Pathogenesis of hypospadias--more questions than answers

Most researchers believe that hypospadias arises from malformation of the penile urethra. However, this concept has been recently rejected, and it has been suggested that the opening of the urethra is "pushed forward" by growth of the perineum. In order to obtain more information on the development of the urethra, late stages of phallic development were studied in 220 rat embryos with scanning electron microscopy (SEM). In our study, signs of rupture of the urogenital membrane or fusion of the urethral folds could not be found. Therefore, we could not confirm the traditional concept for the development of the phallic urethra. A new concept of urethral development is suggested and the pathogenesis of hypospadias is discussed.     

Gastrointestinal Stromal Tumour Presenting Acutely as Gastroduodenal Intussusception

Introduction : Gastrointestinal stromal tumours (GISTs) are uncommon tumours of the gastrointestinal (GI) tract. We report a case of a gastric GIST that presented acutely as a gastroduodenal intussusception. Case presentation : A 59-year-old woman presented with a week’s history of vomiting anything she swallowed. Physical examination revealed a mildly tender abdomen without guarding or rebound tenderness. An epigastric mass was, however, palpated. Abdominal ultrasonography suggested an intussusception. At laparotomy, a tumour on the anterior wall of the stomach causing intussusception of the stomach into the duodenum was found. After reducing the intussusception, a wedge resection of the tumour was performed, which proved to be a GIST.

Discussion : GISTs represent a rare group of neoplasms of the GI tract. Gastric intussusception is a rarely documented condition. Symptoms range from intermittent epigastric pain to sudden onsets of severe pain with vomiting and shock. Pre-operative diagnosis can be difficult and diagnosis cannot be confirmed until surgery. The treatment of choice for localised gastric GIST is surgical resection.

Conclusion : Although gastroduodenal intussusception, particularly secondary to a GIST, is uncommon, clinicians need to have a high index of suspicion in acutely vomiting patients, especially if they have experienced similar symptoms intermittently in the immediate past.     

IRF6 gene variants in Central European patients with non‐syndromic cleft lip with or without cleft palate

Variants in the interferon regulatory factor 6 (IRF6) gene have repeatedly been associated with non‐syndromic cleft lip with or without cleft palate (NSCL/P). A recent study has suggested that the functionally relevant variant rs642961 is the underlying cause of the observed associations. We genotyped rs642961 in our Central European case–control sample of 460 NSCL/P patients and 952 controls. In order to investigate whether other IRF6 variants contribute independently to the etiology of NSCL/P, we also genotyped the non‐synonymous coding variant V274I (rs2235371) and five IRF6‐haplotype tagging single nucleotide polymorphisms (SNPs). A highly significant result was observed for rs642961 (P = 1.44 × 10^?6) in our sample. The odds ratio was 1.75 [95% confidence interval (CI): 1.38–2.22] for the heterozygous genotype and 1.94 (95% CI: 1.21–3.10) for the homozygous genotype, values that are similar to those reported in a previously published family‐based study. Our results thus confirm the involvement of the IRF6 variant, rs642961, in the etiology of NSCL/P in the Central European population. We also found evidence suggestive of an independent protective effect of the coding variant V274I. In order to understand fully the genetic architecture of the IRF6 locus, it will be necessary to conduct additional SNP‐based and resequencing studies using large samples of patients.     

Activity patterns of proteasome subunits reflect bortezomib sensitivity of hematologic malignancies and are variable in primary human leukemia cells.

Proteasomal proteolysis relies on the activity of six catalytically active proteasomal subunits (beta1, beta2, beta5, beta1i, beta2i and beta5i). Applying a functional proteomics approach, we used a recently developed activity-based, cell-permeable proteasome-specific probe that for the first time allows differential visualization of individual active proteasomal subunits in intact primary cells. In primary leukemia samples, we observed remarkable variability in the amounts of active beta1/1i-, beta2/2i- and beta5/5i-type of subunits, contrasting with their constant protein expression. Bortezomib inhibited beta5- and beta1-type, but to a lesser extend beta2-type of subunits in live primary cells in vitro and in vivo. When we adapted the bortezomib-sensitive human acute myeloid leukemia cell line HL-60 to bortezomib 40 nM (HL-60a), proteasomal activity profiling revealed an upregulation of active subunits, and residual beta1/beta5-type of activity could be visualized in the presence of bortezomib 20 nM, in contrast to control cells. In a panel of cell lines from hematologic malignancies, the ratio between beta2-type and (beta1 + beta5)-type of active proteasomal polypeptides mirrored different degrees of bortezomib sensitivity. We thus conclude that the proteasomal activity profile varies in primary leukemia cells, and that the pattern of proteasomal subunit activity influences the sensitivity of hematologic malignancies toward bortezomib.