Gas1 Regulates Patterning of the Murine and Human Dentitions through Sonic Hedgehog.

The mammalian dentition is a serially homogeneous structure that exhibits wide numerical and morphological variation among multiple different species. Patterning of the dentition is achieved through complex reiterative molecular signaling interactions that occur throughout the process of odontogenesis. The secreted signaling molecule Sonic hedgehog (Shh) plays a key role in this process, and the Shh coreceptor growth arrest-specific 1 (Gas1) is expressed in odontogenic mesenchyme and epithelium during multiple stages of tooth development. We show that mice engineered with Gas1 loss-of-function mutation have variation in number, morphology, and size of teeth within their molar dentition. Specifically, supernumerary teeth with variable morphology are present mesial to the first molar with high penetrance, while molar teeth are characterized by the presence of both additional and absent cusps, combined with reduced dimensions and exacerbated by the presence of a supernumerary tooth. We demonstrate that the supernumerary tooth in Gas1 mutant mice arises through proliferation and survival of vestigial tooth germs and that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt and downstream FGF signaling in odontogenic epithelium through facilitation of Shh signal transduction. Moreover, regulation of tooth number is independent of the additional Hedgehog coreceptors Cdon and Boc, which are also expressed in multiple regions of the developing tooth germ. Interestingly, further reduction of Hedgehog pathway activity in Shhtm6Amc hypomorphic mice leads to fusion of the molar field and reduced prevalence of supernumerary teeth in a Gas1 mutant background. Finally, we demonstrate defective coronal morphology and reduced coronal dimensions in the molar dentition of human subjects identified with pathogenic mutations in GAS1 and SHH/GAS1, suggesting that regulation of Hedgehog signaling through GAS1 is also essential for normal patterning of the human dentition.

Transcription profiling of eleven cytochrome P450s potentially involved in xenobiotic metabolism in the mosquito Aedes aegypti.

Transcription profiles of 11 Aedes aegypti P450 genes from CYP6 and CYP9 subfamilies potentially involved in xenobiotic metabolism were investigated. Many genes were preferentially transcribed in tissues classically involved in xenobiotic metabolism including midgut and Malpighian tubules. Life-stage transcription profiling revealed important variations amongst larvae, pupae, and adult males and females. Exposure of mosquito larvae to sub-lethal doses of three xenobiotics induced the transcription of several genes with an induction peak after 48 to 72 h exposure. Several CYP genes were also induced by oxidative stress and one gene strongly responded to 20-hydroxyecdysone. Overall, this study revealed that these P450s show different transcription profiles according to xenobiotic exposures, life stages or sex. Their putative chemoprotective functions are discussed.

PML involvement in the p73-mediated E1A-induced suppression of EGFR and induction of apoptosis in head and neck cancers.

Epidermal growth factor receptor (EGFR) tyrosine kinase is commonly overexpressed in human cancers; however, the cellular mechanisms regulating EGFR expression remain unclear. p53, p63 and p73 are transcription factors regulating many cellular targets involved in controlling the cell cycle and apoptosis. p53 activates EGFR expression, whereas TAp63 represses EGFR transcription. The involvement of p73 in the regulation of EGFR has not been reported. Here, a strong correlation between EGFR overexpression and increased levels of the oncogenic DeltaNp73 isoform in head and neck squamous cell carcinoma (HNSCC) cell lines was observed. Ectopic expression of TAp73, particularly TAp73beta, resulted in suppression of the EGFR promoter, significant downregulation of EGFR protein and efficient induction of cell death in all six EGFR-overexpressing HNSCC cell lines. EGFR overexpression from a heterologous LTR promoter protected lung cancer cells from TAp73beta-induced EGFR suppression and apoptosis. Expression of TAp73beta efficiently induced promyelocytic leukaemia (PML) protein expression and PML knockdown by shRNA attenuated the downregulation of EGFR and induction of apoptosis by p73 in HNSCC cells. Furthermore, PML was found to be important for E1A-induced suppression of EGFR and subsequent killing of HNSCC cells. Our data therefore suggest a novel pathway involving PML and p73 in the regulation of EGFR expression.

