Early male initiation (time frame shift): a possible contributor to their shortened lifespan

Diosgenyl alpha-L-rhamnopyranosyl-(1--2)-[beta-glucopyranosyl-(1--3)]- beta-D-glucopyranoside (gracillin), a monodesmosidic saponin isolated from paris, dioscorea, and costacea species with promising cardiovascular and antitumor activities, was synthesized by stepwise glycosylation.     

Potential bioreductively activated hypoxia probes and post-irradiation radiosensitizers related to NITP

NITP (1) is an effective marker of hypoxia in tumours for both microscopy and cell sorting studies and, additionally, the compound shows post-irradiation sensitization, probably by inhibition of repair of radiation damage to DNA. However, NITP does not have the substitution pattern which the immunochemical reagents are raised to recognize and the compound has very low solubility in water. We report the synthesis of an isomer (13) of NITP which has the desirable substitution pattern and is also soluble in very weak aqueous base. The successful synthesis of 13 uses a nitrosation and cyclization of a substituted uracil (16), but earlier approaches from 5 and 12 yielded the pyridoxanthine derivative 6. The preparative use of nitro group displacement reactions from 8-nitrocaffeine is shown to be a useful entry to a range of 8-substituted caffeines and is utilized to obtain two derivatives of NITP which carry aliphatic amine chains, i.e. 34 and 35.     

Treatment of cutaneous Bowen's disease with particular emphasis on the problem of lower leg lesions

Bowen's disease has a particular predilection for the lower leg, especially in women. A review of the literature for treating Bowen's disease is presented and the problems associated with treating the lower leg emphasized. Evidence for the various treatment modalities used to treat Bowen's disease largely comes from studies that lack good methodology in terms of standardized techniques, patient controls and adequate follow-up. In particular the widely accepted recommendation for excision is not supported by evidence that this treatment is superior to other modalities. The choice of treatment for Bowen's disease should take into account the patient's general condition, the site and size of the lesion.     

Tumor cell cytotoxicity of a novel metal chelator

We have synthesized a novel six-coordinate metal chelator from the triamine cis-1,3,5-triaminocyclohexane by the addition of a 2-pyridylmethyl pendant arm on each nitrogen, which we term tachpyr. The experiments described here were designed to explore whether this compound exhibits potential antitumor activity. When added to MBT2 or T24 cultured bladder cancer cells, tachpyr was profoundly cytotoxic, with an IC50 of approximately 4.6 micromol/L compared with 70 micromol/L for desferioxamine. To explore the mode of action of tachpyr, several metal complexes were prepared, including Fe(II), Ca(II), Mn(II), Mg(II), Cu(II), and Zn(II) tachpyr complexes. Of these, the Zn(II), Cu(II), and Fe(II) complexes were without toxic effect, whereas the Ca(II), Mn(II), and Mg(II) complexes remained cytotoxic. To further probe the role of Zn(II) and Cu(II) chelation in the cytotoxicity of tachpyr, sterically hindered tachpyr derivatives were prepared through N-alkylation of tachpyr. These derivatives were unable to strongly bind Fe(III) or Fe(II) but were able to bind Zn(II) and Cu(II). When added to cells, these sterically hindered tachpyr derivatives were nontoxic, consistent with a role of iron depletion in the cytotoxic mechanism of tachpyr. Further, the addition of tachpyr to proliferating cultures resulted in an early and selective inhibition of ferritin synthesis, an iron storage protein whose translation is critically dependent on intracellular iron pools. Taken together, these experiments suggest that tachpyr is a cytotoxic metal chelator that targets intracellular iron, and that the use of tachpyr in cancer therapy deserves further exploration.     

