New developments in the pharmacotherapy of inflammatory bowel disease.

In this article the clinical features and aetiology of inflammatory bowel diseases are described and current pharmacotherapeutic possibilities are explored. Also reviewed are recent developments and future prospects for the pharmacotherapy of inflammatory bowel diseases, including aminosalicylates, corticosteroids, immunosuppressants, lipoxygenase inhibitors, fish oil, sucralfate, bismuth compounds, free radical scavengers, (hydroxy)chloroquine, sodium cromoglycate and methotrexate.


Catecholamines in critical care. The commonly used catecholamines: receptor and clinical profile, indications and dosages.

The pharmacology, pattern of receptor activation and resulting clinical impact of the currently most widely used intravenous catecholamines are reviewed. A brief physiological description of the alpha, beta and dopaminergic receptors is used in order to explain the clinical effects of norepinephrine, epinephrine, isoproterenol, dopamine, dobutamine and dopexamine. Each drug is discussed separately according to receptor profile, indications, dosages and current application in critical care. Tables are provided for comparison of relative strengths of these drugs regarding receptor activation, haemodynamic effects, organ perfusion and recommended dosages. The use of combinations of catecholamines to meet a variety of circulatory demands is commented upon.


Didanosine, a new antiretroviral drug. A review.

In this article the literature about didanosine, an antiretroviral drug, is reviewed. The mechanism of action, biochemical pharmacology, pharmacokinetics, and clinical results of phase-I trials are discussed. Serious adverse effects such as pancreatitis and peripheral neuropathy have occurred in these trials. An antiretroviral effect was observed in terms of an increase in CD4+ lymphocytes and a decrease in p24 antigen levels in HIV-infected individuals. Didanosine seems to be a promising drug against HIV infection, but knowledge about its clinical efficacy is scanty.


Drug transport across the blood--brain barrier. I. Anatomical and physiological aspects.

This review describes various aspects of the transport of drugs across the blood-brain barrier and comprises three parts. In this first part, the anatomical and physiological aspects of blood-brain transport are discussed. It appears that the blood-brain barrier has an anatomical basis at the endothelium of the capillary wall. This endothelium is characterized by the presence of very tight junctions. As a result, the transport by passive diffusion of drugs with a low lipophilicity, is restricted. For certain classes of closely related relatively hydrophilic compounds, however, the presence of specialized carrier systems has been demonstrated which may facilitate transport. Also evidence is presently available, that the permeability of the blood-brain barrier may be under active regulatory control. It is expected that improved knowledge of the anatomical and physiological aspects of the blood-brain barrier and its regulation will provide a scientific basis for the development of strategies to improve the transport of drugs into the central nervous system.


The comprehensiveness of Medline and Embase computer searches. Searches for controlled trials of homoeopathy, ascorbic acid for common cold and ginkgo biloba for cerebral insufficiency and intermittent claudication.

To assess the comprehensiveness of Medline and Embase computer searches for controlled trials. Comparison of articles found after an exhaustive search of the literature with the yield of a Medline or Embase search. This was performed for controlled clinical trials on the efficacy of three interventions: homoeopathy, ascorbic acid for common cold, and ginkgo biloba for intermittent claudication and cerebral insufficiency. The number of controlled trials found by exhaustive search of the literature was 107, 61 and 45, respectively. For homoeopathy, ascorbic acid and ginkgo the proportion of all trials found by Medline was 17%, 36% and 31% respectively and for Embase 13%, 25% and 58% respectively. After checking of the references in the Medline articles 44%, 79% and 76% of all trials were identified. After checking of the references in the Embase articles 42%, 72% and 93% of all trials were identified. About 20% of the articles was not correctly indexed. Of the best trials 68%, 91% and 83% could be found with Medline and 55%, 82% and 92% of the best trials were identified through Embase. For the topics mentioned, Medline and Embase searches are sufficient to get an impression of the evidence from controlled trials, but only if references in the articles are followed for further evidence. If one wants to get a more complete picture, additional search strategies make sense. Of course, this picture may be different for other topics.


Assessment of trace element compatibility in total parenteral nutrition infusions.

The application of X-ray energy dispersive spectroscopy to detect elements collected from TPN mixtures on membrane filters has been investigated. Many simple total parenteral nutrition mixtures prepared aseptically in large bags can be stored for extended periods. Trace elements are normally excluded from such bags, because not enough is known about their long-term stability and compatibility in total parenteral nutrition mixtures. Assessing the compatibility of many trace elements by conventional methods that rely on detecting concentration changes is extremely difficult. Analysis of precipitates from total parenteral nutrition mixtures confirmed that the proposed method was capable of identifying a number of elements from the mixture in complex precipitates, including calcium, phosphorus, iron, copper and selenium.


Capacity-limited renal glucuronidation of probenecid by humans. A pilot Vmax-finding study.

Probenecid shows dose-dependent pharmacokinetics. When in one volunteer the dose is increased from 250 to 1,500 mg orally, the t1/2 increased from 3 to 6 h. The Cmax was 14 micrograms/ml with a dosage of 250 mg, 31 micrograms/ml with 500 mg, 70 micrograms/ml with 1,000 mg and 120 micrograms/ml with 1,500 mg. The tmax remained 1 h for all four dosages. The AUC/dose ratio increased with the dose, indicating nonlinear elimination. The total body clearance declined from 64.5 ml/min for 250 mg to 26.0 ml/min for 1,500 mg. The renal clearance of probenecid remained constant, 0.6-0.8 ml/min. Protein binding of probenecid is high (91%) and independent of the dose. The phase I metabolites show lower protein binding values (34-59%). The protein binding of probenecid glucuronide in vitro (spiked plasma) is 75%. Probenecid is metabolized by cytochrome P-450 to three phase I metabolites. Each of the metabolites accounts for less than 10% of the dose administered; the percentage recovered in the urine is independent of the dose. The main metabolite probenecid glucuronide is only present in urine and not in plasma. The renal excretion rate--time profile of probenecid glucuronide shows a plateau value of approximately 700 micrograms/min (46 mg/h) with acidic urine pH. The duration of this plateau value depends on the dose: 2 h at 500 mg, 10 h at 1,000 mg and 20 h at 1,500 mg. It is demonstrated that probenecid glucuronide must be formed in the kidney during its passage of the tubule. The plateau value in the renal excretion rate of probenecid value reflects its Vmax of formation.


Intramembrane charge movement in developing skeletal muscle cells from fetal mice.

The development of intramembrane charge movement was studied in freshly isolated skeletal muscle cells from 13- to 19-day-old mouse fetuses. Charge movement was present in myotubes from 13-day-old fetuses. The relationship between charge movement and membrane potential could be described by a two-state Boltzmann equation. The amount of maximum charge movement (Qmax) increased substantially with the age of the fetuses from 2.84 +/- 0.39 nC/microF (n = 10) at day 13 to 10.01 +/- 0.97 nC/microF (n = 15) at day 19. Nifedipine (1 microM) consistently reduced Qmax by 33 +/- 2% (n = 37) of the control value at each age studied. Increasing the concentration of nifedipine to 20 microM had no further effect, suggesting that the charge movement in developing myotubes consists of at least two components: a nifedipine-sensitive charge movement (Qns) and a nifedipine-resistant one (Qnr). Both Qns and Qnr increased exponentially with a distinct enhancement of rate at day 16.


Estimating transit time for capillary blood in selected muscles of exercising animals.

The mean minimal capillary transit time was estimated in muscles of various animals using a combination of physiological and morphometric methods. Radioactive microspheres were injected intravascularly in various animals running on a treadmill at maximum oxygen consumption rate (VO2,max) to label blood flow to individual muscles. The muscles were then removed and preserved by standard methods for electron microscopy. The volume density of mitochondria was measured to assess muscle oxidative capacity. Capillary densities in muscle cross-sections, capillary diameters and tortuosities were incorporated into an estimate of capillary volume per unit muscle mass. Mean capillary transit time (tc) in the exercising muscles was estimated by dividing mass-specific capillary volume by mass-specific blood flow. Estimates of tc ranged from values near 1 s in horse heart and thigh muscles to 0.2 s in duck gastrocnemius. The relationship between muscle blood flow and tc was hyperbolic. The experimental data indicate a limiting value of 0.2 s for transit times at very high blood flows. There was no correlation between tc and body-mass-specific VO2,max.


The reflex effect of changes in renal perfusion on hindlimb vascular resistance in anaesthetized rabbits.

This study was designed to characterise the response of the hindlimb vasculature to reduced renal perfusion in the anaesthetized rabbit and to elucidate whether the stimulus was dependent upon reduced renal perfusion pressure (RPP) or blood flow (RBF). Acute decreases in renal perfusion resulted in rapid and reversible increases in femoral perfusion (FPP). This vascular response was completely abolished following renal denervation indicating that the afferent components of the reflex is neurally mediated. Acute hindlimb responses to changes in renal perfusion pressure were present whether the limb was perfused with homologous blood or cross-perfused with blood from a donor rabbit, demonstrating that the efferent component of the response is also neurally mediated. There was a 28-s latency for initiation of the hindlimb vasoconstriction, which is consistent with recent evidence for renal autocoid stimulation of the afferent renal nerve receptors. Decreasing RPP indirectly, by altering flow, resulted in a hindlimb vasoconstriction below approximately 55 mm Hg (7.3 kPa) RPP or 15 ml/min RBF. However, decreasing RPP by directly reducing pressure in graded steps resulted in increases in FPP, which reflected the changes in renal flow; thus during the autoregulatory phase, where flow did not change as pressure fell, FPP also remained stable. The results of these protocols suggest that a neurally mediated hindlimb vascular reflex is stimulated by decreased renal flow rather than pressure.


Membrane conductance and cell volume changes evoked by vasoactive intestinal polypeptide and carbachol in small intestinal crypts.

We have used the perforated-patch whole-cell recording mode of the patch-clamp technique to monitor membrane potential and measured cell volume changes by image analysis, to determine the nature of the response to secretagogues of isolated whole guinea-pig small-intestinal crypts. Vasoactive intestinal polypeptide (VIP) produced a dose-dependent depolarisation (EC50 = 30 nM) and an increase in membrane conductance that could be potentiated by carbachol. Similar depolarisations were observed with forskolin. The depolarisation induced by 100 nM VIP was smaller when pipette [Cl-] was 60 mM than when it was 145 mM, suggesting an effect through Cl- conductance activation. Carbachol alone produced a hyperpolarisation (EC50 = 2 microM). The Cl- channel blocker 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) produced a small hyperpolarization. When VIP was added in the presence of NPPB, the depolarisation was observed instead, consistent with the parallel activation of a K+ conductance. Both carbachol (100 microM) and VIP (100 nM) induced a 25%-30% shrinkage of crypts, which was maximal 8 min after addition of the secretagogue. The induced shrinkage was sustained in the continued presence of agonist and was reversed upon washout. Shrinkage induced by the agonists was abolished by increasing extracellular K+ from 6 mM to 20 mM and was inhibited partially in the presence of 100 microM anthracene-9-carboxylic acid in the bath. The decrease in volume induced by 100 nM VIP was totally abolished in the presence of 100 microM NPPB. The results are consistent with the view that both VIP and carbachol induce secretion in small-intestinal crypts.


