Effect of 5-aminosalicylic acid (5-ASA) and other salicylates on short-chain fat metabolism in the colonic mucosa. Pharmacological implications for ulcerative colitis

5-Aminosalicylic acid (5-ASA) suppressed nitrite-stimulated oxidation of the fatty acid n-butyrate in a dose-dependent manner in isolated human and rat colonic epithelial cells. 4-ASA had one-sixth of the capacity of 5-ASA and sulphapyridine (SP) little of the capacity of 5-ASA to suppress fatty acid oxidation in human colonic epithelial cells. Sulphasalazine (SASP), azodisalicylic acid (ADS), acetyl-5-ASA and acetyl salicylic acid (ASA) did not suppress fatty acid oxidation in rat colonocytes. The suppression index of fatty acid oxidation (SIFO) of respective salicylic acids correlated with the reported clinical effectiveness of each drug against ulcerative colitis (UC). The capacity of 5-ASA to affect nitrite-stimulated oxidation of fat in the colonic mucosa suggests that nitrite ions and control of fatty acid oxidation play a central role in the development and therapy of active UC.     

IGFBP-3 is a metastasis suppression gene in prostate cancer

The insulin-like growth factor binding protein IGFBP-3 is a proapoptotic and antiangiogenic protein in prostate cancer (CaP). Epidemiologic studies suggest that low IGFBP-3 is associated with greater risk of aggressive, metastatic prostate cancers, but in vivo functional data are lacking. Here we show that mice that are genetically deficient in IGFBP-3 exhibit weaker growth of primary prostate tumors but higher incidence of metastatic disease. Prostates in IGFBP-3 knockout mice (IGFBP-3KO mice) failed to undergo apoptosis after castration. Spontaneous prostate tumors did not develop in IGFBP-3KO mice, but splenic lymphomas occurred in 23% of female IGFBP-3KO mice by 80 weeks of age. To assess the effects of IGFBP-3 deficiency on prostate cancer development, we crossed IGFBP-3KO mice with a c-Myc-driven model of CaP that develops slow-growing, nonmetastatic tumors. By 24 weeks of age, well-differentiated prostate cancers were observed in all mice regardless of IGFBP-3 status. However, by 80 weeks of age IGFBP-3KO mice tended to exhibit larger prostate tumors than control mice. More strikingly, lung metastases were observed at this time in 55% of the IGFBP-3KO mice but none in the control animals. Cell lines established from IGFBP-3KO:Myc tumors displayed more aggressive phenotypes in proliferation, invasion, and colony formation assays, relative to control Myc tumor cell lines. In addition, Myc:IGFBP-3KO cells exhibited evidence of epithelial-mesenchymal transition. Our findings established a function for IGFBP-3 in suppressing metastasis in prostate cancer, and they also offered the first reported transgenic model of spontaneous metastatic prostate cancer for studies of this advanced stage of disease.     

Posthemicricoidectomy reconstruction with a composite hyoid-sternohyoid osseomuscular flap: the Rethi–Ward technique

Our objective was to introduce a new technique for cricoid cartilage reconstruction. A 74-year-old male patient with a history of a 6-month progressively worsening dyspnea was found to have an extensive mass of the left cricoid cartilage. Although the extent of his disease would necessitate total laryngectomy, the patient underwent an open extended left hemicricoidectomy with reconstruction of the defect by a pedicled osseomuscular flap composed of the body of the hyoid bone and the contralateral sternohyoid muscle. Both frozen section and subsequent histopathological evaluation gave the diagnosis of a chondrosarcoma. A Montgomery T-tube was left in place for 3 months and was subsequently replaced by a tracheostomy tube to be removed 1 month later. Six months postoperatively, the patient remains in an excellent respiratory condition. The reconstructed site is patent without any signs of restenosis as up to date. We conclude that our technique appears to be a reliable alternative to total laryngectomy in cases of extended chondrosarcomas, as well as in cases where reconstruction of the cricoid cartilage is mandated. Further follow-up and additional cases are warranted. Presented at the 6th Congress of the European Laryngological Society, 31 August–2 September 2006, Nottingham, UK.     

