Partitioning behaviour of local anesthetic fomocaine derivatives. The octanol/water partitioning behaviour of local anesthetic fomocaine derivatives has been investigated. The true partition coefficients obtained from log P(app) values reflect well the high lipophilicity of these aminoalkylaryl-ether type compounds. A consequence of this is that the partitioning of the protonated form is not negligible as was proved by the log P(i) values of the ionized molecule measured at pH 4.0. The effect of ionization on partitioning was studied and characterized by the pQ values. This ionization influence on lipophilicity was found quite constant (pQ approximately 4) among the hydroxypiperidine analogs. A parabolic relationship was obtained between the acute toxicity and the log P values of several of the examined compounds.


Bioavailability of two formulations of acetylsalicylic acid gums. Bioavailability studies have been performed with ten healthy volunteers on different dosage forms of acetylsalicylic acid (ASA) in order to assess the bioavailability of two different ASA gums compared with commercial ASA tablets. The results of this study show that ASA is more readily absorbed and eliminated after administration of gum formulations than after administration of tablets, but the bioavailability obtained from the gums was lower than that observed from the tablets.


[Mucus models for investigation of intestinal absorption mechanisms. 2. Mechanisms of drug interactions with intestinal mucus]. Using in vitro models previously described [1] mucus retention and mucus diffusion of polar and non-polar drugs were measured. It could be shown that drug interaction with pig intestinal mucus was based on non-specific binding. The pH-dependence of retention by mucus does not confirm electrostatic interaction of drugs with mucus but favour drug distribution to hydrophobic areas within the mucus. High lipophilicity and retention by mucus correlate with low diffusion of drugs through mucus.


Effects of the nootropic AWD 52-39 on the blood-brain transfer of leucine, choline and glucose in rats after 14-d exposure to ethanol. The transport of the neutral amino acid L-leucine as well as of choline and D-glucose across the blood-brain barrier (BBB) of male Wistar rats was studied after 14-day exposure to ethanol and treatment with the nootropic drug AWD 52-39 (1). After ethanol exposure the half-saturation constant (Km) and the maximum velocity of transport (Vmax) declined in the majority of the investigated brain regions. Also, the treatment elicited a regionally different increase of the permeability-surface area (PS) product of choline (between 10% and 33%) and glucose (between 12% and 27%). The changes in the blood-brain transfer of the three compounds were diminished or prevented by additional application of 1. The cerebral blood flow was increased by the exposure to ethanol by maximally 44%. After additional administration of 1 the changes were reversed and the blood flow reached control values. In addition, the activity of the enzyme acetylcholine esterase was determined in the striatum and the hippocampus. After ethanol exposure the enzyme activity declined by 32%. It was less diminished after treatment with 1. The latter effects let assume that the changes of the BBB permeability elicited by ethanol and 1 are related to alterations of brain metabolism.


[Effects of valerian root oil, borneol, isoborneol, bornyl acetate and isobornyl acetate on the motility of laboratory animals (mice) after inhalation]. The aromatherapeutical use of commercial valerian root oil (Chinese origin) and of pure fragrance compounds--borneol, isoborneol, bornyl acetate (main constituent of the proved valerian root oil) and isobornyl acetate--as potentially drugs with sedative effects after inhalation was investigated in an animal experiment (mice). In additional analyses the mice were treated i.p. by caffeine and distinct sedative effects were observed only by inhalation of the cited substances.


[Activity of new iminium compounds against bacteria and fungi. 28. Synthesis of 1-ethyl-, 1-n-dodecyl-2-phenyl-3-(n-alkylthiomethyl)- and 1-ethyl-, 1-n-dodecyl-2-phenyl-3-(n-alkoxymethyl)imidazolium chlorides]. The synthesis of quaternary imidazolium compounds was performed by reaction of 1-ethyl- or 1-n-dodecyl-2-phenylimidazole with chloromethyl-n-alkyl ether or chloromethyl-n-alkyl sulfid. The antibacterial properties of the compounds obtained were tested on 13 strains of bacteria and fungi. 1-Ethyl-2-phenyl-3-(n-decylthiomethyl)-, 1-ethyl-2-phenyl-3-(n-dodecylthiomethyl)imidazolium chloride and 1-n-dodecyl-2-phenyl-3-(n-butylthiomethyl)-, 1-n-dodecyl-2-phenyl-3-(n-hexylthiomethyl)imidazolium chloride indicated the best antibacterial activity.


[Kentjur--a little-known asiatic spice and medicinal plant]. Detailed description of the morphological and anatomic characteristics of Indian originating Kentjur plant (Kaempferia galanga L., Zingiberaceae family) which is cultivated in Java and the Sudan. In case of suspected falsification of the Kentjur powder by other Zingiberaceae rhizome powders or their starches it is difficult to differentiate. The quality determining components are described as well as the utilization as spice and medicinal herb.


In vivo evidence that ethosuximide is a substrate for cytochrome P450IIIA. The role of various subfamilies of rat hepatic cytochrome P450 in the oxidation of ethosuximide was evaluated by comparing ethosuximide clearance in control rats and those pretreated with relatively selective P450 inducers and/or inhibitors. Clotrimazole pretreatment increased ethosuximide clearance threefold (p less than 0.005). Dexamethasone increased ethosuximide clearance twofold (p less than 0.001), and the dexamethasone effect was completely abolished by a single dose of triacetyloleandomycin. These results suggest a prominent role for cytochrome P450IIIA in ethosuximide metabolism in the rat. Isoniazid increased ethosuximide clearance twofold (p less than 0.001), and this effect was abolished by a single dose of diallylsulfide, suggesting that ethosuximide is also processed by cytochrome P450IIE1 in rats. Phenobarbital pretreatment increased ethosuximide clearance 2-2.7 fold (p less than 0.001); an effect that was only partially reversed by orphenadrine, an inhibitor of cytochrome P450IIB/IIC enzymes. This suggests a quantitatively less important role for the IIB/IIC subfamilies in processing ethosuximide, since phenobarbital is an inducer of P450 subfamilies IIB, IIC, IIE, and IIIA. Neither the cytochrome P450IA inducer, beta-naphthoflavone, nor the inhibitor, alpha-naphthoflavone altered ethosuximide clearance. Ajmaline, an inhibitor of cytochrome P450IID, had no effect on ethosuximide clearance. Together, these findings suggest that ethosuximide is principally oxidized by cytochrome P450IIIA, and that cytochrome P450IIE may play an important role. Cytochromes P450IIB/C play less prominent roles in ethosuximide oxidation, and neither cytochrome P450IA nor cytochrome P450IID is involved.


Pharmacokinetics of pyrazinoyl-guanidine, 3-aminopyrazinoyl-guanidine and their corresponding pyrazinoic acid metabolites in humans and dogs. Pyrazinoylguanidine (PZG), 3-aminopyrazinoylguanidine (NH2PZG) and their pyrazinoic acid metabolites were measured by a new reverse-phase HPLC method in the serum of dogs and humans after administration of PZG, NH2PZG or 2-pyrazinoic acid (PZA). Kinetic properties of PZG and its principal metabolite, PZA, were studied in normal humans and also in azotemic patients, since PZG acts on renal tubules of patients with kidney failure to increase urea elimination. In humans and dogs, PZG was rapidly hydrolyzed to PZA. The serum half-life (t1/2) of PZG was 1 h. In turn, PZA was metabolized to 5-hydroxy-PZA, but no evidence appeared for conjugation of PZA with glycine. The apparent volume of distribution of PZG and its 3-amino analog, NH2PZG, exceeded that of total body water. In the dog the serum t1/2 for NH2PZG was twice that of PZG. Compared to PZG, NH2PZG and its metabolite, 3-aminopyrazinoic acid, were much stabler in vitro in serum and water.


