Destruction of WiDr multicellular tumor spheroids with the novel thymidylate synthase inhibitor 1843U89 at physiological thymidine concentrations

The activity of a novel thymidylate synthase inhibitor, 1843U89, against WiDr human colon carcinoma multicellular tumor spheroids was investigated. Continuous exposure of the spheroids to 3 nM 1843U89 for 10 days resulted in spheroid disruption, whereas 100 nM methotrexate (MTX) was required for similar effects. Short-term treatment experiments demonstrated that a 3-day exposure to 100 nM 1843U89 caused spheroid disruption 9 days after drug removal. A 4-day exposure to 10 nM 1843U89 caused spheroid disruption 8 days after drug removal. In contrast, treatment with 10 or 100 nM 1843U89 for 6–48 h or treatment with 1 nM 1843U89 for up to 5 days caused only growth delay. Continuous exposure of spheroids to 30 nM 1843U89 in the presence of 0.05–0.3 M thymidine was as effective in causing spheroid disruption as treatment in the absence of thymidine, but treatment in the presence of 0.7–3.0 M thymidine caused partial reversal of spheroid disruption. The results of these experiments suggest that 1843U89 should have potent solid tumor activity in humans but should be less effective in mice due to differences in circulating thymidine levels (0.1 vs 1 M, respectively).     

MR line scan diffusion imaging of the brain in children

BACKGROUND AND PURPOSE: MR imaging of the self-diffusion of water has become increasingly popular for the early detection of cerebral infarction in adults. The purpose of this study was to evaluate MR line scan diffusion imaging (LSDI) of the brain in children. METHODS: LSDI was performed in four volunteers and 12 patients by using an effective TR/TE of 2736/89.4 and a maximum b value of 450 to 600 s/mm2 applied in the x, y, and z directions. In the volunteers, single-shot echo planar imaging of diffusion (EPID) was also performed. The patients (10 boys and two girls) ranged in age from 2 days to 16 years (average age, 6.6 years). Diagnoses included acute cerebral infarction, seizure disorder, posttraumatic confusion syndrome, complicated migraine, residual astrocytoma, encephalitis, hypoxia without cerebral infarction, cerebral contusion, and conversion disorder. In all patients, routine spin-echo images were also acquired. Trace images and apparent diffusion coefficient maps were produced for each location scanned with LSDI. RESULTS: In the volunteers, LSDI showed less chemical-shift and magnetic-susceptibility artifact and less geometric distortion than did EPID. LSDI was of diagnostic quality in all studies. Diffusion abnormalities were present in five patients. Restricted diffusion was present in the lesions of the three patients with acute cerebral infarction. Mildly increased diffusion was present in the lesions of encephalitis and residual cerebellar astrocytoma. No diffusion abnormalities were seen in the remaining seven children. CONCLUSION: LSDI is feasible in children, provides high-quality diffusion images with less chemical-shift and magnetic-susceptibility artifact and less geometric distortion than does EPID, and complements the routine MR examination.     

Genitourinary surgery and Arthur Jacobs: father of urology in Glasgow

Arthur Jacobs (1899-1974) was the father of urology in Glasgow. His extensive experience with genitourinary tuberculosis, ureterosigmoidostomy, and bladder augmentation were far ahead of his time. He became an expert in retropubic prostatectomy and was a pioneer in early imaging techniques.     

