Crystallization and preliminary X-ray diffraction studies on a soluble Escherichia coli quinone oxidoreductase

Single crystals suitable for X-ray diffraction studies have been obtained from a soluble Escherichia coli NAD(P)H-dependent quinone oxidoreductase (QOR) of molecular mass 35 kDa. Crystals were grown by the vapour diffusion method in the presence of NADPH and diffract strongly to beyond 2.0 A. The space group was determined to be P2(1)2(1)2(1) with unit cell dimensions of a = 107.44 A, b = 104.06 A, c = 77.45 A. There is one dimer in the asymmetric unit.     

Phase II study of liarozole in advanced non-small cell lung cancer

The aim of this phase II study was to investigate the efficacy and tolerability of liarozole, a novel benzimidazole derivative, in non-small cell lung cancer (NSCLC). Liarozole 300 mg twice daily orally was evaluated in 14 patients with stage IIIB and IV NSCLC. 8 patients had received prior treatment with chemotherapy and/or radiotherapy. WHO toxicity grading and response criteria were used. Liarozole was well tolerated. Grade 2 toxicities included alopecia (1 patient), dermatological toxicity (5 patients), dry mouth (2 patients) and nausea and vomiting (2 patients). Leukocytosis was seen in 5 patients, including 2 cases with an elevated white cell count pretreatment. Liarozole was discontinued in 1 patient who developed intolerable progressive pruritus associated with an erythematous rash. No objective tumour response was seen, all 14 patients developing progressive disease within 4 months of commencing treatment. Liarozole was well tolerated but was ineffective as single agent therapy in the management of NSCLC. The side-effect profile was compatible with inhibition of retinoic acid degradation.     

Stereoselective interaction of the azole antifungal agent SCH39304 with the cytochrome P-450 monooxygenase system isolated from Cryptococcus neoformans

We investigated the stereoselective inhibition of growth and ergosterol biosynthesis by SCH39304 in the pathogenic fungus Cryptococcus neoformans obtained from four AIDS patients who failed fluconazole therapy and compared the results to those obtained with a wild-type strain. For all strains, the MICs of the RR isomer were approximately half those of the racemate, with the SS enantiomer showing no inhibitory activity. The 50% inhibitory concentrations for in vitro ergosterol biosynthesis correlated with the MIC data, indicating stereoselective inhibition of their target P-450 enzyme, sterol 14alpha-demethylase, as the cause of this difference. The RR enantiomer produced classical type II spectra on addition to microsomal extracts of the strains, whereas the SS enantiomer showed an absence of binding. Stereo- and regio-specific localization of N-1 substituent groups of SCH39304 within the active site of the enzyme determined the unique discrimination between its two enantiomers, and the inability to bind to sterol 14alpha-demethylase is also true of other P-450 enzymes contained in the microsomal fraction. As previously observed for other antifungal azoles, isolates obtained following failure of fluconazole therapy showed resistance to SCH39304 and its RR enantiomer. This resistance could be associated with an alteration in the sensitivity of ergosterol biosynthesis in vitro. These alterations did not cause any changes allowing the SS enantiomer to bind to the P-450 mediating sterol 14alpha-demethylation.     

Computed axial tomography tandem and ovoids (CATTO) dosimetry: three-dimensional assessment of bladder and rectal doses

The purpose of this work is to compare bladder and rectal dose rates in brachytherapy for carcinoma of the cervix using two different dosimetry systems: traditional orthogonal radiograph-based dosimetry vs. computed axial tomography tandem and ovoids (CATTO) dosimetry. Twenty-two patients with carcinoma of the uterine cervix received the brachytherapy component of their radiotherapy with a computed-tomography compatible Fletcher-Suit-Delclos device. A total of 27 implants were performed. The average maximum bladder dose (Bmax) for the implants was 85.8 cGy/hr using the CATTO system as compared to 42.6 cGy/hr using traditional dosimetry, (P < 0.005). The average maximum rectal dose (R.) using the CATTO system was 59.2 cGy/hr as compared with 46.3 cGy/hr using the traditional system (P < 0.05). The traditional methods for choosing points to determine bladder and rectal dose rates underestimated the true Bmax in all cases and the R. in most. Based on the complication rates published in the literature, it is likely that the maximum tolerance dose of both the rectum and bladder, but especially the bladder, is higher than previously thought.     