Activated astrocytes, but not pyramidal cells, increase glucose utilization in rat hippocampal CA1 subfield after ischemia. The local cerebral glucose utilization (CMRglc) in the damaged rat hippocampal CA1 subfield increases 7 days after 10 min of cerebral ischemia. We have used the N-methyl-D-aspartate antagonist (NMDA antagonist) ketamine in rats 7 days after sham operation or cerebral ischemia to determine whether the elevated postischemic CMRglc of the CA1 subfield is due to long-lasting hyperexcitation of surviving or injured neurons, or, alternatively, to the metabolism of other cell types. The autoradiographic data were interpreted with the aid of histochemical analysis of the postischemic hippocampal cell changes. Anesthetic doses of ketamine significantly reduced the CMRglc in the CA1 strata oriens, pyramidale and radiatum of sham-operated rats, while the postischemic increases in CMRglc in these hippocampal CA1 strata were not affected by ketamine. In addition, there were ketamine-induced increases in the CMRglc of the CA1 stratum lacunosum moleculare of both sham-operated and postischemic rats. The immunoreactivity of the microtubule-associated protein 2 (MAP2), a postsynaptic protein marker, was decreased markedly in the CA1 subfield in postischemic rats, while the presynaptic protein marker, synaptophysin, remained the same in sham-operated and postischemic rats. The glial fibrillary acidic protein (GFAP) immunoreactivity of astrocytes raised markedly in the ischemically damaged CA1 subfield. Although it could be demonstrated that presynaptic terminals remain intact in the postischemic damaged CA1 subfield, the lacking ketamine effect on CA1 pyramidal neurons indicated that the increase in CMRglc in this brain area is not due to postsynaptic neural hyperexcitation, but probably has to be attributed to astrocytes activated by neuronal damage.


Sulphydryl-containing agents stimulate the healing of duodenal ulceration in man. This prospective randomized double-blind study examined whether sulphydryl-containing agents stimulate the healing and prevent the recurrence of duodenal ulceration in man. To this end, DL-methionine methyl sulphonium chloride (MMSC, 500 mg four times daily) or DL-cysteine (200 mg four times daily) were orally administered with cimetidine. Symptomatic endoscopy-proven duodenal ulcer patients who were smokers and social drinkers were randomized to receive for 8 weeks cimetidine (400 mg b.d.), cimetidine (400 mg b.d.) with MMSC, or cimetidine (400 mg b.d.) with cysteine. These patients were then kept on their respective oral regimens (except for cimetidine which was changed to 400 mg at bedtime) for 1 year (maintenance) and followed up for another. After 8 weeks of treatment, the ulceration healed in 65 patients (74%) given cimetidine alone but in all the patients given MMSC (n = 87) or cysteine (n = 86) with cimetidine (p less than 0.01). During the maintenance year, 15 patients (29%) given cimetidine at night relapsed. Addition of MMSC or cysteine to cimetidine incurred a significantly (p less than 0.001) lower relapse rate. During the year following maintenance therapy, the relapse rate in the group that had been previously treated with cimetidine alone (63%, n = 51) was significantly (p less than 0.001) higher than that in the groups previously treated with MMSC and cimetidine (6%, n = 67) or cysteine with cimetidine (6%, n = 64). The results suggest that sulphydryl-containing agents stimulate the healing and protect against the recurrence of duodenal ulceration.


Antitumor activity of siwenmycin: a novel anthracycline antibiotic. A novel anthracycline antibiotic, siwenmycin, isolated from the culture of Streptomyces galilaeus var. siwenesis, was examined for its antitumor activities against P388, K562, B16-F10, HeLa, HEp-2 and Lewis lung carcinoma cell lines. The results showed that siwenmycin was effective against P388, K562, HeLa and HEp-2 tumor cell lines in vitro, and significantly inhibited the growth of the Lewis lung carcinoma cell line in vivo. Siwenmycin could also suppress spontaneous and artificial pulmonary metastases of B16-F10 and Lewis lung carcinoma cell lines in C57BL/6 mice. The inhibitory effect of siwenmycin on spontaneous pulmonary metastasis of Lewis lung carcinoma in C57BL/6 mice was even stronger than that of adriamycin (ADM), which is, at present, commonly used in clinical practice. Furthermore, the double-labeling test used in this study has verified that siwenmycin can inhibit cellular RNA synthesis at about one tenth the concentration required to inhibit DNA synthesis to the same degree, indicating that the antitumor mechanism of siwenmycin also differs from that of ADM. The acute toxicity of siwenmycin was very low, and it was as effective in vivo as in vitro, suggesting that this newly found antibiotic should be studied for possible clinical antitumor applications.


Relationships between ondansetron systemic exposure and antiemetic efficacy and safety in cancer patients receiving cisplatin. Single concentration estimators of systemic exposure to the serotonin type 3 receptor antagonist and antiemetic, ondansetron, were established in 55 cancer patients receiving cisplatin-based chemotherapy plus a daily regimen of ondansetron given every 4 h for 3 doses on each day of chemotherapy. Ondansetron plasma concentration measured 4 h after the first daily dose of ondansetron (C[4h]) proved to be a reliable index of AUC and hence of systemic exposure. In patients receiving dosages of cisplatin < 95 mg/m2, the risk of emesis was greatest among those with the lowest systemic exposure to ondansetron. Most patients (64%) experienced emesis if C[4h] was < 20 ng/ml, whereas emesis did not occur in any patient with C[4h] > 80 ng/ml. Among patients receiving very high dosages of cisplatin (> 95 mg/m2), comparable levels of systemic exposure were not totally effective in preventing emesis. For these patients, more ondansetron was required to block the greater emetic stimulus produced by higher doses of cisplatin. This difference reflects a shift in the log exposure versus response relationship, and is consistent with serotonin antagonism at a receptor. In contrast, reported side effects of ondansetron were not related to exposure.


Comparison of the in vitro effects of K+ channel modulators on detrusor and portal vein strips from guinea pigs. The effects of K+ channel openers and blockers on smooth muscles of vascular and nonvascular origin from guinea pigs have been investigated. Cromakalim, pinacidil, nicorandil and minoxidil sulfate all abolished the spontaneous myogenic activity of the guinea pig portal vein and the KCl-evoked activity of detrusor strips with the same rank order of ptoency. Whereas both apamin and charybdotoxin stimulated myogenic activity of the detrusor strips, they produced insignificant effects on spontaneously active portal vein strips and failed to antagonize the mechanoinhibitory effects of cromakalim in the two tissues. Glibenclamide, on the other hand, only stimulated the myogenic activity of portal vein strips but antagonized the mechanoinhibitory effects of cromakalim, pinacidil, nicorandil and minoxidil sulfate in both tissues. Rubidium, at millimolar concentrations, stimulated the myogenic activity, and antagonized the actions of cromakalim in both tissues. The data indicate that there are definite functional dissimilarities as exhibited by the differential response of the two tissues to K+ channel modulators. These findings may be exploited in the design of new drugs with tissue selectivity.