Contractile activation properties of ventricular myocardium from hypothyroid, euthyroid and juvenile rats.

Contractile activation properties of intact and chemically skinned ventricular myocardium preparations were studied in juvenile (3-4 weeks old), adult euthyroid and adult hypothyroid rats. The rats were made hyperthyroid by treatment with iodine-131 and propylthiouracil. The ventricular muscle of euthyroid rats contains a mixture of isozymes of myosin while the myocardium of juvenile and hypothyroid rats are relatively pure in regard to V1 and V3 types of myosin respectively. No significant differences were found in either the maximum Ca2+ activated or rigor force developed by "chemically skinned" preparations in either the juvenile or hypothyroid groups compared with euthyroid adults, suggesting that there is no difference between myocardia with different isozymes of myosin in the intrinsic capacity to generate force. In the hypothyroid (V3) preparations there was a significant shift in the force/pCa relation to the left compared with the euthyroid adult (mixture of V1 and V3 isozymes). The force/pCa relation for the juvenile lay in between that for the hypothyroid and euthyroid adults. The greater apparent Ca2+ sensitivity to activation in the hypothyroid group may relate to a slower cross-bridge cycling rate or altered Ca2+ kinetics in ventricular myocardium with exclusively V3 isozyme. In intact papillary muscles differences were found in the dependence of force on extracellular [Ca2+] such that a higher extracellular [Ca2+] was required for muscles from hypothyroid animals to attain maximum twitch force than those from juveniles. The force/frequency relations also differed, with the hypothyroid group being better able to sustain force as stimulation frequency increased than the juvenile group.(ABSTRACT TRUNCATED AT 250 WORDS)


The effects of intracellular and extracellular alkalinization on contractions of the isolated rat uterus.

The effects of changing pH on a spontaneously active smooth muscle, the myometrium, is examined. We show, for the first time in any smooth muscle, that the frequency of contraction is greatly increased when intracellular pH is raised. Three weak bases, trimethylamine, diethylamine and ammonium, were used to raise intracellular pH (pHi), at constant external pH, in isolated uteri of pregnant and non-pregnant rats. Each base increased spontaneous uterine contractile activity, particularly by raising the frequency, in a concentration-dependent manner. At the highest concentrations (40-50 mM) frequency was so increased that a maintained contraction resulted. Intracellular alkalinization during a high-K-maintained uterine contraction produced a small, but significant, fall in force. When external pH was increased, the results were greatly influenced by gestational state; in uteri from non-pregnant animals there was no effect whereas uteri from pregnant rats were found to be extremely sensitive to a raised external pH above 7.4; spontaneous contractions were reduced. In pregnant uteri, when both internal and external pH were elevated, spontaneous contractions were immediately reduced, thus the effects of external pH predominated. These findings may have significance in labour.


Intracellular Ca2+ signalling is modulated by K+ channel blockers in colonic epithelial cells (HT-29/B6).

We investigated the inhibitory action of K+ channel blockers on carbachol-stimulated Ca2+ entry into human Cl(-)-secretory colonic epithelial cells (HT-29/B6). Digital imaging of the fluorescent calcium indicator dye fura-2 was performed to monitor effects of K+ channel blockers on cytosolic calcium in resting and carbachol-stimulated HT-29/B6 cells. Stimulation with the muscarinic agonist carbachol (100 microM) caused a clearly biphasic intracellular calcium (Cai) response: Cai was stimulated from resting levels (85 +/- 3 nM, n = 100) to a sudden transient peak (821 +/- 44 nM) followed by a sustained plateau (317 +/- 12 nM). The maintained elevation was dependent on external Ca2+ and represented a new steady state between Ca2+ entry and exit across the plasma membrane. A monophasic Ca2+ response was induced in the absence of external Ca2+ and after the initial peak Cai returned to baseline. The Cai plateau was reduced to resting levels by either the muscarinic antagonist atropine (1 microM) or the inorganic Ca2+ channel blocker lanthanum (effective concentration for 50% inhibition of Cai plateau EC50 = 68 +/- 18 nM), but it was unaffected by the organic Ca2+ channel blockers verapamil and nifedipine. Barium, lidocaine and 4-nitro- 2-(3-phenylpropylamino)benzoate (NPPB), well-known blockers of basolateral K+ channels of HT-29/B6 cells, rapidly and reversibly reduced carbachol-stimulated Ca2+ entry.(ABSTRACT TRUNCATED AT 250 WORDS)


Acetazolamide inhibition of basolateral Cl-/HCO3- exchange in rabbit renal proximal tubule S3 segment.

Cell pH (pH(i)) and cell membrane potential (Vb) were measured in isolated S3 segments of rabbit renal proximal tubule with double-barrelled microelectrodes to search for a possible effect of the carbonic anhydrase inhibitor, acetazolamide (ACZ), on Cl-/HCO3- exchange in the basolateral cell membrane. ACZ was found to retard and reduce the pH(i) response to bath Cl- removal reversibly with half-maximal inhibition at 0.42 mmol/l and a rather flat concentration dependence (Hill coefficient approximately 0.36). To determine whether the retardation resulted from inhibition of cytoplasmic carbonic anhydrase, which might have delayed the attainment of HCO3-/CO2 equilibrium, we have measured the response of pH(i) to step changes in PCO2 in the presence and absence of ACZ. ACZ greatly retarded the pH(i) response to CO2 steps; however, the concentration dependence differed (half-maximal inhibition at 18 mumol/l) and even at maximal ACZ concentrations the response to CO2 steps was more than twice as fast as the response to Cl- replacement. Since, in addition, the ACZ inhibition of Cl-/HCO3- exchange could not be overcome by increasing PCO2 we conclude that the ACZ effect on Cl-/HCO3- exchange in rabbit proximal tubule S3 segments does not result from inhibition of cytosolic or membrane-bound carbonic anhydrase, but from a direct interaction with the exchanger molecule.


Acetazolamide inhibition of basolateral base exit in rabbit renal proximal tubule S2 segment.

The influence of the carbonic anhydrase inhibitor acetazolamide (ACZ) was investigated on HCO3- transport mechanisms in the basolateral cell membrane of rabbit renal proximal tubule. Experiments were performed on isolated S2 segments using double-barrelled microelectrodes to measure cell membrane potential (Vb) and cell pH (pH(i)) during step changes in bath perfusate ion concentrations. Peritubular application of ACZ (1 mmol/l) reduced the initial Vb response to 10:1 reduction of bath HCO3- concentration only slightly, from +53.8 +/- 4.2 mV to +49.1 +/- 0.3 mV (n = 5), but caused an intermittent overshooting repolarization in the secondary Vb response. In conjunction with these effects it left the initial pH(i)) response virtually unchanged but induced a secondary slow acidification. These observation indicate that--under the present experimental conditions--ACZ does not block the Na(+)-HCO3- cotransporter but acts via inhibition of cytosolic carbonic anhydrase. This was confirmed by studying the effect of elevated intracellular HCO3- concentrations under reduced flux conditions and by comparing the concentration dependence of the Vb response with the inhibition kinetics of cytosolic carbonic anhydrase. In contrast, peritubular ACZ inhibited Na(+)-independent Cl-/HCO3- exchange in the basolateral cell membrane of S2 segments directly in a similar way to that described in the preceding publication for S3 segments.


G-protein-mediated regulation of a Ca(2+)-dependent K+ channel in cultured vascular endothelial cells.

The purpose of the present study was to determine the mechanism by which bradykinin activates the small conductance, inwardly rectifying, Ca(2+)-activated K+ channel (KCa) found in cultured bovine aortic endothelial cells. Channel activity was studied using the patch-clamp technique in whole-cell, cell-attached, inside-out and outside-out configurations. Channel conductance at potentials positive to 0 mV was 10 +/- 2 pS and at potentials negative to 0 mV 30 +/- 3 pS (n = 7) when examined in symmetrical K+ (150 mmol/l) solutions. The channel open probability (P(o)) was only weakly voltage dependent changing approximately 0.2 units over 160 mV. In contrast, raising the intracellular Ca2+ concentration from 100 nmol/l to 10 mumol/l at -60 mV produced a graded increase in channel P(o) from 0.15 to 0.96; the concentration required for half-maximum response (apparent K0.5) was 719 nmol/l. At a constant Ca2+ concentration, application of guanosine triphosphate (GTP) to the cytoplasmic surface of the patch increased channel P(o). This effect was dependent upon the simultaneous presence of both GTP and Mg2+, and was reversed by the subsequent application of the guanosine diphosphate (GDP) analogue, guanosine-5'-O-(2-thiodiphosphate) (GDP beta S). The hydrolysis-resistant GTP analogue, guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S), induced a long-lasting increase in channel P(o). In the presence of Mg(2+)-GTP, the apparent K0.5 for Ca2+ decreased from a control value of 722 nmol/l to 231 nmol/l. Addition of bradykinin to outside-out patches previously exposed to intracellular Mg(2+)-GTP further enhanced KCa activity, shifting the apparent K0.5 for Ca2+ from 228 nmol/l to 107 nmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)


Activation of cationic amino acid transport through system y+ correlates with expression of the T-cell early antigen gene in human lymphocytes.

Lysine influx (2 microM) into activated human B and T lymphocytes through transport systems y+ and y+L was measured. In activated T cells very substantial activation of system y+ was detected; system y+L was also activated in these cells but with a slower time course and to a smaller extent. No stimulation of either system was found in activated B cells. The time course of activation of system y+ precisely matched the expression of the T cell early antigen gene described by MacLeod et al, 1990. The functional significance of these observations with respect to L-arginine transport and nitric oxide synthesis in activated T lymphocytes is discussed.


[Adverse reactions to low osmolar iodine contrast media (second report)].

