproteins, was studied in dogs. Antisera to glycoproteins of the fetal alimentary canal were raised. Histologic mucosal specimens and glycoprotein fractions of gastric juice which were taken from four dogs during a 15.5-month period after MNNG administration, were examined immunohistologically and by immunodiffusion for the appearance of fetal-like antigens. Fetal-like structures appeared in a stepwise manner in both the acid and neutral glycoprotein fractions of the gastric juice, and showed gradual crossreactivity between macromolecules obtained from gastric juice samples obtained during the observation period. Eight immunizations carried out using physicochemically different glycoprotein fractions of fetal canine alimentary canal mucosa, produced a similar response, thus indicating that the same antigenic structures are incorporated into all mucus glycoproteins, even though they do differ physicochemically. It is suggested that this "omnipotential" incorporation picture could also be found after exposure to MNNG and is, by its nature, typically fetal.

Radiologic bone changes of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy.

More than 50 cases of polycystic lipomembranous osteodysplasia (PLO) with sclerosing leukoencephalopathy (SL) have been described in Finland, Sweden, Japan, and in the USA. Radiographic bone changes, including symmetrical cystic lesions in the small bones of the extremities and trabecular loss in the distal ends of the long tubular bones, represent primary abnormalities in the diagnosis of the disease. Neuropsychiatric symptoms, frontal syndrome, and pyramidal signs make the patients dangerous to themselves. They are often involved in traffic accidents and are prone to multiple spontaneous or almost spontaneous fractures. PLO usually starts with slight bone pain around the age of 20 years. Progress is very slow during the next ten years, but faster after the age of 40 years. The patients usually die before the age of 50 years having total dementia and epileptiform convulsions.

Clinicopathological study of gastric cancers and precancerous states detected by fetal sulfoglycoprotein antigen screening.

A clinicopathological analysis is presented of gastric cancer cases detected in a mass screening trial in Finland, using the oncofetal antigen, fetal sulfoglycoprotein antigen, as a marker. The survey covered a population of 53,020 between the ages of 40 and 70, the percentage of participation being 74.8%. Of these participants, 3,508 subjects (8.8%) were found to be fetal sulfoglycoprotein antigen secretors, and among them 36 gastric cancers, one gastric carcinoid, and 10 tubular adenomas were detected. Both main histological types of gastric cancer, intestinal and diffuse, were represented. There were 15 early cancers. In addition, there were three widely spread superficial cancers. Because of early diagnosis, the prognostic view for these cases is clearly better than that found in the clinic by conventional means, curative resection being carried out in 28 cases (78%).

Ultrastructure of intestinal and diffuse type gastric carcinoma.

Samples from 56 resected stomachs, including 28 cases of intestinal and 14 of diffuse type gastric carcinoma, were studied by electron microscopy. The main ultrastructural features of intestinal and diffuse type gastric carcinomas were described and compared to the ultrastructure of normal gastric mucosal cells and cells occurring in intestinal metaplasia of the gastric mucosa. Many similarities were demonstrated between intestinal metaplasia and intestinal type carcinomas. The cells of diffuse type carcinomas closely resembled the goblet cells of intestinal metaplasia. Microvilli, similar to those in the brush border of the intestinal columnar cells, could be demonstrated in the carcinomatous surface epithelium and occasionally also in individually spreading cells of the diffuse type carcinoma. Intracellular cysts with microvilli on the cyst wall were occasionally found in both types of carcinoma. The histogenetic origin of gastric carcinoma was discussed.

Intracellular cysts in gastric carcinoma.

Intracellular cysts were often found in the tumour cells in gastric carcinomas of intestinal as well as diffuse type in specimens from stomachs resected for gastric cancer. In the light microscope, the cysts appeared usually as solitary cytoplasmic vacuoles. In the electron microscope, the intracellular cysts were seen as round cavities, often containing homogenous or granular mucous material which stained with the periodic acid-silver methenamine (PASM)-method. Relatively long microvilli were lining the cysts and, not infrequently, abundant cytoplasmic microfilaments would surround the cyst wall. Similar cysts have been observed in a number of other tumours and, accordingly, their diagnostic significance must be considered in connection with other methods such as differential staining of cellular mucosubstances.

Subclinical elastofibromas in the scapular region in an autopsy series.

In a series of 235 autopsies, changes in the subcapscular thoracic fascia similar to elastofibroma dorsi (Järvi & Saxen 1959, -et al. 1969) were found in 39 cases, all at least 58 years old. In people over 55 years, the frequency was 24.4 per cent in females and 11.2 per cent in males. In addition to hypertrophy and secondary degeneration of elastic fibres, necrosis of collagenous-, adipose-, muscular-, and nervous tissue, as well as formation of clefts, cysts and bursae was found in 85 per cent of cases presenting elastic changes--both in connection with them and outside the degenerated areas--as well as in 39 per cent of cases where no elastic degeneration occurred. Other changes included extensive scarring of the tissue, followed by reduction of fat and, more seldom, oedema and inflammatory infiltration. Breaks in the elastic cage, necrosis and fibrosis of arterial walls were found in 44 per cent of cases of elastic degeneration and in 14 per cent of cases without degeneration. In veins, more extensive wall fibrosis occurred, leading to necrosis; in cases of elastic degeneration the adventitial elastic network was also involved. Venous changes were found in 90 per cent of the cases of elastic degeneration and in 30 per cent of cases without degeneration. Direct mechanical stress on elastic tissue may be an important cause of hypertrophy and secondary degeneration of elastic fibres, and also of diffuse increase of collagenous tissue. On the other hand, nutritional deficiency due to failing resistance of the vascular system against friction of the scapula and streching movements of the upper extremities may play a main part in necrotic tissue changes.