Transport of cimetidine across the basolateral membrane of rabbit kidney proximal tubules: interaction with organic anions. Since in whole animal studies and in man the renal clearance of cimetidine was prolonged by the coadministration of probenecid, the aim of the present study was to examine the interaction of the organic base cimetidine with the organic anion transport system at the basolateral membrane of isolated non-perfused rabbit proximal tubules. S2 segments of proximal tubules were incubated at 37.5 degrees C with 3H-cimetidine (2 x 10(-7) mol/l) or 3H-PAH (4 x 10(-6) mol/l, as a marker for the organic anion transport system) and 14C-inulin (marker for the extracellular space) for 25 min to achieve a steady state. Afterwards, a nonradiolabelled substance was added to the bath, and the change of the cellularly stored radioactivity was measured at 5-min intervals. Probenecid (5 x 10(-5) mol/l) decreased the cellular amount of 3H-cimetidine to 26% of the control value. At this concentration, furosemide and Na2SO4 had no effect. At a concentration of 10(-3) mol/l, these substances reduced the cellular 3H-cimetidine uptake to 33% (furosemide) and 57% (Na2SO4) of the control value. 10(-4) and 10(-3) mol/l succinate diminished the steady-state uptake of cimetidine to 77% and 53% of the control value, respectively. On the other hand, cimetidine (10(-3) mol/l) decreased the cellular uptake of 3H-PAH to 52% of the control value. N1-methylnicotinamide (5 x 10(-5) mol/l and 10(-3)mol/l) had no effect on the steady-state uptake of 3H-PAH. These results indicate that the organic base cimetidine, besides its high affinity for the cation transporter, also interacts with the organic anion transport system at the basolateral membrane of rabbit proximal tubules.


Endothelins and sarafotoxins: physiological regulation, receptor subtypes and transmembrane signaling. The endothelins and sarafotoxins are two structurally related families of potent vasoactive peptides. Although the physiological functions of these peptides are not entirely clear, the endothelins are probably involved in pathophysiological conditions such as hypertension and heart failure. This review summarizes the state of the art in some areas of this intensively studied subject, including: (1) structure-function relationships of ET/SRTX, (2) ET concentrations in plasma, (3) ET/SRTX receptor subtypes and (4) signaling events mediated by the activation of ET/SRTX receptors.


Aldose reductase inhibitors and diabetic complications. Aldose reductase inhibitors impede flux of glucose through the sorbitol pathway in diabetes mellitus. They therefore reduce the accumulation of the pathway metabolites, sorbitol and fructose, reduce the impact of the flux on the cofactors used by the pathway and reduce other derived phenomena, such as osmotic stress and myo-inositol depletion. As drugs, their targets are the chronic complications of diabetes--neuropathy, retinopathy, nephropathy and vasculopathy. In experimental models there is proof of activity against biochemical, functional and structural defects in all of the involved tissues, but we await full clinical verification of this potential.


Ornithine decarboxylase as an enzyme target for therapy. Interest in ornithine decarboxylase (ODC) and the therapeutic effects of its inhibition with the consequent depletion of polyamine biosynthesis has been widespread since the late 1970s and 1980s. This review covers new information about the properties of ODC, recent findings with ODC inhibitors and a discussion of the mechanism of inactivation of ODC by eflornithine. Recent in vivo therapeutic approaches of ODC inhibition are also discussed including: cancer and cancer chemoprevention; autoimmune diseases; polyamines and the blood-brain barrier, ischemia and hyperplasia; the NMDA receptor and modulation by polyamines; hearing loss; African trypanosomiasis; Pneumocystis carinii pneumonia and Cryptosporidium in AIDS; and other infectious diseases/organisms.


Mitochondrial DNA damage by anticancer agents. Mitochondrial DNA (mtDNA) is susceptible to damage by a number of anticancer agents either directly or indirectly. This damage is of little consequence if only a few of the mtDNA molecules are damaged. However, multiple drug treatments could result in a significant effect on a cell's ability to survive. The differential effect of anticancer agents on either organ specific toxicities or selective tumor kill can be partially accounted for by differential mtDNA content of cells and on the basis of differential protective mechanisms within mitochondria of various organs or tumor tissue. The concept of damage to mitochondria, especially its genome, is a subject of active investigation in various laboratories. This area of research may provide mechanism(s) by which organ specific toxicities or tumor specific toxicities may be elaborated. Also, the concept of targeting tumor specific mitochondria and/or mtDNA by anticancer agents is very attractive but has not come to fruition due to a lack of understanding of the regulation of the genome in tumor cells. Future investigations in this arena will enhance our knowledge on the interaction between anticancer agents and extranuclear DNA.


Feasibility study of an electret dosimetry technique. Characteristics of a radiation charged electret dosimeter are described. The dosimeter is based on a parallel-plate ionization chamber with the exception that the collecting electrode is covered by a thin polymer, Teflon or Mylar. During the charging of the dosimeter, ions produced in the sensitive volume by an external radiation source drift in the externally applied electric field and become trapped on the polymer surface forming an electret. Once the external supply is removed, a field across the sensitive volume is produced by the electret charge, such that during any subsequent irradiation, ions opposite in sign to those on the electret surface are attracted to the electret and deplete the charge layer in an amount proportional to the air kerma. The remaining charge on the electret is read by an electrometer, through further irradiation. This technique allows the dosimeter to be simultaneously charged and calibrated, used in the field, simultaneously discharged and read, and reused again in situ without dismantling the dosimeter. Various parameters, however, were considered by direct discharge, rather than by initial exposure and subsequent measurement. Calibration, energy dependence, air kerma range, and reproducibility are discussed, and guard-ring effects on the linearity of the chamber are presented. Measurements of natural charge decay on the electrets are introduced.


Optimization of the electric field distribution in a large volume tissue-equivalent proportional counter. Large volume tissue-equivalent proportional counters are of interest in radiation protection metrology, as the sensitivity in terms of counts per unit absorbed dose in these devices increases as the square of the counter diameter. Conventional solutions to the problem of maintaining a uniform electric field within a counter result in sensitive volume to total volume ratios which are unacceptably low when counter dimensions of the order of 15 cm diameter are considered and when overall compactness is an important design criterion. This work describes the design and optimization of an arrangement of field discs set at different potentials which enable sensitive volume to total volume ratios to approach unity. The method has been used to construct a 12.7 cm diameter right-cylindrical tissue-equivalent proportional counter in which the sensitive volume accounts for over 95% of the total device volume and the gas gain uniformity is maintained to within 3% along the entire length of the anode wire.


Precision of mean transit time measurements in 99Tcm-DTPA renal scintigraphy: a Monte Carlo study. The precision of renal mean transit time (MTT) measurements by 99Tcm-DTPA scintigraphy was studied by a Monte Carlo procedure. Data were obtained from twenty mild essential hypertensives with normal renal function. An ensemble of equivalent data sequences was constructed for each renal time-activity curve (TAC), assuming the dominant noise in the data to be Poisson in character. TACS were deconvolved by the matrix method and MTT was inferred from retention functions by a procedure entailing a nonlinear least-squares minimization. For every ensemble of data sequences a distribution of MTTs was generated. The population-averaged coefficients of variation for these distributions were 1.6% and 2.6%, for whole-kidney and cortical data, respectively. We conclude that the precision of MTT determination from clinical data is comparable to that from simulated data. MTT measurements may be useful for detecting functional changes in individual kidneys following an intervention such as angiotensin-converting-enzyme inhibition.