From January to December 1990, we performed a prospective survey of adverse reactions to contrast media at two different institutes of Juntendo University. We collected a total of 4555 case sheets during the period. The radiological procedures we investigated were computed tomography, intravenous urography, arteriography, venography and myelography. Low osmolar iodine contrast medium was used almost exclusively (except for five cases). The overall incidence of adverse reactions was 7.0%, and there were no severe or fatal reactions. The incidence of adverse reactions was higher in females (8.5%) than in males (6.1%). The incidence of adverse reactions increased according to the dose of contrast medium, especially when more than 101 ml was injected. Intra-arterial injection caused adverse reactions most often, followed by regular intravenous injections, followed by bolus intravenous injections. Adverse reactions occurred most often during injection. The next occurred in 5 minutes after injection, and then, 5-10 minutes after the injection of contrast medium. The incidence of adverse reactions was higher in patients with a history of allergy or previous reactions. Allergic adverse reactions were observed at a higher frequency. Pretesting was performed in 56.7% of the cases.


[Pseudodynamic MR imaging of temporomandibular joint disorders].

Magnetic resonance (MR) imaging of the temporomandibular joint (TMJ) has now been established as a procedure of choice in the evaluation of TMJ disorders. In this study, we evaluated the dynamics of TMJ motion on MR imaging, which resembles arthrography. Sixty-eight TMJs in 38 symptomatic patients and one healthy volunteer were examined using pseudodynamic images with gradient echo sequences using a 0.5 Tesla MR unit and 8 cm circular planar surface coil. For depiction of each compartment of the meniscus, the optimum sequence was 200/15/2 (TR/TE/excitations) with 50 degrees or 60 degrees flip angle in gradient refocused acquisition in steady-state (GRASS) sequences. Three contiguous slices on sagittal MR images were routinely obtained at 14-18 different phases of the opening cycle and displayed in closed-loop cine fashion. Internal derangement was observed in 57% of 68 joints. The most common type was anterior meniscal displacement without reduction. Sideway and rotational displacements, observed in 10% each, were noted on both sagittal multislice images and axial reference images. As a pseudodynamic MR technique, jaw movement specifically designed to check bite procedure to adjust splints is useful for detecting the exact time of meniscal redisplacement on the second click. After conservative therapy for arthrosis, pseudodynamic MR provided information on changes in the meniscus and condylar relationship. Pseudodynamic MR with multiple phases is suitable for evaluating subtle motion abnormality of the meniscus and for post-therapeutic monitoring.


[Hemodynamics in the territory of balloon occluded internal iliac artery--problems of balloon occluded arterial infusion therapy for urinary bladder cancer].

Balloon occluded arterial infusion therapy (BOAI) with anticancer drugs has been performed widely for urinary bladder cancer. It is expected that a dense anticancer drug would perfuse the territory of the vesical arteries under occlusion of the bilateral internal iliac arteries. In balloon occluded internal iliac arteriography, however, contrast media are gradually washed out in spite of complete occlusion of the bilateral internal iliac arteries. This washout process takes place via collateral flow to the acute occlusion and varies according to the position of occlusion and arterial variations in branching. We wondered whether anticancer drug administered by BOAI would perfuse the territory of the vesical arteries as expected. We analyzed the washout process of balloon occluded internal iliac arteriography in 41 patients with urinary bladder cancer in whom preoperative BOAI had been performed. We estimated the hemodynamics and perfusion of the anticancer drug to the urinary bladder on the basis of analysis of balloon occluded internal iliac arteriography in each case. Perfusion scintigraphy and histological examination of surgical specimens of urinary bladder cancer (21 cases) confirmed the validity of our estimates. In some cases it was presumed that the anticancer drug did not reach the territory of the vesical arteries.


[CT of pulmonary dirofilariasis--differential diagnosis from lung cancer].

We present here four cases of pulmonary dirofilariasis in which histological examination of the surgical specimen showed occlusion of the peripheral pulmonary artery by filariae and formation of a necrotic mass surrounded by reactive inflammation and hemorrhage. Radiological examination showed a solitary pulmonary nodule in three cases and a wedge-shaped consolidation in one case. Although pulmonary nodules in dirofilariasis closely mimic bronchogenic carcinoma on radiographs , it is possible to distinguish them from bronchogenic carcinoma on the basis of the following findings: (1) coexistence of subtle satellite lesions, (2) absence of pleural involvement, (3) fine marginal speculations, and (4) lack of concentric marginal speculations (eccentric speculation). In each case of dirofilariasis, CT showed the peripheral pulmonary artery entering the mass. This finding differentiates this disease from metastatic lung tumor, because in tumor metastasis via the pulmonary arteries, visible vessels are not usually involved.


[CT assessment of gallbladder opacification 12-24 hours after angiography].

After the injection of conventional contrast agents that are largely excreted in urine, gallbladder opacification is observed in patients with renal dysfunction. However, some reports have noted that gallbladder opacification on plain radiographs occurs frequently in patients without renal impairment after the intravenous administration of Ioxaglate, one of the new low-osmolality agents. We carried out CT examination 12-24 hours after angiography with various kinds of contrast media in 437 patients to examine the incidence of gallbladder opacification. The influence of hepatobiliary and renal function on the excretion of contrast medium is discussed. Gallbladder opacification was observed in more than 60% of the patients. This result indicates that gallbladder opacification is not a rare phenomenon, and is even common in delayed CT examinations of patients with normal renal function. The high frequency of gallbladder opacification was recognized not only in the renal dysfunction group but also in the normal liver function group. Gallbladder opacification in delayed CT examination shows that the hepatobiliary tract is important in the excretion of contrast medium.


[Preclinical evaluation of iotrolan as a contrast medium for angiography and urography].

Efficacy and tolerability of iotrolan, a nonionic isotonic dimer, as a contrast medium for angiography and urography were investigated in animals. In the arteriography of rabbit femur, the efficacy of iotrolan 280 mgI/ml was as good as iopamidol 300 mgI/ml and better than meglumine diatrizoate 306 mgI/ml. In rat urography, the efficacy of iotrolan 280 mgI/ml was better than both iopamidol 370 mgI/ml and iohexol 350 mgI/ml. Vascular pain was less with iotrolan 280 mgI/ml than with iohexol 300 mgI/ml in rats. Effect of iotrolan on the pulmo-cardiovascular parameters, arterial pO2, hematocrit and plasma osmolality was less than iopamidol and diatrizoate in rabbits. Iotrolan induced no renal dysfunction and diuresis where iopamidol induced diuresis in rats. Effect of iotrolan on the blood coagulation was similar to nonionic monomers and less than diatrizoate in rabbits. Because of its isotonicity, iotrolan induced little water shift in the blood vessel and urinary tract, which would result in good efficacy and tolerability. These results suggest that iotrolan is superior to ionic and nonionic monomers for angiography and urography.


[Clinical evaluation of lumbosacral nerve root and lateral stenosis using coronal MR imaging].

MR imaging is being used more frequently to study the lumbar spine and is becoming the modality of choice in the assessment of patient with low back pain. Using a new technique of coronal and half coronal scan with MR imaging, it was possible to visualize L4, L5 and S1 nerve roots accurately. We described the MR findings of lateral stenosis using this technique. Several characteristic MR findings were identified, and the most important one was nerve root impingement in the intervertebral foramen. We consider that coronal and half coronal scan with MR imaging is useful in diagnosis of lateral stenosis.


[The value of frequent positioning of treatment field in radiotherapy of esophageal cancer].

Since 1983 a clinical trial of proton beam radiotherapy has been conducted at the Proton Medical Research Center (PMRC) of the University of Tsukuba. We have made it a rule to do field localization by X-ray pictures before each treatment. For this purpose we have developed a localize-verify system consisting of a fluoroscopic unit and a real time digital image processing device. By using this system as well as X-ray films, field placement errors or corrected distance at field localization were measured in 11 patients with esophageal cancers. Measurements of corrected distances on a total of 177 localization attempts disclosed that correction by > 5 mm was necessary in 30.6% and by > 10 mm in 10.2% of all localization attempts. Corrected distances appeared to increase with age, possibly because the skin becomes looser and ambulatory status tends to be more limited in older patients. Field placement corrections of more than 5 mm were required in 66.7% of 60 localizations in patients > 80 years old. Two patients in whom the anatomical positions of the esophagus were easily movable are presented. The following common characteristics of these patients were considered high risk factors: they were more than 80 years old; lesions were located in the lower esophagus; and they had T1 tumors. These findings suggested that frequent positioning and verification of treatment fields are necessary in the accurate treatment of esophageal cancers, especially those in high-risk patients.


[Detectability of diagonal branch disease by 201TlCl exercised myocardial scintigraphy].

The detectability of diagonal branch disease in 10 patients (five with angina pectoris, five with myocardial infarction) with isolated diagonal branch lesions (more than 75% luminal stenosis in coronary angiography) was reviewed. In exercised 201TlCl myocardial scintigraphy, chest pain occurred in four of 10 patients, electrocardiographic change indicating myocardial ischemia was seen in four, and diagonal branch lesion was detected in only four patients by planar images. In contrast, diagonal branch lesions were detected in 10 of 10 patients by SPECT (single photon emission computed tomography). In planar images, perfusion defects appeared high in the anterolateral, posterolateral, and anterior walls of the left ventricle. In SPECT images they appeared high in the anterior to anterolateral wall. The extent of diagonal branch lesions could be quantitatively evaluated by coronary territory maps developed from unfolded maps of exercised SPECT. The mean ratio of the extent of diagonal branch lesion to left anterior descending branch territory was 24.7%, and the extent of myocardial infarction was significantly larger than that of angina pectoris (p < 0.05). In conclusion, SPECT is useful for detecting diagonal branch lesions and can quantitatively show the extent of these lesions by coronary territory map.


[Utility of helical CT for the secondary mass screening of lung cancer].

From December 1991 to 1992, helical CT scan was performed in 55 patients with having abnormal shadow in the chest X-ray on the secondary screening for lung cancer. In all patients with suspected pulmonary lesions at first screening, helical CT scan was performed with 10 mm slice thickness for 300 mm. The moving speed of the patients table is 20 mm/l rot./1.5 sec for 300 mm in a single breath-hold. Helical CT allowed shortening of examination time and providing both better data continuity and resolution than conventional CT. In conclusion, helical CT can be useful for secondary screening of lung cancer but it was considered that there are some problems such as method of final pathological diagnosis and treatment for small nodular lesion.


[MR imaging during arterio-portography (MR-AP) in the detection of hepatic cancer].

Magnetic resonance imaging during arterio-portography (MR-AP) was performed in 2 patients of hepatic cancer. Low dose of meglumine gadopentetate (4 ml of a 0.5 mmol/L solution) was injected into a superior mesenteric artery during acquisition of a Turbo-FLASH sequence. An increase in liver to lesion contrast was obtained with MR-AP and it is also useful in the late phase to distinguish a flow defect lesion due to portal obstruction from the tumor.