Detection of optic disc changes with Glaucoma-Scope probability maps

Before use of cardiovascular surgical techniques and procedures in humans, many experiments, e.g., hypothermic circulatory arrest and cardiopulmonary bypass using the heart-lung machine, have been performed in the dog. As a consequence experimental canine cardiovascular surgery is highly developed. This has not resulted in the routine performance of open heart surgery in veterinary medicine, probably because of the high costs. Cardiovascular surgery in the dog is generally limited to interventions not depending on hypothermic circulatory arrest or cardiopulmonary bypass. The clinical cardiovascular surgery in dogs can be divided into routine and more specialized interventions. The first category includes correction of peritoneopericardial diaphragmatic hernia, pericardial fenestration in dogs with pericardial effusion, treatment of persistent right aortic arch, and patent ductus closure. The specialized interventions include dilation of pulmonic and aortic stenoses and pacemaker implantation. The diagnosis and surgical treatment of such diseases is described. New developments in cardiovascular surgical treatment that can be expected include catheter techniques for occlusion of shunts and dilations using balloons, because the financial costs of these procedures are not prohibitive.     

Re-accreditation, re-certification and the postgraduate database

Anemia associated with ACE inhibitors is rare but it may cause problems especially in patients with renal disease. This study assessed the acute effect of trandolapril, an ACE inhibitor, on serum erythropoietin (EPO) levels in uremic and hypertensive patients. Trandolapril 2 mg/day was given orally for three days and blood samples were collected on the first and third day. Trandolapril led to a significant decrease in serum EPO in patients with chronic renal failure. Although the drug lowered serum EPO in hypertensive patients, this effect was not statistically significant. This drop in serum EPO levels may be one of the mechanisms by which ACE inhibitors cause anemia, or worsen anemia, in uremic patients and further studies are needed to clarify this point.     

Synthesis and biological activities of phenyl piperazine-based peptidomimetic growth hormone secretagogues

A new class of potent, orally active phenyl piperazine-based GH secretagogues have been discovered from attempts to mimic the arrangement of the phenyl substituent in the spiroindanyl piperidine and spiroindoline sulfonamide privileged structures of 4 and 1, respectively. The best of these compounds, 18 (EC50 = 2.8 nM) is nearly as potent as MK-0677 for releasing GH from rat pituitary cells.     

Identification and characterization of human metabolites of CAI [5-amino-1-1(4''-chlorobenzoyl-3,5-dichlorobenzyl)-1,2,3-triazole- 4-carboxamide)

BACKGROUND: Bronchoscopic bronchoalveolar lavage in children to investigate bronchial disorders such as asthma has both ethical and procedural difficulties. OBJECTIVE: The aim of this study was to establish a standardized non-bronchoscopic method to perform bronchoalveolar lavage in children attending for elective surgery to obtain normal cellular data. METHODS: Bronchoalveolar lavage was performed on normal children (n = 55) by infusing saline (20 mL) through an 8 FG suction catheter passed after endotracheal intubation. Oxygen saturation, heart and respiratory rate were monitored during the bronchoalveolar lavage procedure. Cellular analysis and total protein estimation of the lavage fluid were performed. Epithelial lining fluid volume was calculated (n = 15) using the urea dilution method. RESULTS: The procedure was well tolerated by all children. Total cell count and differential cell count for children (macrophages 70.8 +/- 2.3%, lymphocytes 3.8 +/- 0.6%, neutrophils 5.7 +/- 1.0%, eosinophils 0.14 +/- 0.03%, epithelial cells 19.6 +/- 2.1%, mast cells 0.21 +/- 0.02%) were similar to those reported for adults. Age and sex comparisons revealed no differences between groups. The mean total protein recovered in the cell free supernatant was 49.72 +/- 4.29 mg/L and epithelial lining fluid volume was 0.82 +/- 0.11% of return lavageate. CONCLUSION: This method allows bronchoalveolar lavage to be performed safely and quickly on children attending for routine elective surgery. Using this method and taking the 'window of opportunity' of elective surgery, the presence or absence of airway inflammation could be studied in children with various patterns of asthma during relatively asymptomatic periods.