Antitumour prodrug development using cytochrome P450 (CYP) mediated activation

An ideal cancer chemotherapeutic prodrug is completely inactive until metabolized by a tumour-specific enzyme, or by an enzyme that is only metabolically competent towards the prodrug under physiological conditions unique to the tumour. Human cancers, including colon, breast, lung, liver, kidney and prostate, are known to express cytochrome P450 (CYP) isoforms including 3A and 1A subfamily members. This raises the possibility that tumour CYP isoforms could be a focus for tumour-specific prodrug activation. Several approaches are reviewed, including identification of prodrugs activated by tumour-specific polymorphic CYPs, use of CYP-gene directed enzyme prodrug therapy and CYPs acting as reductases in hypoxic tumour regions. The last approach is best exemplified by AQ4N, a chemotherapeutic prodrug that is bioreductively activated by CYP3A. This study shows that freshly isolated murine T50/80 mammary carcinoma and RIF-1 fibrosarcoma 4-electron reduces AQ4N to its cytotoxic metabolite, AQ4 (T50/80 Km = 26.7 microM, Vmax = 0.43 microM/mg protein/min; RIF-1 Km = 33.5 microM, Vmax = 0.42 microM/mg protein/min) via AQM, a mono-N-oxide intermediate (T50/80 Km = 37.5 microM; Vmax = 1.4 microM/mg protein/min; RIF-1 Km = 37.5 microM; Vmax = 1.2 microM/mg protein/ min). The prodrug conversion was dependent on NADPH and inhibited by air or carbon monoxide. Cyp3A mRNA and protein were both present in T50/80 carcinoma grown in vivo (RIF-1 not measured). Exposure of isolated tumour cells to anoxia (2 h) immediately after tumour excision increased cyp3A protein 2-3-fold over a 12 h period, after which time the cyp protein levels returned to the level found under aerobic conditions. Conversely, cyp3A mRNA expression showed an initial 3-fold decrease under both oxic and anoxic conditions; this returned to near basal levels after 8-24 h. These results suggest that cyp3A protein is stabilized in the absence of air, despite a decrease in cyp3A mRNA. Such a 'stabilization factor' may decrease cyp3A protein turnover without affecting the translation efficiency of cyp3A mRNA. Confirmation of the CYP activation of AQ4N bioreduction was shown with human lymphoblastoid cell microsomes transfected with CYP3A4, but not those transfected with CYP2B6 or cytochrome P450 reductase. AQ4N is also reduced to AQ4 in NADPH-fortified human renal cell carcinoma (Km = 4 microM, Vmax = 3.5 pmol/mg protein/min) and normal kidney (Km = 4 microM, Vmax = 4.0 pmol/mg protein/min), both previously shown to express CYP3A. Germane to the clinical potential of AQ4N is that although both normal and tumour cells are capable of reducing AQ4N to its cytotoxic species, the process requires low oxygen conditions. Hence, AQ4N metabolism should be restricted to hypoxic tumour cells. The isoform selectivity of AQ4N reduction, in addition to its air sensitivity, indicates that AQ4N haem coordination and subsequent oxygen atom transfer from the active-site-bound AQ4N is the likely mechanism of N-oxide reduction. The apparent increase in CYP3A expression under hypoxia makes this a particularly interesting application of CYPs for tumour-specific prodrug activation.     

Human eosinophil major basic protein augments bronchoconstriction induced by intravenous agonists in guinea pigs

The direct effect of intratracheal (IT) administration of human major basic protein (MBP) on pulmonary inspiratory pressure (PIP), and the effect on agonist-induced change in PIP, were determined in anesthetized, ventilated guinea pigs. 500 g MBP increased PIP from 24.1±4.3 to 49.8±7.4 cm H₂O (p<>n=10). Maximum PIP was achieved within 30 min after 500 g MBP. The direct PIP response to 250 g MBP was not different from vehicle. The PIP responses to intravenous (IV) acetylcholine (Ach) and 5-hydroxytryptamine (5-HT) were measured before and after administration of 250 g MBP (n=12). MBP caused a modest, but significant potentiation of the increase in PIP induced by 1, 3 and 10 g/kg Ach (24, 32 and 28%, respectively,p<0.02) and=" to=" 1=">g/kg 5-HT (43%p<0.02). we=" conclude=" that=" mbp=" at=" a=" dose=" that=" does=" not=" directly=" affect=" inspiratory=" pressure=" is=" capable=" of=" augmenting=" the=" pip=" response=" to=" iv=" ach=" and=">in vivo.     