[Transjugular intrahepatic portosystemic shunt: a case report].

Transjugular intrahepatic portosystemic shunt (TIPS) was performed in one patient with refractory esophageal varices due to portal hypertension by liver cirrhosis. Rösch modified Z-stent was placed to keep the lumen. The shunt lowered average portal pressure from 45 to 24 mmHg, and then decompressed the esophageal varices. The shunt was patent still for three months after the creation. No significant complication was observed. This initial success of TIPS in Japan encouragingly support the safeness and effectiveness of this therapy.


Yeast SKO1 gene encodes a bZIP protein that binds to the CRE motif and acts as a repressor of transcription.

We have cloned a yeast gene, SKO1, which in high copy number suppresses lethal overexpression of cAMP-dependent protein kinase. SKO1 encodes a bZIP protein that binds to the CRE motif, TGACGTCA. We found that SKO1 also binds to a CRE-like site in SUC2, a yeast gene encoding invertase which is under positive control by cAMP. A disruption of the SKO1 gene causes a partial derepression of SUC2, indicating that SKO1 is a negative regulator of the SUC2 gene. SKO1 interacts positively with MIG1, a zinc finger protein that mediates glucose repression of SUC2. A kinetic analysis revealed a complex regulation of the SUC2 mRNA in response to glucose. First, MIG1 mediates a rapid and strong repression of SUC2, which is complete within 10 minutes. Second, a MIG1-independent process causes a further slow reduction in the mRNA. Third, in the absence of MIG1, there is also a rapid but transient glucose induction of the SUC2 mRNA. This induction is correlated with a transient loss of SKO1-dependent repression.


Oligonucleotide-directed triple helix formation at adjacent oligopurine and oligopyrimidine DNA tracts by alternate strand recognition.

A significant limitation to the practical application of triplex DNA is its requirement for oligopurine tracts in target DNA sequences. The repertoire of triplex-forming sequences can potentially be expanded to adjacent blocks of purines and pyrimidines by allowing the third strand to pair with purines on alternate strands, while maintaining the required strand polarities by combining the two major classes of base triplets, Py.PuPy and Pu.PuPy. The formation of triplex DNA in this fashion requires no unusual bases or backbone linkages on the third strand. This approach has previously been demonstrated for target sequences of the type 5'-(Pu)n(Py)n-3' in intramolecular complexes. Using affinity cleaving and DNase I footprinting, we show here that intermolecular triplexes can also be formed at both 5'-(Pu)n(Py)n-3' and 5'-(Py)n(Pu)n-3' target sequences. However, triplex formation at a 5'-(Py)n(Pu)n-3' sequence occurs with lower yield. Triplex formation is disfavored, even at acid pH, when a number of contiguous C+.GC base triplets are required. These results suggest that triplex formation via alternate strand recognition at sequences made up of blocks of purines and pyrimidines may be generally feasible.


Evolution of codon usage patterns: the extent and nature of divergence between Candida albicans and Saccharomyces cerevisiae.

Codon usage in a sample of 28 genes from the pathogenic yeast Candida albicans has been analysed using multivariate statistical analysis. A major trend among genes, correlated with gene expression level, was identified. We have focussed on the extent and nature of divergence between C.albicans and the closely related yeast Saccharomyces cerevisiae. It was recently suggested that significant differences exist between the subsets of preferred codons in these two species [Brown et al. (1991) Nucleic Acids Res. 19, 4293]. Overall, the genes of C.albicans are more A + T-rich, reflecting the lower genomic G + C content of that species, and presumably resulting from a different pattern of mutational bias. However, in both species highly expressed genes preferentially use the same subset of 'optimal' codons. A suggestion that the low frequency of NCG codons in both yeast species results from selection against the presence of codons that are potentially highly mutable is discounted. Codon usage in C.albicans, as in other unicellular species, can be interpreted as the result of a balance between the processes of mutational bias and translational selection. Codon usage in two related Candida species, C.maltosa and C.tropicalis, is briefly discussed.


RFP is a DNA binding protein associated with the nuclear matrix.

We reported that the RFP gene encodes a protein with putative zinc finger domains and was involved in the activation of the ret proto-oncogene. To further characterize the RFP protein, we developed a polyclonal antibody against the product synthesized from a fragment of the RFP cDNA expressed in Escherichia coli. Western blot analysis showed that RFP was identified as a 58 kDa protein in cell lysates from four human and rodent cell lines and from mouse testis. In addition, a unique 68 kDa protein was detected in the testis. Using AH7974 (rat ascites hepatoma) and Raji (human Burkitt lymphoma) cells, we demonstrated strong association of RFP with the nuclear matrix. Furthermore, RFP solubilized from the nuclear matrix had DNA-binding activity although it appears to bind more preferentially to double-stranded DNA than to single-stranded DNA. These results thus suggest that RFP may play a role in molecular processes which occur in the nuclear matrix.


Random mutagenesis of the human immunodeficiency virus type-1 trans-activator of transcription (HIV-1 Tat).

A new method is described for the direct construction of randomly mutagenized genes by applying the polymerase chain reaction (PCR) to an oligonucleotide synthesized using doped nucleotide reservoirs. We have demonstrated the utility of this method by generating a library of mutant HIV-1 tat genes. Several arbitrarily selected, inactive tat clones were sequenced to evaluate the extent of the mutagenesis. Moreover, fourteen recombinants encoding varying levels of transcriptional trans-activator activity were isolated by transient transfection of sub-library pools into a HeLa cell line bearing an HIV-LTR-chloramphenicol acetyltransferase (CAT) reporter gene. Sequence data revealed a spectrum of alterations including nucleotide substitutions, insertions, and deletions, suggesting that mutations arose from both the doped DNA synthesis and the subsequent PCR 'rescue' of full-length product. Sequence comparison between inactive and active Tat clones revealed a selection pressure against amino-acid substitutions within the N-terminal domains of Tat, indicating the importance of this region to trans-activation competence. In addition, single and double missense mutations within the basic-rich, TAR RNA-binding domain were seen to be tolerated within active Tat clones.


A spliced intron accumulates as a lariat in the nucleus of T cells.

The vast majority of mammalian genes are interrupted by non-coding segments of DNA termed introns. Introns are spliced out of RNA transcripts as lariat structures, and then are typically debranched and rapidly degraded. Here, we described an unusual spliced intron from the constant region of the T cell receptor-beta (TCR-beta) locus that is relatively stable in mammalian cells. This intron, IVS1C beta 1, accumulates as a set of lariat RNA structures with different length tails in the nucleus of T cells. The accumulation of this spliced intron is developmentally regulated during murine thymocyte ontogeny. The property of stability appears to be evolutionarily conserved since the human version of this intron also accumulates in T cells. The stability is selective since other spliced TCR-beta introns do not detectably accumulate in T cells. The unusual stability of this intron does not depend on T cell specific factors since non-T cells transfected with TCR-beta gene constructs also accumulate spliced IVS1C beta 1. The discovery of a mammalian intron that accumulates as a lariat in vivo provides an opportunity to elucidate mechanisms that regulate intron debranching, stability, and nuclear localization.


Characterization of Chlorella virus PBCV-1 CviAII restriction and modification system.

A second DNA site-specific (restriction) endonuclease (R.CviAII) and its cognate adenine DNA methyltransferase (M.CviAII) were isolated from virus PBCV-1 infected Chlorella strain NC64A cells. R.CviAII, a heteroschizomer of the bacterial restriction endonuclease NlaIII, recognizes the sequence CATG, and does not cleave CmATG sequences. However, unlike NlaIII, which cleaves after the G and does not cleave either CmATG or mCATG sequences, CviAII cleaves between the C and A and is unaffected by mCATG methylation. The M.CviAII and R.CviAII genes were cloned and their DNA sequences were determined. These genes are tandemly arranged head-to-tail such that the TAA termination codon of the M.CviAII methyltransferase gene overlaps the ATG translational start site of R.CviAII endonuclease. R.CviAII is the first chlorella virus site-specific endonuclease gene to be cloned and sequenced.


Analysis of chimeric mRNAs derived from the STE3 mRNA identifies multiple regions within yeast mRNAs that modulate mRNA decay.

In the yeast Saccharomyces cerevisiae unstable mRNAs decay 10-20 fold more rapidly than stable mRNAs. In order to examine the basis for the differences in decay rate of the unstable STE3 mRNA and the stable PGK1 and ACT1 mRNAs we have constructed and measured the decay rates of numerous chimeric mRNAs. These experiments indicate that multiple regions within yeast mRNAs are involved in modulating mRNA decay rates. Our results suggest that at least two regions within the STE3 mRNA are involved in stimulating rapid decay. One region is located within the coding region and requires sequences between codons 13 and 179. In addition, the STE3 3' UT can also function to stimulate decay. Surprisingly, the STE3 3' UT is not sufficient to accelerate the turnover of the stable PGK1 transcript unless portions of the PGK1 coding region are first deleted. These results not only identify sequences that function within yeast to stimulate mRNA turnover but also have important implications for an understanding of the basis of differences in eukaryotic mRNA decay rates.


A new interaction between the mouse 5' external transcribed spacer of pre-rRNA and U3 snRNA detected by psoralen crosslinking.

The first cleavage in mammalian pre-rRNA processing occurs within the 5' external transcribed spacer (ETS). We have recently shown that the U3 snRNP is required for this cleavage reaction, binds to the rRNA precursor, and remains complexed with the downstream processing product after the reaction has been completed (1). Using psoralen crosslinking in mouse cell extract we have detected a new interaction between U3 RNA and the mouse ETS processing substrate and its processed product. The crosslinked sites on both U3 and ETS RNAs have been mapped by RNase H cleavage and primer extension analyses. The crosslinked sites in U3 RNA map to C5, U6, and U8. U8 lies within and C5 and U6 are adjacent to an evolutionarily conserved U3 sequence termed box A'. In the ETS the crosslinked sites are U1012 and U1013, 362 nucleotides downstream from the processing site. Although the crosslinked site is dispensable for the primary processing reaction in vitro, a short conserved sequence just 3' to the cleavage site (nucleotides 650-668) is absolutely required for crosslink formation. We conclude that the interaction between U3 RNA and the 5' ETS detected by psoralen crosslinking may play a role in subsequent step(s) of pre-rRNA processing.


Cytosine nucleoside inhibition of the ATPase of Escherichia coli termination factor rho: evidence for a base specific interaction between rho and RNA.