Superior gluteal artery haemorrhage following pelvic features controlled by embolisation.

Successful embolisation of active bleeding from the superior gluteal artery seen in two patients within the last 12 months is described. Both patients had extensive abdominal and pelvic injuries. One patient eventually died from renal failure and a perforated colon. The other patient is mobile and has been periodically seen in the out-patient department over the past nine months. In both instances, haemorrhage was at the sacrosciatic notch. Early angiography, in patients with extensive pelvic trauma and major blood requirements, with intent to embolise any identifiable bleeding source would appear to be the best initial manoeuvre to prevent exsanguination.

Embolization of extensive peripheral angiodysplasias. The alternative to radical surgery.

We describe two patients with extensive pelvic and lower limb angiodysplasias, in whom hemodynamic complications subsequently developed. These have been treated by selective angiography and multiple percutaneous transcatheter embolizations with satisfactory results (1 1/2 to four years of follow-up). One patient had had three previous operations with no improvement; amputation was the only surgical alternative. In the other patient, hip disarticulation and hemipelvectomy was seriously considered because of cardiac failure not responding to medical therapy. We review the literature and use our cases to illustrate points of technique and reemphasize the essential role of therapeutic embolization in the management of extensive angiodysplasia.

CT in localization of impalpable cryptorchid testes.

Computed tomography was used for preoperative localization in 12 patients with undescended testes. Because three patients had bilateral involvement, 15 absent or undescended testes were studied. Surgical confirmation of the CT findings was obtained in 12 instances. Confirmation was not obtained in one patient who refused operation and it was considered incomplete in another due to limited surgical exploration. There was one incorrect localization. The procedure is quick, simple, noninvasive, and can be performed at all ages. The testicular radiation exposure was considered acceptable on the basis of phantom measurement. The lowest possible exposure factors were used on all patients. CT findings assisted planning of operative procedures and in some cases enabled more limited and shorter operations.

Ungual tufts in the follow-up of patients on maintenance hemodialysis.

A recent publication showed the earliest signs of renal osteodystrophy in patients on maintenance hemodialysis (MHD) to occur in the tufts [1]. We present three patients on MHD, in two of whom the earliest unequivocal radiographic improvement was seen in the tufts. The third patient had been on MHD and, following subtotal parathyroidectomy, showed significant osseous improvement in the hands with relatively equal improvement in the hands with relatively equal improvement in the tufts and middle phalanges. It appears that, with the use of routine primary or secondary magnification, the tufts are radiographically a highly sensitive site for both the early occurrence and improvement of osteodystrophy in patients on MHD. We are not aware of any previous publication pointing out exclusive improvement in the tufts in patients on MHD with virtually no change in the mid-phalanges. Two of these three cases illustrate that renal osteodystrophy is reversible by maintenance hemodialysis alone.

CT as a primary diagnostic method in evaluating intraabdominal abscess.

In 19 cases, a correct diagnosis of intraabdominal abscess was made by CT body scanning. There was one false-positive diagnosis and initially one false-negative diagnosis. CT proved to be an efficient imaging method for diagnosis, for planning of therapeutic procedures, and in monitoring response to operative or conservative treatment. It has advantages over ultrasound and gallium scanning especially in severely ill, postoperative, and obese subjects. In addition, needle aspiration under CT control is readily performed and can be undertaken at the same examination. Confirmation of the diagnosis and therapeutic aspiration with or without introduction of a drainage catheter can then be undertaken.

Terminal phalangeal tufts: earliest site of renal osteodystrophy findings in hemodialysis patients.

Direct magnificaiton of the hands of 44 patients on maintenance hemodialysis showed that the earliest unequivocal changes of renal osteodystrophy occur in the tufts. Some workers made a similar observation, but no previous objective study confirmed or refuted the sensitivity of the tufts in the diagnosis of renal osteodystrophy. The macroradiograph is consistently reproducible and serves as an excellent visual record of subtle changes.