Blood-derived gene-expression profiling in unravelling susceptibility to recessive disease.

Identification of new disease predisposition genes with chip-based technologies typically requires extensive financial and sample resources. We have recently shown that combining peripheral blood genome and transcriptome (BGT) information in highly selected materials can be a successful low-cost approach to unravelling dominant tumour susceptibility. In this study, we extended our investigations to recessively inherited tumour predisposition, and identified a homozygous germline mutation in the damage-specific DNA binding protein 2 (DDB2) gene in a patient with several facial tumours, for which doctors had been unable to provide a diagnosis. Our results provide proof of principle that BGT is a powerful approach for both dominant and recessive genes. In addition to tumour susceptibility, the method may be useful in characterising genetic defects underlying other disease phenotypes.

Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis.

Serrated colorectal carcinomas (CRCs) are morphologically different from conventional CRCs and have been proposed to follow a distinct pathway of CRC formation. Despite studies of single molecular events in this tumor type, the diagnosis of serrated CRC relies on morphology and the putative unique biological character of these tumors has not been established. Here we show that the gene expression profiling of 37 CRCs separated serrated and conventional CRCs into two distinct branches in unsupervised hierarchical clustering (P-value 7.8 x 10(-7)), and revealed 201 differentially expressed genes representing potential biomarkers for serrated CRC. Immunohistochemistry was utilized to verify the key findings in the 37 CRCs examined by expression profiling, and a separate validation set of 37 serrated and 86 conventional CRCs was examined to evaluate the candidate biomarkers in an extended sample material. Ephrin receptor B2, hypoxia-inducible factor 1-alpha and patched appeared as proteins important for genesis of serrated CRC. This study establishes serrated CRCs as a biologically distinct subclass of CRC and represents a step forward in the molecular classification of these cancers. The study also provides a platform to understand the molecular basis of serrated CRC and in long term may contribute to the development of specific treatment options for this tumor type.

An introduction of a pyridine group into the structure of prolyl oligopeptidase inhibitors.

A series of ionizable prolyl oligopeptidase inhibitors were developed through the introduction of a pyridyl group to the P3 position of the prolyl oligopeptidase inhibitor structure. The study was performed on previously developed prolyl oligopeptidase inhibitors with proline mimetics at the P2 position. The 3-pyridyl group resulted in equipotent compounds as compared to the parent compounds. It was shown that the pyridyl group improves water solubility and, in combination with a 5(R)-tert-butyl-l-prolyl group at the P2 position, good lipophilicity can be achieved.

Annual injection of vitamin D and fractures of aged bones.

In order to investigate the effect of a supplementation of vitamin D in the prophylaxis of fractures of the bones of aged people, an annual intramuscular injection of ergocalciferol (150,000-300,000 IU) was given to two series of aged subjects: first to 199 (45 male) of 479 subjects (110 male) aged more than 85 years who were living in their own home, and second to 142 (29 male) of 320 (58 male) subjects aged 75-84 and living in a home for aged people. This prospective series was divided into treatment groups according to month of birth. These injections were given annually from September to December in the years 1985-1989, two to five times to each participant. The fracture rates, laboratory values, vitamin D levels, possible side effects, and mortality were followed until October 1990. A total of 56 fractures occurred in the 341 vitamin D recipients (16.4%) and 100 in 458 controls (21.8%) (P = 0.034). The fracture rate was about the same in both outpatient and municipal home series. Fractures of the upper limb were fewer in the vitamin D recipients, 10/341 = 2.9% (P = 0.025), than in the controls, 28/458 = 6.1%, during the follow-up. A similar result was obtained in fractures of ribs, 3/341 = 0.9% and 12/458 = 2.6%, respectively. Fractures of the lower limbs occurred almost as frequently, 31/341 = 9.1%, among the vitamin D recipients as among the controls, 49/458 = 10.7%. The fracture rate was higher in females (22.2%) than in males (9.5%). The fractures were fewer in the vitamin D recipients only in females.(ABSTRACT TRUNCATED AT 250 WORDS)

Atlanto-axial dislocation in an 18-year-old female with Yersinia arthritis.

A case of anterior atlanto-axial dislocation in an 18-year-old female with arthritis due to Yersinia enterocolitica 3 is reported. We draw attention to the importance of investigating the cervical spine even in young patients with a short history of arthritis. Physical treatment indications and contra-indications should be taken into consideration.

Precision and accuracy of foundry dust exposure estimates from air sampling data.

Errors in the sampling methods and in the determination of respirable size quartz in foundry dust have been evaluated and discussed. In general, the total precision of dust sampling and analysis was better than 20%. The term "exposure dose" is introduced and defined. The temporal variation associated with measuring exposure dose is assessed with reference to the use of a log-normal distribution of air sampling results. The logarithmic standard deviations of dust concentrations at fixed sites and jobs are calculated.

Dust exposure in Finnish foundries.

Dust measurements were made in 51 iron, 9 steel, and 8 nonferrous foundries, at which 4,316 foundrymen were working. The sampling lasted at least two entire shifts or work days continuously during various operations in each foundry. The dust samples were collected at fixed sites or in the breathing zones of the workers. The mass concentration was determined by weighing and the respirable dust fraction was separated by liquid sedimentation. The free silica content was determined by X-ray diffraction. In the study a total of 3,188 samples were collected in the foundries and 6,505 determinations were made in the laboratory. The results indicated a definite difference in the dust exposure during various operations. The highest dust exposures were found during furnace, cupola, and pouring ladle repair. During cleaning work, sand mixing, and shake-out operations excessive silica dust concentrations were also measured. The lowest dust concentrations were measured during melting and pouring operations. Moderate dust concentrations were measured during coremaking and molding operations. The results obtained during the same operations of iron and steel foundries were similar. The distribution of the workers into various exposure categories, the content of respirable dust and quartz, the correlation between respirable dust and total dust, and the correlation between respirable silica and total dust concentrations are discussed. Observations concerning dust suppression and control methods are briefly considered.

Effect of foundry size on the dust concentration of different work phases.

The dust concentrations of different work phases in iron foundries of different sizes were studied. The results of the total dust measurements made during the Finnish Foundry Project were considered according to the eight main work phases, and the 51 iron foundries were divided into four groups according to the number of foundry workers. The division between the groups at 25, 50, and 100 workers is related to the degree of mechanization in Finnish foundries. The total dust concentration clearly increased in sand making and melting as the size of the foundry increased. The concentration decreased in molding, coremaking, knock-out, and cleaning as the number of workers increased. No significant differences between the foundry groups could be found during casting. The factors affecting the differences in dust concentrations are discussed.