The function of rho factor in transcription termination depends on interactions with nascent RNA molecules that contain unpaired cytidylate residues. We show that cytidine, as a free nucleoside, inhibits the binding of rho to lambda cro mRNA and is a competitive inhibitor of rho-ATPase activity with lambda cro mRNA as cofactor. The relative ability of various cytidine analogs and other nucleosides to inhibit the rho-RNA interaction was used to probe features responsible for the base specificity of rho action. The results suggest that rho has a specificity pocket in its polynucleotide-binding site that apparently can make H-bond interactions with the side of the cytosine ring that normally faces away from the sugar ring and that may involve a relatively close fit along the edge of the ribose ring at the C2' carbon. The nature of the complex of rho with cytidine nucleotides was analyzed further by determining whether incubation with BrCMP caused inactivation of rho ATPase. Although BrCMP could form Michaelis inhibition complexes, it did not activate rho. Rho thus lacks a diagnostic property of enzymes that make specific covalent addition complexes with pyrimidines.


Molecular characterisation of a DNA ligase gene of the extremely thermophilic archaeon Desulfurolobus ambivalens shows close phylogenetic relationship to eukaryotic ligases.

A 3382 bp fragment containing a gene for a DNA ligase from the extremely thermophilic, acidophilic, and facultatively anaerobic archaeon (archaebacterium) Desulfurolobus ambivalens was cloned and sequenced. The deduced amino acid sequence (600 amino acids, 67619 molecular weight) showed 30-34% sequence identity with the ATP-dependent eucaryal (eukaryotic) DNA ligases of Schizosaccharomyces pombe, Saccharomyces cerevisiae, the human DNA ligase I, and with the Vaccinia DNA ligase. Distant similarity to the DNA ligases from the bacteriophages T3, T4, T6, T7 and the African swine fever virus was found, whereas no similarities were detectable to the NAD-dependent DNA ligases from the bacteria (eubacteria) Escherichia coli and Thermus thermophilus, to the ATP-dependent RNA-ligase of bacteriophage T4, and to the tRNA-Ligase from S.cerevisiae. A detailed comparison of the phylogenetic relationship of the amino acid sequences of all known DNA and RNA ligases is presented including a complete alignment of the ATP-dependent DNA ligases. The in vivo-transcription initiation and termination sites of the D.ambivalens gene were mapped. The calculated transcript length was 1904-1911 nt.


A repetitive DNA sequence in Paramecium macronuclei is related to the beta subunit of G proteins.

A repeated DNA sequence has been identified in the macronucleus of several Paramecium species. In P.tetraurelia the repeat was identified in the subtelomeric region of four randomly selected telomere clones, as well as downstream of the A type variable surface protein gene. The complete sequence of the A gene linked repeat consists of 15 tandem repeats of exactly 126 nucleotides that contain an open reading frame with significant similarity to the beta subunits of trimeric G proteins. The most striking consensus feature is the amino acid sequence DX omega WD where X is any amino acid and omega is I, L, or V spaced at precise 42 amino acids intervals. This sequence and spacing are found in G-protein beta subunits and other members of this protein motif family. Analysis of the five cloned telomeric restriction fragments showed the repeats can be found in either orientation with respect to the telomere. Poly(A) RNA transcripts containing this sequence have been identified in Paramecium tetraurelia. The conserved presence of this sequence in several species of Paramecium suggests an important physiological function, and the study of this repeat may reveal information about the evolution of this common protein motif.


DeoR repression at-a-distance only weakly responds to changes in interoperator separation and DNA topology.

The interoperator distance between a synthetic operator Os and the deoP2O2-galK fusion was varied between 46 and 176 bp. The repression of the deoP2 directed galK expression as a function of the interoperator distance (center-to-center) was measured in vivo in a single-copy system. The results show that the DeoR repressor efficiently can repress transcription at all the interoperator distances tested. The degree of repression depends very little on the spacing between the operators, however, a weak periodic dependency of 8-11 bp may exist.


In vivo stage- and tissue-specific DNA-protein interactions at the D. melanogaster alcohol dehydrogenase distal promoter and adult enhancer.

We performed a high resolution analysis of the chromatin structure within the regions required for distal transcription of the Drosophila melanogaster alcohol dehydrogenase gene (Adh). Using dimethyl sulfate, DNase I, and micrococcal nuclease as structural probes, and comparing chromatin structure in tissues isolated from several developmental stages, we have identified several sites of stage- and tissue-specific DNA-protein interactions that correlate with distal transcription initiation. Most were within previously identified cis-acting elements and/or in vitro protein binding sites of the adult enhancer (AAE) and distal promoter, including the TATA box. We also detected a novel stage-specific DNA-protein interaction at the Adf-2a binding site where a non-histone protein was bound to the DNA on the surface of a positioned nucleosome previously identified between the distal promoter and adult enhancer. In addition to footprints, we have also revealed stage- and tissue-specific DNA helix deformations between many of the non-histone protein binding sites. These helix distortions suggest there are interactions among the adjacently bound proteins that result in bending or kinking of the intervening DNA. The distal promoter and AAE have an accessible chromatin conformation in fat body prior to the third larval instar and many of the regulatory proteins that bind in these regions are also available before distal transcription begins. Nevertheless, the timing of DNA-protein interactions in the distal promoter and AAE suggest these proteins do not bind individually or assemble progressively as they and their binding sites become available. Instead, there appears to be a coordinated assembly of a large cooperative complex of proteins interacting with the distal promoter, the positioned nucleosome, the enhancer of the distal promoter (the AAE), and each other.


Characterization of a novel T lymphocyte protein which binds to a site related to steroid/thyroid hormone receptor response elements in the negative regulatory sequence of the human immunodeficiency virus long terminal repeat.

We have previously identified a T lymphocyte protein which binds to a site within the LTR of the human immunodeficiency virus type 1 (HIV-1) and exerts an inhibitory effect on virus gene expression. The palindromic site (site B) recognized by this protein is related to the palindromic binding sites of members of the steroid/thyroid hormone receptor family. Here we characterize the T cell protein binding to this site as a 100 kD protein which is most abundant in T cells and which binds to site B as a 200 kD complex. This protein is distinct from other members of the steroid/thyroid hormone receptor family including the COUP protein which has a closely related DNA binding specificity.


Genes for Xenopus laevis U3 small nuclear RNA.

Genomic Southern blots showed there are only 14 to 20 copies of U3 snRNA genes per somatic genome in Xenopus laevis, unlike the highly repetitive, tandem arrangement of other snRNA genes in this organism. Sequencing of two U3 snRNA genes from lambda clones of a genomic library revealed striking similarity upstream, but much more divergence downstream. Consensus motifs common to other U snRNA genes were also found: a distal sequence element (DSE, octamer motif at -222 to -215), a proximal sequence element (PSE, at -62 to -52) and a 3' Box (15 or 16 bp downstream of the U3 genes). The DSE of mammals also has an inverted CCAAT motif specific for U3 snRNA genes, and we find this is conserved in the amphibian U3 snRNA genes. The Xenopus inverted CCAAT motif is exactly one helical turn further upstream of the octamer motif than its mammalian counterpart, suggesting interaction of putative transcription factors bound to these motifs. Mutation of the inverted CCAAT motif and part of an adjacent Sp1 site greatly depresses transcription of the mutant U3 snRNA gene in Xenopus oocytes, implying a role in transcriptional efficiency. Electrophoretic mobility shift assays implicate transcription factor binding to this region.


The Crithidia fasciculata CRK gene encodes a novel cdc2-related protein containing large inserts between highly conserved domains.

A gene (CRK) encoding a cdc2-related protein has been identified in the trypanosomatid Crithidia fasciculata. CRK has a high degree of sequence identity with the human cdc2 gene and contains the sixteen amino acid PSTAIR motif, characteristic of p34cdc2 protein-serine/threonine kinases, with four amino acid substitutions in the motif. In addition, two inserts of more than sixty amino acids have been found between conserved domains of this putative protein-serine/threonine kinase. CRK is a single copy gene and is expressed on a 3.8 kb mRNA. Anti-CRK antibodies detect a 53kDa protein in extracts of C.fasciculata in agreement with the size predicted from the nucleotide sequence of the cloned gene. These antibodies also recognize proteins of 48 and 60 kDa in extracts of the trypanosomatid Leishmania tarentolae. Antibodies against the human PSTAIR peptide detect the p34cdc2 protein in human nuclear extracts but fail to detect a 34 kDa protein in C.fasciculata extracts. These results suggest that novel higher molecular weight forms of the cdc2 protein family may be involved in cell cycle control in trypanosomes.


Crystal structure of a B-DNA dodecamer containing inosine, d(CGCIAATTCGCG), at 2.4 A resolution and its comparison with other B-DNA dodecamers.

The crystal structure of the dodecamer, d(CGCIAATTCGCG), has been determined at 2.4 A resolution by molecular replacement, and refined to an R-factor of 0.174. The structure is isomorphous with that of the B-DNA dodecamer, d(CGCGAATTCGCG), in space group P2(1)2(1)2(1) with cell dimensions of a = 24.9, b = 40.4, and c = 66.4 A. The initial difference Fourier maps clearly indicated the presence of inosine instead of guanine. The structure was refined with 44 water molecules, and compared to the parent dodecamer. Overall the two structures are very similar, and the I:C forms Watson-Crick base pairs with similar hydrogen bond geometry to the G:C base pairs. The propeller twist angle is low for I4:C21 and relatively high for the I16:C9 base pair (-3.2 degrees compared to -23.0 degrees), and the buckle angles alter, probably due to differences in the contacts with symmetry related molecules in the crystal lattice. The central base pairs of d(CGCIAATTCGCG) show the large propeller twist angles, and the narrow minor groove that characterize A-tract DNA, although I:C base pairs cannot form the major groove bifurcated hydrogen bonds that are possible for A:T base pairs.


The basic RNA-binding domain of HIV-2 Tat contributes to preferential trans-activation of a TAR2-containing LTR.

Human immunodeficiency viruses HIV-1 and HIV-2 encode a Tat protein that trans-activates the respective viral genome through RNA targets (TAR1 and TAR2). Tat-1 and Tat-2 have considerable homology. However, an interesting biological observation has been that Tat-1 activates the HIV-1 and HIV-2 LTRs equally while Tat-2 activates the former, in comparison to the latter, poorly. Here, we present evidence that it is the TAR2 RNA target together with the basic RNA-binding protein domain of Tat-2 that dictate this non-reciprocity in trans-activation.


Challenging misperceptions about nurses' moral reasoning.