Dose rate distributions around 60Co, 137Cs, 198Au, 192Ir, 241Am, 125I (models 6702 and 6711) brachytherapy sources and the nuclide 99Tcm. Simple analytical functions derived from our point source Monte Carlo calculations on the combined attenuation and scatter factor, B exp(-mu r), for 60Co, 137Cs, 198Au, 192Ir, 241Am, 125I (models 6702 and 6711) brachytherapy sources and the nuclide 99Tcm, for water spherical geometries of radii R = 15 and 20 cm, are presented. Our results for the broadly used 60Co, 137Cs, 198Au and 192Ir brachytherapy sources can be compared directly and found in excellent agreement with the widely accepted data of Meisberger et al in the limited distance range for which the latter are valid. Our data, however, can be used with high accuracy outside this distance range. Many discrepancies observed among different data sets available in recent literature are attributable to differences in geometries used. The results for the recently introduced 241Am source are very dissimilar to those produced by any other currently used brachytherapy source. Dose rate distributions, based on the above simple functions, are proposed in accordance with the recommendations for calibration of the brachytherapy sources in terms of reference air kerma rate and were found to be in good agreement with data available in the literature. Our calculations for 125I sources (models 6702 and 6711), provided that the characteristic x-rays from titanium encapsulation are taken into account, support recent experimental and theoretical dose rate distributions indicating that currently accepted values for 125I may be overestimated.


Photon absorption measurements of bone density in the presence of scattered radiation. Bone density measurements are frequently carried out using photon absorptiometry techniques. The analysis of data collected in this way depends upon scatter-free detector signals. In practice the detector and source collimation lead to high levels of scattered radiation being detected. An analysis of the problem using photon transport computer models has shown that the current systems are reasonably insensitive to the scatter contribution except where patient changes occur over a long series of measurements or where new results taken with DEXA are compared with those taken on older systems such as DPA. This is frequently the case since the major body of data related to serial bone density measurements has been achieved with DPA. Inclusion of scattered radiation in the bone density calculations can lead to a 0.5-3.5% reduction between system types. Patient size changes could lead to a reduction in bone density of 0.5% (femoral neck measurement) to 1% (lumbar spine measurement).


Water-equivalent plastic scintillation detectors for high-energy beam dosimetry: I. Physical characteristics and theoretical consideration. A minimally perturbing plastic scintillation detector has been developed for the dosimetry of high-energy beams in radiotherapy. The detector system consists of two identical parallel sets of radiation-resistant optical fibre bundles, each connected to independent photomultiplier tubes (PMTs). One fibre bundle is connected to a miniature water equivalent plastic scintillator and so scintillation as well as Cerenkov light generated in the fibres is detected at its PMT. The other 'background' bundle is not connected to the scintillator and so only Cerenkov light is detected by its PMT. The background signal is subtracted to yield only the signal from the scintillator. The water-equivalence of plastic scintillation detectors is studied for photon and electron beams in the radiotherapy range. Application of Burlin cavity theory shows that the energy dependence of such detectors is expected to be better than the commonly used systems (ionization chambers, LiF thermoluminescent dosimeters, film and Si diodes). It is also shown that they are not affected by temperature variations and exhibit much less radiation damage than either photon or electron diode detectors.


Water-equivalent plastic scintillation detectors for high-energy beam dosimetry: II. Properties and measurements. The properties of a new scintillation detector system for use in dosimetry of high-energy beams in radiotherapy have been measured. The most important properties of these detectors are their hgh spatial resolution and their nearly water-equivalence. Measurements have shown that they have excellent reproducibility and stability, and a linear response versus dose-rate. It is also shown that they have better spatial resolution than ionization chambers and have much less energy or depth dependence in electron fields due to the removal of the influence of the polarization effect. Dose distributions in water, using miniature plastic scintillation detectors, have been measured for different high-energy photon and electron beams.


The mass angular scattering power method for determining the kinetic energies of clinical electron beams. A method for determining the kinetic energy of clinical electron beams is described. The method is based on the measurement in air of the spatial spread of a pencil electron beam which is produced from the broad clinical electron beam. As predicted by the Fermi-Eyges theory, the dose distribution measured in air on a plane, perpendicular to the incident direction of the initial pencil electron beam, is Gaussian. The square of its spatial spread is related to the mass angular scattering power which in turn is related to the kinetic energy of the electron beam. The measured spatial spread may thus be used to determine the mass angular scattering power, which is then used to determine the kinetic energy of the electron beam from the known relationship between mass angular scattering power and kinetic energy. Energies obtained with the mass angular scattering power method agree with those obtained with the electron range method. The angular scattering power method is relatively cumbersome, but allows us to determine the kinetic energies of electron beams from first principles, in contrast to the empirical methods based on range measurements in water.


Tissue maximum ratios (and other parameters) of small circular 4, 6, 10, 15 and 24 MV x-ray beams for radiosurgery. Small, circular, x-ray beams are commonly used for radiosurgery applications. Dosimetric characteristics of 4, 6, 10, 15 and 24 MV circular x-ray beams ranging in size from 10 to 40 mm are reported. These characteristics include the measurement of TMR, beam profiles and relative output factors. Measurements of these parameters were performed in a solid water phantom using film, a small diode, small parallel-plate and cylindrical ionization chambers and TLD. Comparison of relative dose measurements of small, circular beams performed using these detectors showed that the small diode, film and TLD results consistently agreed for circular beams as small as 10 mm diameter. Beam profiles were measured using film dosimetry. Comparison of TMR values of a 10 mm diameter beam measured using film and a small parallel-plate ionization chamber showed no significant differences. Tertiary collimators designed with tapered, divergence-matching holes, and straight-drilled holes have been used for radiosurgery applications. Measurement of beam penumbra produced with either of these types of tertiary collimators showed minimal differences between them.


A megavoltage CT scanner for radiotherapy verification. We have further developed a system for generating megavoltage CT images immediately prior to the administration of external beam radiotherapy. The detector is based on the scanner of Simpson (Simpson et al 1982)--the major differences being a significant reduction in dose required for image formation, faster image formation and greater convenience of use in the clinical setting. Attention has been paid to the problem of ring artefacts in the images. Specifically, a Fourier-space filter has been applied to the sinogram data. After suitable detector calibration, it has been shown that the device operates close to its theoretical specification of 3 mm spatial resolution and a few percent contrast resolution. Ring artefacts continue to be a major source of image degradation. A number of clinical images have been presented. The next stage of this work is to use the system to make clinical measurements of patient set-up inaccuracies building on our work making such measurements from digital portal images (Evans et al 1992).


Ultrasound scattering from spherical tumours. The interaction of biomedical ultrasound with spherical tumours in the human body is investigated using analytic methods which predict the angular distribution of the ultrasound scattered by the tumour. Both the tumour and the surrounding tissue are considered to be lossy elastic media, which support shear-wave modes in addition to the familiar compressional-wave acoustic modes. Exact expressions for the angular distribution of the ultrasonic energy scattered by the tumour are used to illustrate graphically the behaviour of plane ultrasound wave interactions.


The dielectric parameters of excised EMT-6 tumours and their change during hyperthermia. The electrical impedance from 100 Hz to 40 MHz of freshly excised EMT-6 tumours was measured periodically while the tumours were exposed to typical hyperthermia heating regimens. During hyperthermia, the EMT-6 tumour displays a characteristic response sequence which includes cellular swelling, progressive membrane damage, cellular shrinking and subsequent progressive histolysis. It was found that the changes in the tumour tissue dielectric properties reflected these hyperthermia-induced histological changes. In particular the parameters delta epsilon, sigma s and fc progressed to, reached, and retreated from extrema as the cells swelled to a maximum and then contracted. These parameters continued retreating beyond their original values as the beta-dispersion progressively collapsed during the period of progressive histolysis. The Cole-Cole parameter alpha increased during most of these histological changes, indicating a broadening of the dispersion, which suggests differential cell response during this period. Differences in the time-course between dielectric components may reflect the combined effects of cellular swelling and concurrent progressive membrane changes. Changes in rate and shape of the dielectric response with hyperthermia temperature are discussed in terms of possible cellular responses during hyperthermia.