Contrast optimization for the detection of focal hepatic lesions by MR imaging at 1.5 T

The relative efficacies of different spin-echo pulse sequences at 1.5 T were evaluated in the detection of focal hepatic disease. Pulse sequences compared were spin-echo with a repetition time (TR) of 200 msec and echo time (TE) of 20 msec, with six excitations; TR = 300 msec, TE = 20 msec, with 16 excitations (T1-weighted sequences); and a double spin-echo with TR = 2500 and TE = 25 and 70, with two excitations (proton-density-weighted and T2-weighted pulse sequences, respectively). Respiratory-motion compensation, which involved a recording of the phase-encoding gradients (Exorcist), was used for the last two sequences. Spin-echo with TR = 2500 msec and TE = 70 msec was superior in lesion detection and contrast-to-noise ratio. The proton-density-weighted and T2-weighted sequences with respiratory compensation produced better artifact suppression than did the short TR, short TE T1-weighted sequence with temporal averaging. In contradistinction to prior results at 0.6 T, T2-weighted pulse sequences appear superior to T1-weighted pulse sequences with multiple excitations for both lesion detection and artifact suppression at 1.5 T.     

Vancomycin concentrations in infected and noninfected human bone.

Concentrations of vancomycin in bones of 14 patients undergoing total hip arthroplasty (group 1) and 5 patients with osteomyelitis (group 2) were studied. Group 1 received vancomycin, 15 mg/kg intravenously, 1 h prior to anesthesia. Group 2 received doses adjusted to achieve peak levels in serum of 20 to 30 micrograms/ml and trough levels of less than 12 micrograms/ml; bone specimens were collected during surgical debridement. The specimens were pulverized and eluted into phosphate buffer, and the supernatants were analyzed for vancomycin content by fluorescence polarization immunoassay. In group 1, vancomycin was detectable in all cancellous specimens with a mean concentration of 2.3 +/- 4.0 micrograms/g (range, 0.5 to 16 micrograms/g); 10 of 14 cortical specimens had detectable vancomycin; the mean cortical concentration was 1.1 +/- 0.8 micrograms/g (range, not detectable to 2.6 micrograms/g). In group 2, vancomycin was detectable in only two of five cortical bone specimens (mean concentration, 5.9 +/- 3.5 micrograms/g). Cancellous bone was obtained in one patient; the vancomycin concentration was 3.6 micrograms/g. In most patients the vancomycin levels in bones were higher than the MIC for susceptible staphylococci following single prophylactic doses. In the few infected patients studied, penetration was variable and deserves further study.     

The ATP-binding site of type II topoisomerases as a target for antibacterial drugs

DNA topoisomerases are essential enzymes in all cell types and have been found to be valuable drug targets both for antibacterial and anti-cancer chemotherapy. Type II topoisomerases possess a binding site for ATP, which can be exploited as a target for chemo-therapeutic agents. High-resolution structures of protein fragments containing this site complexed with antibiotics or an ATP analogue have provided vital information for the understanding of the action of existing drugs and for the potential development of novel anti-bacterial agents. In this article we have reviewed the structure and function of the ATPase domain of DNA gyrase (bacterial topoisomerase II), particularly highlighting novel information that has been revealed by structural studies. We discuss the efficacy and mode of action of existing drugs and consider the prospects for the development of novel agents.     

Koilocytes indicate a role for human papilloma virus in breast cancer

Background:

High-risk human papilloma viruses (HPVs) are candidates as causal viruses in breast cancer. The scientific challenge is to determine whether HPVs are causal and not merely passengers or parasites. Studies of HPV-related koilocytes in breast cancer offer an opportunity to address this crucial issue. Koilocytes are epithelial cells characterised by perinuclear haloes surrounding condensed nuclei and are commonly present in cervical intraepithelial neoplasia. Koilocytosis is accepted as pathognomonic (characteristic of a particular disease) of HPV infection. The aim of this investigation is to determine whether putative koilocytes in normal and malignant breast tissues are because of HPV infection.

Methods:

Archival formalin-fixed normal and malignant breast specimens were investigated by histology, in situ PCR with confirmation of the findings by standard PCR and sequencing of the products, plus immunohistochemistry to identify HPV E6 oncoproteins.

Results:

human papilloma virus-associated koilocytes were present in normal breast skin and lobules and in the breast skin and cancer tissue of patients with ductal carcinoma in situ (DCIS) and invasive ductal carcinomas (IDCs).

Interpretation:

As koilocytes are known to be the precursors of some HPV-associated cervical cancer, it follows that HPVs may be causally associated with breast cancer.