Discussions in the nursing literature about the usefulness of Kohlberg's theory of moral reasoning for women and nurses, and assertions about the level of moral reasoning scores of nurses have been clouded by inaccuracies and misperceptions. In this article, theoretical and measurement issues related to moral reasoning are clarified and a critical review of the literature is provided about the moral reasoning of nursing students and nurses as measured by the Defining Issues Test (DIT). The review indicates the need for greater rigor in studies of moral reasoning among nurses and the need for accuracy in interpreting and reporting moral reasoning scores. The data show that the moral reasoning of nurses, like that of other groups, tends to increase with formal education. Nurses' scores are usually comparable to, and sometimes higher than, scores of their academic peers.


The HOME scale: the influence of socioeconomic status on the evaluation of the home environment.

Caldwell's Home Observation for Measurement of the Environment (HOME) was developed to provide specific and sensitive information about the home and maternal environment as a stimulus to infant learning and development. The use of the HOME scale was examined in a sample of 118 middle- and lower-income mothers and their low-birth-weight (LBW) or very-low-birth-weight (VLBW) infants. The analysis of data demonstrated limited variability in the HOME scale total scores within each income group, and income alone was found to account for 41% of the variance in the sample. These findings raise questions about the effectiveness of the HOME scale in making useful discriminations about family functioning within an income group.


Validation of the PRQ85 social support measure for adolescents.

The purposes of this study were to factor analyze the 25-item Personal Resource Questionnaire (PRQ) 85-Part II, a social support measure, and to establish construct validity for the instrument among adolescents by testing two hypotheses derived from theoretical propositions by Weiss (1974) concerning the relational provisions of social support. The purposes were accomplished using a sample of 325 adolescents, aged 12 to 21. According to the criteria used in this study, a four-factor structure, resulting from a principal components analysis with an oblique rotation, best represented the multidimensionality of the PRQ85-Part II in adolescents. A second-order factor analysis indicated that the four first-order factors correlated to form one factor, which consisted of 17 items and was labeled Perceived Social Support. Evidence in support of construct validity for both the 17-item and 25-item PRQ85-Part II was provided by statistically significant correlations found between the two scales and the theoretically relevant variables of perceived health status and symptom patterns. The contributions of this study to the psychometric properties of the PRQ85-Part II can be used in future research concerning social support in adolescents.


Concurrent validity of a new instrument for measuring nutritive sucking in preterm infants.

The purpose of this study was to examine the concurrent validity of the Whitney strain gage for the measurement of nutritive sucking in preterm infants. Ten preterm infants were studied continuously during at least one entire bottle feeding per week, from admission into the study until discharge from the nursery. Sucking was measured simultaneously by an adapted nipple and the Whitney gage. The two instruments were compared on the following measures: number of sucking bursts, number of sucks per burst, and duration of bursts and pauses between bursts. Total percent agreement for the occurrence of a sucking burst was 99.3% (K = .99). Sucks per burst varied from 2 to 113, with 89.3% of the pairs of sucking bursts differing by < or = 1 suck per burst. The mean absolute difference between the two instruments for the duration of sucking bursts and pauses was .64 s and .72 s, respectively. These results demonstrate the concurrent validity of the Whitney gage for measurement of sucking events in preterm infants.


Instrument development: cardiac diet and exercise self-efficacy.

Self-efficacy has been documented as a strong predictor of health behaviors. Unfortunately, availability of reliable and valid measures of self-efficacy for a range of health behaviors is still limited. This study validated two measures of cardiac risk factor self-efficacy: the Cardiac Diet Self-Efficacy Instrument (CDSEI) and the Cardiac Exercise Self-Efficacy Instrument (CESEI). A sample of 370 cardiac rehabilitation participants provided data for principal factor analyses showing the unidimensionality of each instrument. Known groups construct validity was supported by a comparison of CDSEI and CESEI scores for cardiac rehabilitation participants and marathon runners. The value of CDSEI and CESEI scores in predicting subsequent exercise and diet performance was demonstrated with a third group of cardiac rehabilitation participants. Stability and internal consistency estimates in the .80s and .90s, respectively, support the scales' reliabilities.


Patients' reactions to completion of adjuvant breast cancer therapy.

Thirty-eight women with breast cancer were studied to determine the psychological distress they experienced at the completion of adjuvant treatment. Measures were completed at the start of adjuvant chemotherapy, one week after chemotherapy was completed, and following completion of radiotherapy. Approximately 30% of the women reported the termination of treatment was upsetting. For the group as a whole, depression scores decreased significantly from the first to the last measurement. Those who were most upset by termination of treatment had been more depressed since the onset of treatment, tended to view their illness as chronic rather than acute, and had more side effects during their last cycle of chemotherapy. Some women stated they were upset by the termination of treatment per se, but many other problems were reported including side effects that had continued after treatment ended.


Symptoms of preterm labor and self-diagnostic confusion.

The purpose of this study was to learn how women experiencing preterm labor come to know a health deviation exists, and what they do when faced with such a problem. Grounded theory methodology was used as the research approach. Extensive interviews were conducted with 28 women about their care-seeking experiences with preterm labor. Ambiguous symptoms, absence of a meaningful label to attach to symptoms, and the context of pregnancy with its expected discomforts come together to create a situation of diagnostic confusion. Appropriate action to take in response to the diagnostic confusion is not self-evident. Deliberate and protracted efforts to make sense of and deal with symptoms of preterm labor are attempted. Making sense consists of three subprocesses: comparing, gathering data, and seeking information. Strategies used to deal with the symptoms include self-treating, ignoring, positive thinking, and waiting. Recourse to a professional is used as the strategy of last resort when symptoms can no longer be contained.


Finishing first grade: a study of school achievement in very-low-birth-weight children.

Factors that influence school achievement in very-low-birth-weight (< 1,500 g) children were investigated at the completion of first grade. The subjects were 71 children and their primary caregivers. Thirty-nine children were very low birth weight (VLBW) and 32 were normal birth weight (NBW). After controlling for birth weight status, over one third of the variance in children's school achievement was accounted for by the age of the child's mother when she began childbearing. Birth weight status accounted for significant amounts of variance in information processing skills. Significantly more children in the VLBW group required special services and fewer were promoted to second grade, although the difference was not significant.


Post-registration education in three fields of clinical practice.

This paper describes some empirical findings about the take-up of post-registration education by a substantial sample of clinical practitioners in three fields of practice--mental illness nursing, mental handicap nursing and midwifery. Some implications of the results are discussed in the context of the UKCC PREPP Report recommendations, as a contribution to the current debate about their implementation.


Natural dietary ingredients (oats and alfalfa) induce covalent DNA modifications (I-compounds) in rat liver and kidney.

Mammalian tissue DNA has recently been found, via 32P postlabeling, to contain complex profiles of age-dependent bulky carcinogen adductlike covalent modifications, which have been termed I-compounds, referring to their apparent indigenous origin without exposure to exogenous carcinogens. I-compound patterns are highly species, sex, tissue, and diet specific. As shown here, the presence of certain plant ingredients in diet, i.e., ground oats and alfalfa meal, significantly contributed to the formation of these DNA derivatives. Six groups of weanling female Sprague-Dawley rats were fed one of the following diets for three months: a natural ingredient diet containing neither oats nor alfalfa (Wayne MRH 22/5 Rodent Blox), Wayne diet supplemented with oats or alfalfa or both, a purified semisynthetic diet (AIN-76A), and AIN diet supplemented with oats. The natural ingredient diet produced more complex patterns and higher levels of I-compounds than purified diet in both liver and kidney DNA. Supplementation of either diet with oats elicited the formation of four additional oats-specific I-compounds in liver DNA. Oats and alfalfa, individually and in combination, tended to significantly raise nonpolar and diminish polar I-compound levels. To determine whether the oats-related extra spots were derived from mycotoxin contamination, two groups of rats were fed either Wayne diet or Wayne diet containing zearalenone (0.05 mg/kg) for three weeks. Zearalenone significantly increased the uterine weight but did not induce any DNA adduct formation.(ABSTRACT TRUNCATED AT 250 WORDS)


Prolongation of survival in retrovirally induced T cell lymphoma by dietary omega 6 fatty acid.

C57BL/Ka mice were fed diets rich in omega 3 or omega 6 polyunsaturated fatty acids and inoculated with the thymic lymphoma-inducing retrovirus RadLV. Mice receiving the omega 3 diet died significantly sooner than those receiving the omega 6 diet. Of the three known mechanisms by which fatty acids can exert antiviral activity, namely, modification of membrane fluidity, modulation of immune response, and synthesis of metabolites with antiviral activity, the first two can be eliminated in the model under study. It is therefore concluded that differences in survival are due to fatty acid metabolites with distinct antiviral activities.


Vitamin E inhibition of lipid peroxidation and ethanol-mediated promotion of esophageal tumorigenesis.

Promotion of chemically induced esophageal cancer by ethanol may include the generation of highly reactive free radicals and thus may be preventable by the antioxidant vitamin E. In the present study, female C57BL/6 mice received N-nitrosomethylbenzylamine (NMBzA, 0.2 mg/kg ig) three times a week for three weeks. After this esophageal carcinogenic treatment, mice were fed a nutritionally adequate liquid diet with 30% of the calories supplied by ethanol or an isocaloric carbohydrate with or without supplemental alpha-tocopherol (142 mg/kg diet). As a marker of in vivo lipid peroxidation, exhaled ethane was collected and measured 24 hours "before" the mice were killed after 20 weeks of dietary treatment. Hepatic malondialdehyde, lipid fluorescence, and conjugated dienes were determined as markers of products of lipid peroxidation and serum aminotransferases as indexes of liver toxicity. Hepatic liver concentrations of vitamins A and E and the size and frequency of esophageal tumors were also assessed. Ethanol consumption after NMBzA administration significantly increased (p less than 0.05) the size and frequency of esophageal tumors. These ethanol-promoted effects were accompanied by increases in indexes of in vivo and accumulated products of lipid peroxidation. Similarly treated animals that received supplemental dietary vitamin E showed significant reductions (p less than 0.05) in mean tumor size and frequency of tumors as well as a decrease in the indexes of hepatic lipid peroxidation. The results suggest that promotion of NMBzA-induced esophageal tumors by ethanol may in part result from increased lipid peroxidation and that vitamin E reduces carcinogenicity of NMBzA or ethanol promoter effects by inhibiting lipid peroxidation.


Effects of a long-chain fatty amine on mammary carcinogenesis induced in female Sprague-Dawley rats by DMBA.

