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A custom CGH microarray that covers the SOX9 regulatory region. Log2 ratio scatterplot showing individual data points. Blue box highlights copy number gain with 3' breakpoint region magnified.

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Hoxb8 overexpression immortalises haematopoietic progenitor cells in a growth-factor-dependant manner and co-operates with interleukin-3 (IL-3) to cause acute myeloid leukaemia. To further understand how Hoxb8 contributes to myeloid cell immortalisation, we generated IL-3-dependant myeloid cells expressing Hoxb8 under the control of an inducible promoter. Downregulation of Hoxb8, in the presence of IL-3, caused cell-cycle arrest and apoptosis in the majority of cells. Apoptosis was dependant on Bax and Bak and, in part, on Bim, which was repressed by Hoxb8. Deletion of the miR-17∼92 seed sequences in the Bim 3'UTR abolished Hoxb8-dependant regulation of Bim reporter constructs. Expression of all six miRNAs from this cluster were elevated when Hoxb8 was overexpressed. The miR-17∼92 cluster was required for repression of Bim in Hoxb8-immortalised cells and deletion of the miR-17∼92 cluster substantially inhibited Hoxb8, but not Hoxa9, mediated survival and proliferation. Hoxb8 appears to promote miR-17∼92 expression through c-Myc, a known transcriptional regulator of the miR-17∼92 cluster. We have uncovered a previously unrecognised link between Hoxb8 expression and microRNAs that provides a new insight into the oncogenic functions of Hoxb8.

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In an effort to identify novel candidate genes involved in testis determination, we previously used suppression subtraction hybridisation PCR on male and female whole embryonic (12.0-12.5 days post coitum) mouse gonads. One gene to emerge from our screen was Redd1. In the current study, we demonstrate by whole-mount in situ hybridisation that Redd1 is differentially expressed in the developing mouse gonad at the time of sex determination, with higher expression in testis than ovary. Furthermore, Redd1 expression was first detected as Sry expression peaks, immediately prior to morphological sex determination, suggesting a potential role for Redd1 during testis development. To determine the functional importance of this gene during testis development, we generated Redd1-deficient mice. Morphologically, Redd1-deficient mice were indistinguishable from control littermates and showed normal fertility. Our results show that Redd1 alone is not required for testis development or fertility in mice. The lack of a male reproductive phenotype in Redd1 mice may be due to functional compensation by the related gene Redd2.

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The sex of most mammals is determined by the action of SRY. Its presence initiates testis formation resulting in male differentiation, its absence results in ovary formation and female differentiation. We have used suppression subtraction hybridisation between 12.0-12.5 days postcoitum (dpc) mouse testes and ovaries to identify genes that potentially lie within the Sry pathway. Normalised urogenital ridge libraries comprising 8,352 clones were differentially screened with subtracted probes. A total of 272 candidate cDNAs were tested for qualitative differential expression and localisation by whole mount in situ hybridisation; germ cell-dependent or -independent expression was further resolved using busulfan. Fifty-four genes were identified that showed higher expression in the testis than the ovary. One novel gene may be a candidate for interactions with WT1, based on its localisation to Sertoli cells and map position (16q24.3).

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Results are presented of five consecutive annual examinations using the Abnormal Involuntary Movement Scale for 101 community-based chronic psychiatric patients. These 101 patients had a history of longer and more consistent neuroleptic treatment than the 231 patients who initially entered the study, so no conclusions about prevalence of TD can be drawn. At each examination two-thirds of this group showed signs of TD; however, only 45% were TD positive at most examinations and 24% were best described as having fluctuating TD status. Of those patients who were consistently TD positive, 82% showed no overall significant change in summed AIMS scores, 11% improved and 7% became worse.

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In the present study, two raters, a psychologist and a nurse, each made five independent ratings of 30 different video-recorded patient-examinations. Having thus excluded patient fluctuation, individual-rater consistency and between-rater agreement over the 6 weeks of the study are examined. While between-rater agreement was apparently being maintained, mean AIMS scores steadily increased. In the hands of these raters, AIMS items 2 and 4 emerged as very reliable, while items 1, 6, and 7 showed high variability. Some patients appeared to be hard to rate. Differences between the study raters and the author JB highlight the issue: how reproducible is an AIMS rating?

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Tardive dyskinesia (TD) is usually described as fluctuating in its clinical manifestations. We attempted to quantify fluctuations in TD using the Abnormal Involuntary Movement Scale (AIMS). Three psychiatrists rated multiple video-recorded examinations of four outpatients with mild TD. The unexpected finding was that within-rater variability dominated within-patient variability.

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