Calculation of body transport function.

Calculation of body transport function. A new model for simulation of recirculation has been developed which describes the measured concentration-time course of a drug in the aorta. It is based on repetitive convolution of the injected input dilution curve with a body transport function plus the input dilution curve. If the basic shape of a body transport function, i.e. such as log-normal distribution, is known, it is possible to calculate the parameters of this function with a non-linear least-squares procedure from measured tracer dilution data. In the present investigation this algorithm is used to estimate the body transport function for experimental data, obtained in two experiments with sheep. Once the body transport function is known, the formula can be used to describe the dispersion of a drug. Intravascular concentration time curves at different places in the body can also be predicted or the blood volume can be estimated.


Conversion of ionization measurements to radiation absorbed dose in non-water density material. The radiation absorbed dose to non-water equivalent materials of interest in radiotherapy is the dose to lung and the dose to bone. The measurement and calculation of dose to the lung has been of great interest and much effort has gone into the development of accurate lung dose calculation methods. The radiation absorbed dose to the bone is usually not calculated and most absorbed dose calculations have been done without correcting for the presence of bone. For the lower megavoltage photon beams this may be appropriate, however, as the energy of the photon beam increases, the region of electronic disequilibrium becomes larger and pair production which depends on the atomic number of the material becomes significant. Therefore the bone will produce greater perturbations of the dose distribution. The dose to lung-equivalent material is uniquely obtained from ionization measurements. However, in bone-equivalent materials two different calculations of absorbed dose are possible: the absorbed dose to soft tissue plastic (polystyrene) within bone-equivalent material and the dose to the bone-equivalent material itself. Both can be calculated from ionization measurements in phantoms. These two calculations result in significantly different doses in a heterogeneous phantom composed of polystyrene and aluminium (a bone substitute). The dose to a thin slab of polystyrene in aluminium is much higher than the dose to the aluminium itself at the same depth in the aluminium. Monte Carlo calculations confirm that the calculation of dose to polystyrene in aluminium can be accurately carried out using existing dosimetry protocols. However, the conversion of ionization measurements to absorbed dose to high atomic number materials cannot be accurately carried out with existing protocols and appropriate conversion factors need to be determined.


Estimation of effective dose to the patient during medical x-ray examinations from measurements of the dose-area product. Effective dose is likely to be used as a dose index for patient exposures in diagnostic radiology. Calculation of effective dose requires estimates of doses to many organs. In the absence of such dose data it would be useful to be able to directly estimate effective dose from a quantity that can be easily measured in the x-ray room. Relationships between effective dose and each of entrance surface dose, entrance air kerma and dose-area product were studied for common radiographic projections using the organ dose data from Monte Carlo modelling performed at the National Radiological Protection Board, UK. Dose-area product proved to be the best quantity for estimating effective dose and these data are presented. For typical peak generating potentials, estimates of effective dose can be made from dose-area product using a small number of conversion coefficients. For cervical spine, chest, kidneys, abdomen, lumbar spine and pelvis AP projections, the conversion coefficient 0.21 mSv per Gy cm2 will estimate effective dose within 30% of the value obtained using specific organ doses. Conversion coefficients for lateral and PA projections of the trunk are approximately half this value. These coefficients allow the direct estimation of effective dose with sufficient accuracy for most purposes.


Flavin-sensitized photochemically induced dynamic nuclear polarization detection of pyrimidine dimer radicals. A photochemically induced dynamic nuclear polarization (photo-CIDNP) study of carboxymethyllumiflavin-sensitized splitting of pyrimidine dimers has been carried out. In aqueous solution at high pH, an emission signal (delta 3.9 ppm) was observed from the dimer C(6)- and C(6')-protons of an N(1), N(1')-trimethylene-bridged thymine dimer (1). The dimer photo-CIDNP signal was seen only above pD 11.6 and was most intense at pD 12.9. Also observed were weak enhanced absorption signals from the product of splitting, trimethylenebis(thymine) (delta 1.7 and 7.2 ppm). In contrast, cis, syn-thymine dimer (3) gave no photo-CIDNP signals from the dimer. An enhanced absorption at 1.8 ppm, however, due to the product of splitting (thymine) was observed. It was found that dimer 1 and, to a lesser extent, dimer 3 quenched flavin fluorescence. An N(3),N(3')-dimethylated derivative of 1, however, failed to quench flavin fluorescence. Comparison of the pD profile of the dimer photo-CIDNP signal to the pKa values for thymidine dimer suggested that principally the dideprotonated dimer undergoes electron abstraction by the excited flavin.


Photophysical property of sanguinarine in the excited singlet state. The photophysical property of the alkanolamine form of sanguinarine has been studied in aqueous and organic medium under various environmental conditions from the measurement of absorption, fluorescence and NMR spectroscopy. Alkanolamine fluorescence shows an excitation time dependent fluorescence quenching and the rate of quenching increases significantly with increasing pH and concentration of the species, while it decreases with increasing temperature. This phenomenon is explained by excited state intramolecular proton transfer from a 6-OH group to the lone pair of nitrogen through the formation of zwitterion.


Laser mediated release of dye from liposomes. Liposomes made from phospholipids and containing sulforhodamine dye (1-50 mM) have been irradiated with nanosecond and picosecond laser pulses. Individual liposomes were locally heated by laser absorption of dye dimers during a single laser pulse, and heating was sufficient to release the liposome contents. The extent of dye release produced by a single laser pulse was shown to be quantitatively dependent on several interdependent variables, including dye concentration, liposome size, laser excitation parameters and initial temperature of the dye-liposome system. Fluorescence lifetime data having three components have been obtained and analyzed in terms of three dye environments. Quantitative estimates support a photo-induced thermal mechanism for liposome lysis and release of its contents. These results may be useful for laser induced delivery of therapeutic agents or other applications of lasers in biological systems.


Mitotic inhibition by phenylporphines and tetrasulfonated aluminium phthalocyanine in combination with light. This work relates to studies on modes of phototoxicity by tetrasulfonated aluminium phthalocyanine (AlPcS4), tetrahydroxy- and monosulfonated meso-tetraphenylporphines (3-THPP and TPPS1) on culture cells. Toxicity at moderate light exposures appears to be related to inhibition of microtubule function. Treatment of human cervix carcinoma cells of the line NHIK 3025 incubated for 18 h with the sensitizers and exposed to light inhibits multiplication for the first hours after light exposure, a significant fraction of the cells accumulating in mitosis. For the first hours after treatment, the mitotic cells were always mainly found in metaphase; generally seen as c-metaphases and three-group metaphases. During this time, anaphase and telophase cells were absent or greatly reduced in number. Indirect immunofluorescence staining of beta-tubulin showed that the spindle apparatus of mitotic cells was perturbed in all cases. The accumulation in mitosis was more extensive after treatment with AlPcS4 and light than after treatment with 3-THPP or TPPS1 and light. This may be related to the great difference in the lipophilic properties of these sensitizers; i.e. AlPcS4 being highly water soluble while TPPS1 and 3-THPP are lipophilic sensitizers. The lipophilicity of several sensitizers has been measured by two different methods, the partition between an aqueous and a lipophilic phase (Triton X-114) and the binding strength to a reverse phase column. The results show that the measured relative lipophilicity of the sensitizers may be influenced by the method of analysis.