Reports that protein kinase C is inhibited by sphingosine and other long-chain amines and the suggestion that promotion of mammary carcinogenesis by dietary fat is mediated by protein kinase C prompted us to investigate the effects of a long-chain amine, 1-octadecylamine, on mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthracene in rats fed a high-fat diet. Rats fed the amine sulfate at a level of 0.01% in a semipurified diet containing 20% corn oil developed more tumors than those fed the high-fat diet alone, although body weight gain was inhibited slightly. Rats fed the amine sulfate at 0.1% of the diet developed very few tumors compared with those fed either the high-fat diet or a low-fat diet containing 5% corn oil. At the higher level, the C18 amine also caused a marked inhibition of body weight gain.


Dietary intake and risk of lung cancer in women who never smoked.

A case-control study was conducted to examine the influence of dietary factors on the risk of developing lung cancer among women who have never smoked cigarettes. This study included 124 cases of histologically confirmed carcinoma of the lung and 263 community-based controls. Dietary data were collected utilizing the reduced version of the National Cancer Institute (Block) food frequency questionnaire. The results of this analysis, adjusted for age, education, and total calories, indicated a strong protective effect associated with total vegetable consumption and intake of carotene. Individuals in the highest quartile of vegetable consumption experienced the greatest decreased risk with an odds ratio (OR) of 0.2, [confidence interval (CI) 0.1-0.5]. The effect of all vegetables combined was greater than that of green and yellow vegetables alone (highest quartile OR 0.4, CI 0.2-0.7). Similarly, the protective effect of total carotene (highest quartile OR 0.3, CI 0.1-0.6) was somewhat greater than that of beta-carotene alone (highest quartile OR 0.4, CI 0.2-0.8). Retinol intake was not associated with a decreased risk of lung cancer in our population. There was an inverse association between lung cancer risk and vitamin C intake, which was not significant, although a statistically significant trend was noted.


Diet and prognosis of breast cancer.

The relationship between the occurrence of breast cancer and dietary intake, in particular a high-fat diet, has attracted much attention in recent years. In addition, the prognosis of breast cancer patients on the basis of dietary intake is also an interesting subject. The present study utilized breast cancer patients whose dietary intake was carefully assessed about one decade previously in a case-control study to determine whether dietary intake was indeed related to the patients' prognosis. The study included 212 patients who underwent a surgical operation between 1975 and 1978. They were followed-up until 1987, and a total of 47 breast cancer deaths were certified. The 5- and 10-year relative survival rates were 78.5% and 75.3%, respectively. The older patients tended to ingest smaller amounts of all nutrients, except animal fat from fish. Height was significantly correlated with total animal protein intake, whereas there was no significant correlation between body mass index and intake of any nutrient. Although the age-adjusted mean values of the nutrient intakes, other than vegetable fat, decreased with advancing stage, the differences were statistically insignificant. The results of multivariate analyses, in which some confounding factors (e.g., clinical stage) were adjusted using a proportional hazards model, showed that all hazards ratios in each nutrient were close to unity, and no dose-response relationship was seen. The present investigation did not provide any support for the hypothesis that a high-fat diet is a survival determinant for breast cancer patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Mammary cancer prevention by regular garlic and selenium-enriched garlic.

The anticarcinogenic activities of regular (soil-grown) garlic and selenium-enriched garlic (cultivated in the greenhouse) were evaluated using the 7,12-dimethylbenz[a]anthracene-(DMBA) induced mammary tumor model in rats. In Experiment 1, milled regular garlic powder was added to the basal AIN-76A diet at 20 g/kg. The results from different schedules of supplementation suggested that a continuous treatment, which started before DMBA and persisted for the entire duration of the study, was most effective in tumor suppression. In Experiment 2, selected allyl group-containing sulfides that are normal constituents of garlic extract were given by gavage in three single doses immediately before DMBA. Several structurally related compounds were found to be protective during the initiation phase in the mammary cancer model. Although the present study was not designed specifically to elucidate the structure-activity relationship with respect to sulfur chain length or alkyl versus alkenyl substitution, our data showed that diallyl disulfide was more active than diallyl sulfide or allyl methyl sulfide. In Experiment 3, the anticarcinogenic activity of selenium-enriched garlic (containing 150 ppm Se dry weight from growth in a selenium-fertilized medium) was compared with that of regular garlic as well as selenite. Animals given the selenium-enriched garlic (final concentration 3 ppm Se in the diet) developed the fewest mammary tumors. Tissue selenium levels, however, were lower in these animals than in those fed the same amount of selenium from selenite. Our study demonstrated the feasibility of achieving cancer prevention with the use of a selenium-rich food system.(ABSTRACT TRUNCATED AT 250 WORDS)


Antimutagenic and anticarcinogenic effects of carotenoids and dietary palm oil.

Four carotenoids, canthaxanthin, beta-carotene, 8H-apo-beta-carotenal, and 8'-apo-beta-carotene methylester were tested for their ability to suppress the mutagenicity of 1-methyl-3-nitro-1-nitrosoguanidine and benzo[a]pyrene (BP) in Salmonella typhimurium tester strain TA 100. The anticarcinogenic efficacy of the four carotenoids was further assessed in the BP-induced forestomach tumor model in female Swiss mice. The effect of dietary palm oil was also examined in BP-induced neoplasia in the female Haffkine Swiss mouse strain. Canthaxanthin, beta-carotene, 8'-apo-beta-carotenal, and 8'-apo-beta-carotene methylester showed a dose-dependent decrease in the mutagenicity compared with 1-methyl-3-nitro-1-nitrosoguanidine and BP in strain TA 100. In the BP-induced forestomach tumor model, all four carotenoids showed a similar significant anticarcinogenic effect. Dietary administration of palm oil showed a dose-dependent antitumor activity in the animals. Our results show that the intrinsic antimutagenic and anticarcinogenic properties of the carotenoids are not significantly influenced by their conversion to vitamin A.


Differences in dietary intake with smoking, alcohol, and education.

Differences in the frequency of consumption of 30 selected foods and in the estimated intake of total calories and selected nutrients in relation to alcohol drinking, tobacco smoking, and education were described using information obtained from 1,774 controls of a case-control study of digestive tract cancers conducted in northern Italy. Heavy alcohol consumption, tobacco smoking, and lower level of education were associated with a diet poorer in several aspects, including lower consumption of fresh fruit and green vegetables and higher intake of specific indicator foods, such as sausages and canned meat. For instance, the mean number of portions of fresh fruit per week was 10.5 among male nondrinkers vs. 9.0 among heavy drinkers, 10.4 among male nonsmokers vs. 8.1 among heavy smokers, and 8.8 in less educated individuals vs. 10.7 among those more educated. Consequently, intake of beta-carotene, ascorbic acid, and calcium tended to be inversely related to alcohol and tobacco and directly related to education. Most associations were stronger in males, for whom alcohol consumption was also more common in less educated individuals. Calorie intake was directly related to alcohol consumption, largely reflecting calories provided by alcohol itself. However, alcohol drinking was also directly related to fat consumption. In both sexes, there was a strong positive correlation between cigarette smoking and coffee drinking. These results provide quantitative documentation that alcohol drinking, tobacco smoking, and education, three of the major determinants of cancer risks, were also correlates of dietary patterns and, hence, may exert an important confounding or modifying effect on the diet and cancer relationship.


Influence of dietary fat intake on local recurrence and progression of metastases arising from MDA-MB-435 human breast cancer cells in nude mice after excision of the primary tumor.

This study was performed to evaluate the effect of dietary fat on the recurrence and metastasis of human breast cancer solid tumors growing in nude mice after surgical excision of the primary tumor. Female nude mice were fed either a high- (23% corn oil) or a low-fat (5% corn oil) diet, and 7 days later 1 x 10(6) MDA-MB-435 human breast cancer cells were injected into a thoracic mammary fat pad. Tumors at the injection site grew more rapidly in the animals fed the high-fat diet. Nineteen of 30 animals in each dietary group had tumors with a surface are > or = 1 cm2 within 10 weeks of injection, at which point the tumors were excised and the animals were followed for another eight weeks. Tumors recurred at the excision site in 8 of 19 animals fed the high-fat diet and in 9 of 19 animals fed the low-fat diet; however, the growth rate was more rapid in the group fed the high-fat diet. Lung metastases occurred with similar frequency in the two groups with local recurrences, but with a positive correlation between recurrent tumor weight (greater in the animals fed the high-fat diet) and the severity of lung metastatic involvement. In the mice without recurrence, 4 of 11 (36%) animals in the group fed the high-fat diet had macroscopic lung metastases compared with only one mouse, with minimal involvement, in the group fed the low-fat diet.


Reliability of dietary information from surrogate respondents.

A self-administered food frequency questionnaire was included as part of a case-control study of breast cancer in 1980-82. In 1986-87, a second food frequency questionnaire was sent to surviving cases and husbands of deceased cases; 30 spouses (86% response rate) and 263 surviving cases (88% response rate) returned questionnaires. The dietary questions concerned consumption of specific food items by the case before diagnosis of breast cancer. Missing values were less common in the second questionnaire; there was no significant difference in missing values between surviving cases and spouses of deceased cases. Kappa statistics comparing responses in the first and second questionnaires were significantly lower for spouses of deceased cases than for surviving cases. Reported level of confidence by the husbands regarding knowledge about their wives' eating habits did not influence the kappa statistics or the frequencies of missing values. The lack of good agreement has important implications for the use of proxy interviews from husbands in retrospective dietary studies.


The reproducibility of a food frequency questionnaire among controls participating in a case-control study on cancer.

This study was designed to test the reproducibility of a food frequency questionnaire used in a population-based case-control study on diet and pancreatic cancer. Repeat questionnaires covering the same time period were obtained using 63 male and female population controls, 35-79 years of age. For selected food items included in the case-control study, the attenuation of the odds ratios due to random error was estimated. Using 54 male and female population controls, 35-79 years of age, we conducted a second study to examine the agreement between original and repeat interviews when the time interval between interview and the period of interest was constant. In the first study, the median correlation coefficient was 0.72 for foods (ranging from 0.36 and 0.59 for subgroups of vegetables to 0.96 for alcoholic beverages) and 0.77 for nutrients (ranging from 0.62 for beta-carotene to 0.85 for energy and 0.91 for ethanol). In the second study, the median correlation coefficient was 0.68 for foods (ranging from 0.28 for eggs to 0.87 for alcoholic beverages) and 0.75 for nutrients (ranging from 0.48 for beta-carotene to 0.76 for energy). We conclude that for most items the agreement between original and repeat estimates was moderate (r > 0.50) to high (r > 0.70). Moderate agreement was found for 28 of 33 food items (85%) and for all 21 nutrient items (100%) and high agreement for 19 of 33 of food items (56%) and 15 of 21 nutrient items (71%). In the second study, agreement was somewhat lower but closely paralleled the results of the first study. On average, random error presumably attenuated most of the observed diet-cancer relationships only moderately; i.e., an observed odds ratio of 1.5 and a correlation coefficient of 0.70 yield an unattenuated odds ratio of 2.1.


