Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells.

HOX genes are highly expressed in many acute myeloid leukemia (AML) samples, but the patterns of expression and associated regulatory mechanisms are not clearly understood. We analyzed RNA sequencing data from 179 primary AML samples and normal hematopoietic cells to understand the range of expression patterns in normal versus leukemic cells. HOX expression in AML was restricted to specific genes in the HOXA or HOXB loci, and was highly correlated with recurrent cytogenetic abnormalities. However, the majority of samples expressed a canonical set of HOXA and HOXB genes that was nearly identical to the expression signature of normal hematopoietic stem/progenitor cells. Transcriptional profiles at the HOX loci were similar between normal cells and AML samples, and involved bidirectional transcription at the center of each gene cluster. Epigenetic analysis of a subset of AML samples also identified common regions of chromatin accessibility in AML samples and normal CD34(+) cells that displayed differences in methylation depending on HOX expression patterns. These data provide an integrated epigenetic view of the HOX gene loci in primary AML samples, and suggest that HOX expression in most AML samples represents a normal stem cell program that is controlled by epigenetic mechanisms at specific regulatory elements.

Company observational post-marketing studies: drug risk assessment and drug research in special populations--a study-based analysis.

OBJECTIVES: Company observational post-marketing studies (COPS) claim to provide essential data about drug risks and effectiveness in special populations not admitted to pre-approval clinical trials. Since COPS are often mainly regarded as a marketing activity, this study-based analysis tries to evaluate the scientific contributions of COPS. MATERIAL AND METHODS: Thirty-five COPS were identified by hand-searching through medical journals, writing to pharmaceutical manufacturers and using MEDLINE. Fourteen COPS evaluated cardiovascular drugs, 9 evaluated NSAIDs and 12 evaluated various other indications. RESULTS: Thirty-five COPS listed effectiveness, 31 listed safety and 8 listed patient compliance as principal objectives. Not a single COPS included a control group. Seventeen of 21 evaluable COPS mentioned extensive exclusion criteria similar to those in clinical trials. Median observation time was 8 weeks, too short for chronic diseases and for adverse drug reactions with longer latency periods. One new adverse event was regarded. Global assessments of the outcomes by physicians dominated and were not based on objective clinical findings. None of the studies specified any details concerning the standardisation of observations or quality-control procedures. DISCUSSION AND CONCLUSION: The current COPS scheme does not contribute significantly to our knowledge of drug safety and the effects in special populations. Despite serious criticism over the past 20 years, the poor quality of COPS compared with dramatic improvements of pre-approval trials - implies a need for detailed guidelines for non-experimental phase IV research, similar to the Good Clinical Practice-Guideline of the European Community.

Intestinal parasitic infections in black scholars in northern KwaZulu.

Faecal specimens were collected form a total of 7569 scholars at 45 different localities in northern KwaZulu and screened for the presence of intestinal helminth and protozoan parasites. The soil-transmitted nematodes Ascaris lumbricoides, Trichuris trichiura and hookworm sp. were extremely common, with prevalences in certain localities ranking among the highest to be recorded in South Africa. Entamoeba coli was by far the commonest (60%) of the protozoa;p all the other species had prevalences of less than 10%. The distribution age-specific prevalence and the influence of the variables-sex, ara and age-on the occurrence of the various intestinal parasites are described.

A cross-sectional study on the prevalence and intensity of infection with Schistosoma haematobium students of Northern KwaZulu.

The urines of 7,944 students (aged 5--25 years) from 42 different localities in Northern KwaZulu were screened for the presence of Schistosoma haematobium eggs. Fifty-four percent were infected, but prevalence varied from 8--92% depending on conditions existing in the localities. The age-specific prevalence in each of the four topographical areas was unusual in that peaks were not distinct and sharp decreases towards the end of the 2nd decade of life did not occur. Egg output, determined by using a helminth filter and staining of eggs, was expressed in relation to time (2-hour mid-day specimens) rather than urine volume. Unlike the prevalence, egg output decreased considerably after a distinct peak which occurred at 8 years of age in the low prevalence area and at ages 10 and 11 years in the heavily infected areas. Statistical analyses of the results revealed that the observed prevalence of S. haematobium was dependent on area and age but not on sex. The significance of the findings in this area are discussed.

Schistosoma mansoni and S. mattheei infestation in northern Kwazulu.

A survey carried out in northern KwaZulu to determine the prevalence of Schistosoma mansoni and S. mattheei rvealed that, despite the abundance of the relevant snail intermediate hosts, both schistosomes were rather uncommon in Black schoolchildren in the area. The possible reasons for this are discussed.