The phototoxicity of 8-methoxythionepsoralen and 6-methylthionecoumarin. The phototoxicity of 8-methoxythionepsoralen (8-MOTP) and 6-methylthione coumarin (6-MTC) when activated by UV-A has been investigated using a variety of Escherichia coli strains, Haemophilus influenzae transforming DNA and Escherichia coli pBR322 plasmid DNA. The results demonstrate that 8-MOTP is a strictly oxygen independent photosensitizer that is about 500-fold less efficient in forming lesions leading to equivalent lethality than is the parent compound from which it is derived (8-MOP). As is true for 8-MOP, 8-MOTP is capable of inducing histidine independent mutations in E. coli and inactivating transforming DNA consistent with DNA being a target for lesions induced by this molecule in the presence of UV-A. 6-MTC is a strongly oxygen dependent photosensitizer activated by UV-A when tested with either E. coli cells or transforming DNA in contrast to the parent compound (6-methylcoumarin; 6-MC) which is not phototoxic when treated with UV-A. These results imply that the membrane may be an important target leading to lethality. 6-MTC in the presence of UV-A can inactivate pBR322 plasmid and Haemophilus influenzae transforming DNA activity in vitro suggesting that DNA is a potential target for this molecule when activated by UV-A.


Potentiation of oxidative damage to proteins by ultraviolet-A and protection by antioxidants. We have studied the damage of alcohol dehydrogenase (ADH) and glyceraldehyde 3-phosphate dehydrogenase (GAPD) induced by Fe++/EDTA + H2O2 in combination with UV-A (main output at 365 nm). Enzyme inactivation, formation of hydroxyl radicals (measured in the absence of enzymes), increase in protein carbonyls, oxidation of sulfhydryl (SH) groups, loss of native protein fluorescence, and enhanced protease degradation were used to determine protein damage. Hydroxyl radical production was greatly enhanced by the combination of UV-A with Fe++/EDTA + H2O2. The combined treatment increased protein carbonyls but decreased native protein fluorescence and SH groups. The combined treatment caused turbidity in GAPD but not in ADH, whereas trypsin susceptibility was increased more in ADH than in GAPD. These measurements of protein oxidation correlated well with enzyme activities. Glyceraldehyde 3-phosphate dehydrogenase and dithiothreitol were most protective against such damage, while hydroxyl radical and singlet oxygen scavengers were partially effective. Superoxide dismutase had no effect. Thus, UV-A potentiation of protein damage induced by FE++/EDTA + H2O2 appeared to involve hydroxyl radicals and perhaps singlet oxygen but not superoxide radicals. The damage to proteins induced by combination of UV-A with physiological oxidants, iron ions and H2O2 may be relevant to UV-A-induced skin and tissue damage.


Repair of thymine dimers and (6-4) photoproducts in group A xeroderma pigmentosum cell lines harboring a transferred normal chromosome 9. Transfer of a normal chromosome 9 into a xeroderma pigmentosum (XP)-A cell line partially restored its DNA repair activity. XP-A cell lines harboring a transferred chromosome were much more UV-resistant than parental XP-A cells but still more UV-sensitive than normal cells. The amount of UV-induced unscheduled DNA synthesis was only one-third of that in normal cells. The repair of thymine dimers and (6-4) photoproducts in these cell lines was analyzed by using monoclonal antibodies raised against them. Although these XP-A cell lines carrying a normal chromosome 9 could repair (6-4) photoproduct with a little lower efficiency than normal cells, the repair of thymine dimers was completely absent in these cells. The present results suggest a gene-dosage effect in DNA excision repair mechanisms in human cells or a rather complicated mechanism which involves two or more pathways.


Base release from DNA and polynucleotides upon 193 nm laser excitation. Release of bases form calf thymus DNA and three polynucleotides, induced by 20 ns excitation at 193 nm in aqueous solution at pH 7, was detected by HPLC. The quantum yields of formation of free bases (phi B) from double-stranded DNA (0.4 mM) are independent of intensity, indicating a one-quantum mechanism of N-glycosidic bond cleavage. The phi B values increase in the order guanine, thymine, adenine, cytosine, the latter being phi C approximately 7 x 10(-4) for double-stranded DNA under Ar and O2. The larger phi B values in N2O-saturated solution, e.g., phi C = 1.2 x 10(-3), are ascribed to additional base release via OH-adduct radicals. The phi B values of homopolynucleotides increase in the order poly(G), poly(A) and poly(C), e.g. phi C = 7 x 10(-3) under Ar, as do the efficiencies for base release per radical cation (eta B). A comparison of the eta B values with the efficiencies of single-strand breakage for poly(C), poly(A) and DNA shows a similar trend; both are markedly larger for pyrimidines than for purines. Pathways to undamaged bases, initiated from base radical cations, are proposed.


Effects of light beam size on fluence distribution and depth of necrosis in superficially applied photodynamic therapy of normal rat brain. The light fluence distributions of 632.8 nm light incident on the exposed surface of normal rat brain in vivo have been measured using an interstitial, stereotactically-mounted optical fiber detector with isotropic response. The dependence of the relative fluence rate on depth and the spatial distribution of fluence were compared for incident beam diameters of 3 and 5 mm. The fluence rate at depth of 1-6 mm along the optical axis within the brain tissue was approximately 70% greater for a 5 mm diameter beam than for a 3 mm beam, at the same incident fluence rate, although the plots of the relative fluence rate vs depth were parallel over the depth range 1-6 mm. The depths of necrosis resulting from photodynamic treatment of brain tissue using the photosensitizer Photofrin and irradiation by 632 nm light with 3 and 5 mm incident beams were also measured. The observed difference in necrosis depths was consistent with the measured difference in fluence. The importance of beam size in photodynamic treatment with small diameter incident light fields is discussed.


Improved survival from intracavitary photodynamic therapy of rat glioma. The effectiveness of intratumoral photoradiation in photodynamic therapy (PDT) using a polyporphyrin photosensitizer was studied in the RT-2 rat glioma model. One week after intracerebral implantation of RT-2 cells, experimental rats received a single i.p. injection of 2 mg/kg of Photofrin. After administration of the photosensitizer (48 h), the tumors were partially resected and the exposed cavity was irradiated with 15 J of laser light at a wavelength of 630 nm. Further treatment with a large craniectomy significantly enhanced rat survival. Control rats which received no photosensitizer but were treated with surgery, alone or in combination with laser irradiation, succumbed from early tumor recurrence. Photodynamic therapy without decompressive surgery resulted in hemorrhagic infarction of residual tumor and adjacent brain with focal cerebral edema which resulted in cerebral herniation and early death. Our results indicate that photodynamic therapy is effective in treating residual brain tumor but at the expense of brain tissue surrounding the tumor. Unless relieved, intracranial pressure from photodynamic therapy-associated cerebral edema in this animal model resulted in shortened survival.