Bile salt/acid induction of DNA damage in bacterial cells: effect of taurine conjugation.

Bile salts and acids have been implicated in the etiology of colon cancer, possibly through their ability to cause DNA damage. Taurine-conjugated and nonconjugated forms of three bile salts and one bile acid were tested for DNA repair-inducing potential and for cellular toxicity in a recently developed Escherichia coli chromotest system. The taurine-conjugated forms of sodium deoxycholate and lithocholic acid had reduced ability to induce DNA repair. Also the taurine-conjugated form of lithocholic acid had a reduced lethal effect. These observations suggest that the biotransformation step, whereby bacteria in the intestine remove the taurine added to bile salts in the liver, may be significant in the etiology of colon cancer.


Humoral and cellular immune functions are not compromised by the anticarcinogenic Bowman-Birk inhibitor.

Previous studies have demonstrated that the soybean-derived Bowman-Birk protease inhibitor (BBI) is effective as a cancer chemopreventive agent in several animal model systems. Proteases represent a key component of several aspects of immune function; therefore the immune system is a primary target for potential toxicity. The present investigation examines the effect of dietary and intraperitoneally administered BBI on antibody response to keyhole limpet hemocyanin and delayed-type hypersensitivity response to dinitrochlorobenzene. Primary antibody response was not altered by BBI treatment; however, an elevated secondary response was observed in animals receiving dietary BBI at two weeks of age. This effect was not observed at later time points. No change in delayed-type hypersensitivity response was observed in any of the treatment groups.


Fecal ammonia in patients with adenomatous polyps and cancer of the colon.

The correlation between high intakes of protein and high incidence of human colonic cancer is unexplained. Appreciable amounts of ammonia are generated in the large bowel through bacterial degradation of proteins and peptides, and experimental studies indicate that ammonia may select for neoplastic growth. Fecal concentrations of ammonia did not differ among 17 patients with former colonic adenomas [40.6 +/- 4.5 (SE) mM], 17 patients with former colonic cancer (51.4 +/- 3.9 mM), and 16 healthy controls (46.4 +/- 6.1 mM). By use of an in vitro fecal incubation system, possible alterations in bacterial fermentation and formation of ammonia were investigated. Fecal suspensions were incubated for 6 and 24 hours with and without addition of fermentable substrates (ispaghula husk, wheat bran, albumin, and glucose; 10 mg/ml). The in vitro production of ammonia in unsupplemented fecal homogenates from both groups of patients was comparable with the production found in homogenates from healthy controls, and the response to fermentable substrates was similar in all three groups. Addition of albumin caused a marked increase in the production of ammonia, and addition of glucose increased bacterial assimilation of ammonia considerably. These well-known characteristics of bacterial metabolism of ammonia apparently did not differ between healthy individuals and patients investigated more than three months after colonoscopic polypectomy or colonic cancer resection.


Biodistribution of ellagic acid and dose-related inhibition of lung tumorigenesis in A/J mice.

Ellagic acid (EA), derived from fruit ellagitannins, is known to be antimutagenic and anticarcinogenic in various animal tumor models. In this study, EA at a dose of 4 g/kg diet inhibited multiplicity of tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice by 54%. This inhibition was dose related between 0.06 and 4.0 g/kg diet. In contrast, two related compounds, esculin and esculetin, had no effect on lung tumorigenesis. The biodistribution of EA was studied as a function of dose and time after gavage of EA. The levels of EA in the lung were directly proportional to the dose of EA between 0.2 and 2.0 mmol. The maximum level of EA, corresponding to 21.3 nmol/g, was observed 30 minutes after gavage with 2.0 mmol of EA/kg body wt, which corresponds to only 70 ppm of the administered dose. The levels in liver tissues were 10-fold lower and reached a maximum 30 minutes after gavage. At this interval, the blood level of EA was 1 nmol/ml. The inclusion of EA in cyclodextrin doubles the level of EA in lung tissues. These results demonstrate that EA localizes preferentially in lung tissues and confirm that EA administered orally can inhibit lung tumorigenesis.


The carcinogenicity of some antimalarial drugs using the Egyptian toad Bufo regularis as a biological test animal.

Feeding Egyptian toads (Bufo regularis) with chloroquine and primaquine separately induced tumor formation in 14% and 19% of the animals, respectively. When chloroquine and primaquine were given in combination, the tumor incidence increased to 23.5%. Chloroquine feeding resulted in tumors located in the liver (lymphosarcomas) and primaquine in tumors in the kidney (histiocytic sarcomas). Toads fed chloroquine plus primaquine developed tumors in the liver, kidney, lung, and urinary bladder, and all the tumors were diagnosed as histiocytic sarcomas. It is speculated that one or more metabolites of chloroquine and primaquine (e.g., quinone) may be responsible for tumor induction in the toads.


Alcohol consumption and the etiology of colorectal cancer: a review of the scientific evidence from 1957 to 1991.

The relationship between alcohol consumption and colorectal cancer in humans has been examined in 52 major studies in the past 35 years. An association was found in five of the seven correlational studies. An elevated risk was found in about half of the 31 case-control studies and, of these, in 9 of the 10 studies using community controls but in only 5 of the 17 studies using hospital controls (p = 0.008), suggesting that the absence of association when hospital controls are used is due to a high prevalence of alcohol consumption/alcohol-related illness in the hospital controls. Of the 14 cohort studies, an association with alcohol was found in 10, while in 3 of the 4 cohort studies in which an association was not found the alcohol data obtained were somewhat restricted. A positive dose-response effect was found in two of three cohort studies and in all four case-control studies with community controls in which this effect was examined. In both case-control and cohort studies, the association was found for females and males and for colon and rectal cancer. When the type of alcohol consumed was examined separately, beer was the principal type of at-risk alcoholic beverage, with much less risk for spirits and least risk for wine. Statistically significant elevations of risk were more often found in males than in females and slightly more frequently for rectal than for colon cancer and were related almost entirely to beer, rather than to wine or spirit, consumption. The alcohol risk was independent of the dietary risk in those studies that controlled for this factor. There was some confirmatory evidence for alcohol augmentation in rodent models of chemically induced carcinogenesis in six of nine studies. The hypotheses of alcohol as a direct and specific colorectal carcinogen include increased mucosal cell proliferation, the activation of intestinal procarcinogens, and the role of unabsorbed carcinogens, particularly in beer. Also, five of six other human studies showed an association between alcohol/beer consumption and adenomatous polyps, consistent with the hypothesis that alcohol stimulates the colorectal mucosa. General or indirect carcinogenic effects of alcohol include immunodepression, activation of liver procarcinogens, and changes in bile composition, as well as nitrosamine content of alcoholic beverages and increased tissue nitrosamine levels. With alcohol/beer consumption, the overall conclusion on present evidence is that alcohol, particularly beer consumption, is an etiologic factor for colon and rectal cancer for females and males.(ABSTRACT TRUNCATED AT 400 WORDS)


Use of a new fallback function to prevent endless-loop tachycardias: first clinical results. The Investigators of the Multicenter Study.

The methods used for preventing endless-loop tachycardias (ELTs) most often consist of initiating a long postventricular atrial refractory period (PVARP) with the sensing of every event likely to induce ELTs, such as sensed premature ventricular contractions (PVCs). A new fallback function may be useful to prevent the initiation of ELTs. A window of atrial rate acceleration detection (WARAD) is initiated with the sensing of every sinus event and equals 75% of the preceding PP interval. If an atrial event is sensed during this period, as are premature atrial contractions (PACs), no atrioventricular (AV) delay is initiated, but an atrial pulse output is delivered and a subsequent 31-msec AV delay is started. Theoretically retrograde P waves are premature compared to sinus rhythm. They are therefore detected as PACs, and do not initiate AV delay, thus prohibiting the induction of ELTs. This function was tested in six patients, using external or implanted Chorus 2 pacemakers. Short PVARP (203 msec) and high atrial sensibility were programmed. Retrograde conduction was induced either by inefficient atrial pacing or a long programmed AV delay. Two different dual chamber settings were tested: dual chamber pacing with the fallback function On or Off. In every situation, the function proved effective in preventing ELTs: the number of tachycardia episodes went from 124 with the function programmed Off to 5 with the function programmed On for comparable durations. More than 75 ELTs effectively prevented by fallback have been recorded.


Acute renal failure in bone marrow transplantation.

Acute renal failure (ARF) is a serious complication in clients who have undergone bone marrow transplantation (BMT). The majority of cases develop as a result of intrarenal damage. Renal ischemia or nephrotoxic drugs, free hemoglobin, and free myoglobin contribute to acute tubular necrosis (ATN), which is the most likely cause of ARF in BMT clients. Nursing care of hospitalized BMT clients is directed toward the prevention of ARF by identifying clients who are at risk, the early diagnosis of renal impairment, and the administration of comprehensive treatment. Nurses play a vital role in the early diagnosis of renal impairment by assessing the client's fluid status, serum and urine electrolyte levels, and daily weights. The nursing role in managing clients with ARF includes preventing drug nephrotoxicity, maintaining fluid and electrolyte balance, preventing infection, and providing emotional support.


Management of neutropenic enterocolitis in the patient with cancer.

Neutropenic enterocolitis is a life-threatening condition often seen in patients experiencing prolonged periods of neutropenia from conditions such as leukemia and lymphoma and from aggressive chemotherapy regimens. Its exact pathologic process remains unclear; however, it has been proposed that direct cytotoxic damage occurs to the bowel mucosa with subsequent microbial invasion complicated by the lack of adequate neutrophil response. The damage may progress to bowel perforation and septic shock. Early recognition and management by healthcare team members are crucial for the improved prognosis of these individuals. Controversy continues to exist concerning management options and the timing of these interventions. This article outlines nursing and medical management of the patient with neutropenic enterocolitis.


Unconventional cancer treatments: professional, legal, and ethical issues.

A significant number of patients with cancer use or seriously consider using unconventional treatments. When patients or their families seek or use unproven treatment methods, the oncology nurse may face complex professional, legal, and ethical issues. This article addresses the possible reasons why patients and families may choose unconventional treatments. Oncology nurses are challenged to become aware of their many and varied nursing responsibilities. These responsibilities are examined in light of applicable codes and nursing practice standards, the clinical situation, and the values that are unique to each patient and family. Guidelines are offered for the oncology nurse to assist patients and families in choosing among treatment options.