Autocrine actions of endothelin-1 as a growth factor in human ovarian carcinoma cells

The production of endothelin 1 (ET-1) and its receptor-mediated actions on calcium signaling and growth responses were analyzed in human ovarian carcinoma cells. Immuno-reactive ET-1 was released from three of four ovarian tumor cell lines as a function of time in amounts ranging from 56 to 74 fmol/10(6) cells. Reverse-phase HPLC and radioimmuno-assay of conditioned media from tumor cells revealed a single peak coeluting with authentic ET-1. Radioligand binding studies showed that the ET-1-producing cell lines also expressed high-affinity ETA receptors (Kd < 0.1 nM) that ranged in abundance from 2,600 to 43,600 sites/cell. In fura-2-loaded ovarian carcinoma cells, ET-1 induced dose-dependent increases in cytoplasmic Ca2+ concentration. ET-1 also stimulated thymidine incorporation in the three cell lines that expressed ET receptors. In OVCA 433 cells, BQ 123 inhibited the stimulatory actions of ET-1 on thymidine incorporation and cell proliferation, and substantially reduced the basal growth rate of unstimulated ovarian tumor cells. These results demonstrate that ET-1 is produced in ovarian cancer cells and acts as an autocrine growth factor on ETA receptors to stimulate calcium signaling and proliferative responses. Such findings suggest that ET-1 participates in the progression of neoplastic growth in certain ovarian tumors.     

Experimental fetal transesophageal and intracardiac echocardiography utilizing intravascular ultrasound technology

The effects of epidural fentanyl on the incidence of maternal hypoxaemia during labour and on neonatal welfare were examined. Women were randomly allocated to receive one of two epidural infusions, bupivacaine 0.125% alone or bupivacaine 0.0625% with 2.5 micrograms.ml-1 fentanyl, and maternal arterial oxygen saturation was monitored continuously until delivery. The median incidence of desaturation (SpO2 < 95%) during the active phase of the second stage of labour was significantly greater in the fentanyl group than in controls (2.9 versus 0.6 min.h-1, p = 0.02). Similarly, the incidence of desaturation to SpO2 < or = 90% was greater in the fentanyl group than in controls (p = 0.02). There was no correlation between maternal oxygenation or plasma fentanyl concentration and neonatal welfare as measured by umbilical arterial and venous blood gas and acid base status, Apgar score and Neurologic and Adaptive Capacity Score.     

Synthesis and antimycobacterial activity of nitroxanthones. 2nd communication: antimycobacterial activity

Prevention of intraoperative blood loss during liver resection is of prime concern. Intraoperative blood loss has indeed repeatedly been shown to adversely influence the short-term prognosis of patients undergoing liver resection. There is in addition evidence that it could be associated with an increased risk; of recurrence in patients operated for an hepato-biliary malignancy through impairment of the patient's immune response. The prime concern of the hepato-biliary surgeon is to minimize blood loss through the control of the major vascular structures this may be achieved in several ways that range from segmental portal control to total hepatic vascular occlusion. The type of vascular occlusion should be selected according to the indication and in particular location of the tumour and presence of an associated underlying liver disease, the patient's cardiovascular status and the experience of the operator. Aim of the authors is to describe the various types of vascular control as well as their benefits and drawbacks so as to use the most appropriate technique according, to each patient' requirements.     

Vertebral artery injury during anterior decompression of the cervical spine. A retrospective review of ten patients

Ten patients who suffered iatrogenic injury to a vertebral artery during anterior cervical decompression were reviewed to assess the mechanisms of injury, their operative management, and the subsequent outcome. All had been undergoing a partial vertebral body resection for spondylitic radiculopathy or myelopathy (4), tumour (2), ossification of the posterior longitudinal ligament (1), nonunion of a fracture (2), or osteomyelitis (1). The use of an air drill had been responsible for most injuries. The final control of haemorrhage had been by tamponade (3), direct exposure and electrocoagulation (1), transosseous suture (2), open suture (1), or open placement of a haemostatic clip (3). Five patients had postoperative neurological deficits, but most of them resolved. We found direct arterial exposure and control to be safe, quick and reliable. Careful use of the air drill, particularly in pathologically weakened bone, as in infection or tumour, is essential. Arterial injury is best avoided by a thorough knowledge of the anatomical relationships of the artery, the spinal canal, and the vertebral body.