Cellular delivery and retention of photofrin: II. The effects of human versus mouse and bovine serum. The effects of human serum (HS), mouse serum (MS) and fetal bovine serum (FBS) on cellular delivery and retention of Photofrin were examined using human lung tumor cells (A549) cultured in vitro. The results show that these three kinds of sera exhibit substantial differences in: (i) degree of inhibition of Photofrin cellular uptake, (ii) retention capacity of Photofrin delivered to the cells in their presence and (iii) efficacy of promoting the clearance of Photofrin from the cells. It is suggested that these differences originate from unequal interaction of each of the sera with Photofrin material, which in turn is the consequence of variability in composition and in the levels of serum proteins in HS, MS and FBS. The highest degree of Photofrin disaggregation and and competitive binding of its constituents was attributed to HS. The lowest degree of Photofrin disaggregation, and the competitive binding limited mostly to monomeric porphyrin forms was implicated for FBS. For MS, the spectroscopic and cellular data indicated a lesser degree of Photofrin disaggregation than with HS, with little if any consequence in Photofrin retention characteristics. The implication of this comparative analysis is that in vitro studies using FBS may underestimate the extent of interaction of Photofrin with serum proteins in humans, and overestimate the retention capacity of the photosensitizer in human tissues. Studies in vivo using a mouse model may also underestimate the degree of disaggregation of Photofrin in human circulation, and give different photosensitizer tissue retention levels than in humans.


Singlet oxygen quantum yield of sulfur and selenium analogs of psoralen. The quantum yield of singlet oxygen production by eight newly synthesized sulfur and selenium analogs of psoralen irradiated with UV-A (366 nm) has been determined in CCl4 with the help of the steady state luminescence technique. The new psoralen derivatives are generally better singlet oxygen producers than psoralen itself. In particular, the replacement of selenophene for furan and/or of thiopyrone for pyrone induces an important enhancement of the singlet oxygen quantum yield.


Dihydroxy-carotenoid liposomes inhibit phototoxicity in Paramecium caudatum. The phototoxic effects of hematoporphyrin derivative, using Paramecium caudatum as a model system, are significantly reduced in the presence of carotenoid-containing liposomes. Multilammelar large or small unilammelar vesicles, containing specific carotenoids, were effective in protecting the organism, whether administered exogenously in the bathing solution, or via incubation of paramecia in starved culture media containing carotenoid liposomes. The effectiveness of the carotenoids as inhibitors of phototoxic effects was found to depend on the mode of administration, with small unilammelar being more effective than multilammelar large vesicles for all carotenoids tested. Small unilammelar vesicles containing the dihydroxy-carotenoids zeaxanthin or astaxanthin afforded the greatest protection in both exogenous and endogenous studies. The results of this study suggest that carotenoid efficacy may be determined, in part, by the environment of the carotenoid molecules.


Metabolism of garlic constituents in the isolated perfused rat liver. The metabolic and kinetic behaviour of different garlic (Allium sativum L., Alliaceae) constituents were investigated in the isolated perfused rat liver, using aqueous extracts of garlic powder as well as isolated allicin, the main product of the enzymatic degradation of alliin. Allicin (allyl thiosulfinate) showed a remarkable first pass effect and passed the liver unmetabolized only at high concentrations which caused considerable cell injuries. Diallyl disulfide and allyl mercaptan were identified as metabolites of allicin, whereby diallyl disulfide probably is the metabolic precursor of allyl mercaptan as shown by perfusion with diallyl disulfide alone. The metabolites diallyl disulfide and allyl mercaptan could be determined in the perfusion medium as well as in the bile and the liver tissue. Other degradation products of garlic were also investigated in this model. Ajoenes and vinyldithiins were detected in perfusion medium after liver passage but no metabolites of them could be identified up to now.


Effects of Calaguala and an active principle, adenosine, on platelet activating factor. Calaguala, an extract from the fern Polypodium decumanum, has been used to treat psoriasis and related immunological disorders. In an effort to explain Calaguala's medicinal effects the inhibitory activity of the extract in two platelet activating factor (PAF) related models has been investigated. In the first model, PAF was used to induce release of the proteolytic enzyme elastase in human neutrophils. Calaguala inhibited this effect with an IC50 of 0.1 mg/ml. The known PAF antagonist ginkgolide BN 52021 was used as a positive control and had an IC50 of 0.034 mg/ml. In the second model the inhibition of biosynthesis of PAF in neutrophils using lyso-PAF and labeled acetyl-CoA was studied. Also in this assay Calaguala showed a dose-dependent activity, the IC50 being 0.2 mg/ml. Since recent findings have indicated that PAF might be involved in the pathogenesis of psoriasis, it is possible that the activity shown by Calaguala in these PAF assays may contribute to the clinical efficacy of the extract. The PAF induced exocytosis assay was further used to guide the fractionation of the crude extract. From the acetone supernatant the nucleoside adenosine was isolated as an active principle. Pure adenosine dose-dependently inhibited the exocytosis induced by PAF (IC50 = 0.024 micrograms/ml) but was inactive in the biosynthesis assay. Adenosine is most probably one of the bioactive compounds of Calaguala responsible for its therapeutic properties.


Effects of genistein, an isoflavone isolated from Genista tridentata, on isolated guinea-pig ileum and guinea-pig ileal myenteric plexus. The inhibitory action of the major constituent of Genista tridentata L. (Papilionaceae), 4',5,7-trihydroxyisoflavone (genistein), on contractions induced by agonists and electrical field stimulation of smooth muscle was analysed. Genistein inhibited twitches evoked by electrical-stimulation of strips of guinea-pig ileum with an IC50 value of 34 microM. Genistein (34 microM) inhibited contractions of the guinea-pig ileum by several agonists in a non-selective, antispasmodic action and had no effect on inhibition of 3H-ACh release from ileal myenteric plexus. Genistein (34 microM) produces an increase in cAMP levels of guinea-pig ileum which resulted in a smooth muscle relaxation which leads us to think that there must be a blockade of its phosphodiesterase.


Antisickling activity of hydroxybenzoic acids in Cajanus cajan. The amounts of phenylalanine and hydroxybenzoic acid in a Cajanus cajan methanolic extract were estimated. Results showed that the amount of phenylalanine and hydroxybenzoic acid per gram weight of bean was 4.92 mg +/- 0.13 mg and 21.0 mg +/- 3.0 micrograms, respectively. Sickling inhibition was observed to be efficient with the extract which contains a mixture of phenylalanine (0.69 mg/ml) and p-hydroxybenzoic acid (10.5 micrograms/ml), equivalent to those found in bean extract. The additive antisickling effect of both compounds can be therapeutically exploited for the treatment of sickle cell anemia.


Activation of PC12 cells by lipophilic components of Panax ginseng. The lipid soluble fraction of Panax ginseng C. A. Meyer has been found to possess a stimulatory effect on a para-neuronal culture cell line, namely PC12 cells. Addition of the diethyl ether extract (0.025-0.1 mg/ml) of Ginseng radix to a culture medium promoted the outgrowth of neurites from cells dose-dependently as well as their ready differentiation to respond to carbachol and high KCl-evoked membrane depolarization to induce free Ca2+ accumulation in the cells within a week of culture. Effective constituents of the extract were confined to four major substances detected in the extremely lipophilic front area on silica gel TLC.


The molluscicidal activity of coumarins from Ethulia conyzoides and of dicumarol. The molluscicidal principles of Ethulia conyzoides were identified as ethuliacoumarin A (1) and isoethuliacoumarin A (2). Ethuliacoumarin A possessed an LC90 between 19 and 23.5 ppm depending on the age of the snail against Biomphalaria glabrata, and between 12 and 15 ppm against Bulinus truncatus. In addition, ethuliacoumarin A was found to be cercaricidal at 25 ppm and ovicidal. Ethuliacoumarin has the structural requirements considered essential for anticoagulant activity. Consequently the anticoagulant dicumarol (4) was tested and found to be molluscicidal in the range from 2.5 to 10 ppm. In contrast, the coumarin anticoagulant warfarin (3) did not show molluscicidal activity.