Quality assurance in a children's psychiatric hospital

The use of short-term isolation (STI) in a children's psychiatric hospital was examined using the Joint Commission on Accreditation of Hospitals (JCAH) quality assurance mode. A Clinical Care Evaluation addressed two questions: Are we providing quality use of STI? And are we adequately documenting its use? A medical record audit of 78 discharged patients and a review of unit records provided hospital staff with utilization and demographic statistics; structured interviews with staff and inpatients were conducted that provided information about their opinions of STI. The data gathered served as the basis for recommendations that led to planned, informed program changes.     

Probability summation and regional variation in contrast sensitivity across the visual field

Contrast sensitivity at different positions in the visual field has been measured at various spatial frequencies using a patch of grating suitably vignetted to give a stimulus localized in both space and spatial frequency. While contrast sensitivity along a vertical line through the fixation point falls off steadily from a maximum at the centre, sensitivity along a horizontal line displaced 42 periods of the grating above the fixation point is approximately constant, at least out to 32 periods from the mid-line. The way in which detectability increases with increasing number of cycles (2 up to 64) has been measured for gratings with short horizontal bars centred on the fixation point and for gratings with short vertical bars centred on the mid-line 42 periods above it. The relation between sensitivity and number of cycles can in each case be explained exactly assuming probability summation across space as long as the variation in sensitivity across the visual field is taken into account.     

Recruit,screen, and hire: Staff selection and the decision-making process

This article focuses on the role of the clinician-manager in staff selection. The duties of the clinician-manager in a mental health center include those tasks described as recruit, screen, and hire but little or no guidance on the steps involved in this sequence of events is available. The how of hiring is transmitted by word of mouth, by following another's example, or by trial and error. This article examines the component parts of staff selection from the assimilation of procedures, rules, and regulation of the public authority under which a particular mental health center operates, to the compilation of a short list of those to be screened and finally the risk taking and decision-making process by the clinician-manager who makes the choice. Some speculation on the emotional impact it has on the clinician-manager is examined. The impact of personal value judgments of the selector are considered. Recommendations are made for the inclusion of training in staff selection by academic programs for mental health administrators.Sheila Melville, A.C.S.W., is the Director, Partial Hospitalization, Mt. Vernon Center for Community Mental Health, 8119 Holland Road, Alexandria, Virginia 22306.     

Utilization of acute inpatient psychiatric services: “Heavy users” in New York State

The severely and persistently mentally ill (SPMI) population are often forced to rely on emergency/acute inpatient services. The authors analyze Medicaid expenditures and state hospital utilization data to identify and describe the characteristics of heavy users of these services. Also described is New York State's intensive case management (ICM) initiative targeted at this heavy user group. It is postulated that ICM will alter the utilization patterns of participants from over-reliance on the most costly services and more effectively and efficiently serve the SPMI population, specifically the heavy user subpopulation.     

Smoking and catecholamine and c-AMP concentrations in the coronary circulation of man and the effect of oxprenolol

Summary Changes in catecholamine, c-AMP and lactate concentrations in the coronary circulation of man, during smoking, were studied in 12 patients. The heart rate increased from 63±2 beats/min (control) to 74±3 (smoking) (P<0.01), falling to 70±2 (10 min after smoking) (0.05>P>0.01), whilst coronary sinus c-AMP concentrations rose from 11±0.7 nmol/l (smoking) to 11.9±0.8 nmol/l (after smoing) (0.05>P>0.01; one tailed t test). There was no significant change in blood pressure, catecholamine or lactate concentrations. The study was repeated in eight of the patients following intravenous oxprenolol. Coronary sinus catecholamine concentrations increased from 4.1±0.7 nmol/l (control) to 5.5±1.1 nmol/l (after smoking) (0.05>P>0.01; one tailed t test), but heart rate and c-AMP concentrations remained unchanged, confirming that smoking-induced tachycardia is a result of a -adrenergic mechanism, at least part of which is due to a release of cardiac catecholamines. Arterial lactate concentrations increased only following oxprenolol from 0.74±0.07 mmol/l (control) to 0.83±0.09 mmol/l (smoking).