Molecular characterization of breakpoints in patients with holoprosencephaly and definition of the HPE2 critical region 2p21

Holoprosencephaly (HPE) is a common developmental defect involving the brain and face in humans. Cytogenetic deletions in patients with HPE have localized one of the HPE genes (HPE2) to the chromosomal region 2p21. Here we report the molecular genetic characterization of nine HPE patients with cytogenetic deletions or translocations involving 2p21. We have determined the parental origin of the deleted chromosomes and defined the HPE2 critical region between D2S119 and D2S88/D2S391. As a first step towards cloning the HPE2 gene which is crucial for normal brain development we have constructed a YAC contig which spans the smallest region of deletion overlap. Several of these YACs could be identified which span three different 2p21 breakpoints in HPE patients. These YACs narrow the HPE2 critical region to less than 1 Mb and are now being further analyzed to identify the gene causing holoprosencephaly on chromosome 2.      

Risk of relapse in new cases of ulcerative colitis and indeterminate colitis

PURPOSE: Changes in morbidity pattern of ulcerative colitis have created a need to update understanding of the course of the disease. METHOD: A follow-up study was done of relapse rates and progression of inflammation in 571 nonselected patients with ulcerative and indeterminate colitis. RESULTS: Relapse rate ten years after diagnosis was 70 percent in definite ulcerative colitis, 22 percent in probable ulcerative colitis, and 77 percent in indeterminate colitis. During the study period, there was no change in the relapse rate. In relapsing proctitis, 52 percent developed more extensive inflammation. Fifty-four percent of patients with only one attack of colitis had persistent signs of inflammatory bowel disease. CONCLUSIONS: Shift in morbidity pattern to a greater proportion of patients with proctitis at diagnosis and a shorter time from onset of symptoms to diagnosis had no influence on the relapse rate. Indeterminate colitis has a worse prognosis than definite ulcerative colitis. Considering the documented efficacy of sulfasalazine, the high relapse rate calls for studies of the effectiveness of such treatment in everyday practice.     

Evaluation of possibilities for mass screening for colorectal cancer with hemoccult® fecal blood test

Data from a health survey including the Hemoccult^® fecal blood test, together with official cause-specific death rates, were used to assess the magnitude of a controlled trial that would be required to prove a 25 percent reduction of the mortality from colorectal cancer associated with screening. All men in three age groups in the city of malmö, Sweden, were invited, but 46 percent did not participate in, the Hemoccult screening. One carcinoma and 89 adenomas were detected in 56 of the 2422 who did. With the risk function used in our calculation and a complicance rate of 60 percent, a study population among 45- to 69-year-olds of 605,000 is required to prove an expected 25 percent reduction of the mortality with 90 percent power. Considering the size of such a trial, we question whether a controlled trial is feasible. With known risk functions for death from all causes and death from colorectal cancer, the study population was calculated using variable statistical power, participation rate, and risk reduction. Statistical methods and computer programs are given. In addition, alternative study models to assess the benefits associated with screening are discussed.     

A functional comparison of CD34 + CD38- cells in cord blood and bone marrow

We present cell cycling and functional evidence that the CD34+CD38- immunophenotype can be used to define a rare and primitive subpopulation of progenitor cells in umbilical cord blood. CD34+CD38- cells comprise 0.05% +/- 0.08% of the mononuclear cells present in cord blood. Cell cycle analysis with the fluorescent DNA stain 7- aminoactinomycin D showed that the percentage of CD34+ cells in cycle directly correlated with increasing CD38 expression. CD34+CD38- cord blood cells were enriched for long-term culture-initiating cells (LTCIC; cells able to generate colony-forming unit-cells [CFU-C] after 35 to 60 days of coculture with bone marrow stroma) relative to CD34+CD38- cells. In an extended LTCIC assay, CD34+CD38- cells were able to generate CFU-C between days 60 and 100, clearly distinguishing them from CD34+CD38+ cells that did not generate CFU-C beyond day 40. When plated as single cells, onset of clonal proliferation was markedly delayed in a subpopulation of CD34+CD38- cells; clones (defined as > 100 cells) appeared after 60 days of culture in 2.9% of CD34+CD38- cells. In contrast, 100% of CD34+CD38+ cells formed clones by day 21. Although the CD34+CD38- immunophenotype defines highly primitive populations in both bone marrow and cord blood, important functional differences exist between the two sources. CD34+CD38- cord blood cells have a higher cloning efficiency, proliferate more rapidly in response to cytokine stimulation, and generate approximately sevenfold more progeny than do their counterparts in bone marrow.