Anethofuran, carvone, and limonene: potential cancer chemopreventive agents from dill weed oil and caraway oil. Bioassay-directed fractionation of dill weed oil and caraway oil, respectively, from the plants Anethum graveolens L. and Carum carvi L. (Umbelliferae) has led to the isolation of three monoterpenes, anethofuran (1), carvone (2), and limonene (3). Their structures were determined on the basis of spectral analysis. These compounds induced the detoxifying enzyme glutathione S-transferase in several mouse target tissues. The alpha,beta-unsaturated ketone system in carvone appeared to be critical for the high enzyme-inducing activity.


Analysis and stability of Hyperici oleum. Hyperici Oleum (St. John's wort oil) used in wound healing contains no hypericin. By using the sunlight maceration method described in the supplement to DAB 6 (EB 6), lipophilic breakdown products of this compound are obtained which lend the oil its red colour. Hyperforin, which is responsible for the oil's therapeutic activity could, for the first time, be identified and quantitatively determined by TLC and HPLC after solid-phase extraction. The stability of hyperforin is limited; sufficient shelf-life could only be achieved by hot maceration of dried flowers with eutanol G and storage in the absence of air. By gradient HPLC further polar hyperforin analogues were detected in those St. John's wort oils in which hyperforin had decomposed. At the same time flavonoids and xanthones could be identified. A procedure for the quantitative determination of flavonoids in St. John's wort was validated. The action of light during preparation of the oil led to a rise in the content of flavonoids.


[Neurotic symptoms of borderline patients: a case review study]. The author investigated neurotic symptoms of borderline patients by reviewing the clinical charts of twenty-six patients of longer than one year treatment period (8 men, 18 women; 23 patients with DSM III-R borderline personality disorder (BPD), 14 with schizotypal personality disorder (SPD), (11 BPD-SPD overlaps); age at the first contact: mean = 24.3 y. o., SD = 6.7 y. o.; treatment period: mean = 51 months, SD = 35 months). The diagnoses of the comorbid neurotic disorders were obsessive compulsive disorder: 5 cases (19% (BPD: 22%, SPD: 7%)), somatoform disorder: 5 (19% (BPD: 22%, SPD: 21%)), panic disorder: 4 (15% (BPD: 17%, SPD: 14%)), social phobia: 2 (8% (BPD: 9%, SPD: 7%)), dissociative disorder: 2 (8% (BPD: 9%, SPD: 0%)), and generalized anxiety disorder: 1 (4% (BPD: 4%, SPD: 7%)). The neurotic symptoms identified in the charts of the subjects were as follows; symptoms of social phobia: 11 cases (42% (BPD: 43%, SPD: 43%)) including 6 with anthropophobic symptoms (23% (BPD: 26%, SPD: 36%)), obsessive compulsive symptoms and diffuse and floating anxiety: 9 (35% (BPD: 39%, SPD: 38%)), panic attacks: 8 (31% (BPD: 35%, SPD: 36%)), conversion symptoms: 7 (27% (BPD: 30%, SPD: 21%)), dissociative episodes: 6 (23% (BPD: 26%, SPD: 7%)), depersonalization: 5 (19% (BPD: 22%, SPD: 14%)), multiple apprehensive expectations: 4 (15% (BPD: 17%, SPD: 14%)), derealization: 3 (12% (BPD: 13%, SPD: 14%)), hyperventilation attacks: 3 (12% (BPD: 13%, SPD: 7%)), and somatization: 1 (4% (BPD: 4%, SPD: 7%)). In short, 54% (BPD: 61%, SPD: 43%) of the subjects had comorbid neurotic disorders, and 92% (BPD: 91%, SPD: 93%) reported at least one, and 54% (BPD: 61%, SPD: 50%), more than two kinds of neurotic symptoms, though no specific symptom correlating with BPD or SPD diagnosis was found. These findings suggest that neurotic symptoms and neurotic disorders cannot be ignored as peripheral in the borderline symptomatology. By analyzing in detail the neurotic experiences, the author pointed out as their characteristics, ego syntonicity, deterioration of reality sense and symptomatic polymorphism, ambiguity and multiplicity (panneurosis). In the symptoms the author observed signs of defective personality functioning such as disavowal of reality, low anxiety tolerance, various forms of identity disturbances. The findings counted above, suggest that the borderline neurotic symptoms are more severe in nature than those of neurotics, and could be situated in between neurotic and psychotic levels of symptomatic severity. The results indicate that the neurotic experiences of borderline patients are, as a whole, deeply ingrained in the borderline psychopathology.


[Conceptual vs. indexical symptomatologies of schizophrenia]. We discussed the difference of conceptual and indexical symptomatologies of schizophrenia through critics upon the theory of Eugen Bleuler, the diagnostic schema of Kurt Schneider and several recent theories of negative symptoms of schizophrenia. The notion of the group of schizophrenia of Bleuler, which is a descriptive expression of the phenomenon originally grasped in the inter-human relationships, is of conceptual value but confusing when used indexically for the definition of the illness. In the diagnostic concept of Schizophrenia by Schneider, although he explicitly sought for indexical value without any conceptual prejudice, Jaspers' notion of the psychoses defined by understandability is implicitly included. Schizophrenia is regarded as a form of psychosis which is, following Jaspers, a synonym of madness. Since then, the value of Schneider's 1st rank symptoms has been generally acknowledged and they have contributed to the development of operational diagnostic criteria of schizophrenia. However, the general neglect of unproductive symptoms has caused a new stream of operational symptomatology, namely negative symptoms. This stream includes not only biological researches but also ideological investigations of the essential disturbance of schizophrenia, which have been totally ignored in the operational symptomatology. The discussion of negative symptoms of schizophrenia is complexed because it contains both indexical and conceptual symptomatologies: this very complexity also contains the possibility of the integration of these two apparently distant methods.


[Gonadal function in young female affective illness associated with the menstrual cycle--in relation to the polycystic ovary syndrome]. The hypothalamo-pituitary-gonadal axis was studied in 10 young manic-depressive or psychotic women whose symptoms obviously fluctuated in association with the menstrual cycle. The common clinical features of these cases were (1) young female aged between 15 and 25, (2) the symptoms fluctuated obviously in association with the menstrual cycle, and (3) severe manic-depressive, or psychotic symptoms. While, in two cases, the depressive or psychotic phases had repeated many times for several years, the rest eight cases did not have a long psychiatric past history. The common hormonal features among these 10 cases were elevated basal LH (7 of 10 cases), decreased basal FSH (6 of 10), greater response of LH and normal response of FSH to LHRH (8 of 8), lack of or insufficient increase of progesterone in the luteal phase (7 of 8), and elevated serum testosterone (5 of 10), androstenedione (4 of 10) and DHEA-S (3 of 9). These abnormalities resemble those of polycystic ovary syndrome (PCOS). Five of the 10 cases showed mild hirsute signs such as mustache, acne, and/or well-developed musculo-skeletal system. An ultrasonographical study revealed polycystic changes in 7 of 10 cases. Ordinary psychotropic pharmacotherapy was not effective sufficiently and hormonal therapy was tried in these 10 cases. Clomiphene citrate was administered on Day 5-9 of the menstrual cycle at a daily dose of 50mg orally in 9 cases, and it was effective to prevent recurrence of manic episode in one case, and to improve manic-depressive or psychotic symptoms in 6 cases. In these 6 cases, the effects were commonly observed within 1 or 2 weeks subsequent to the administration being completed. Daily dexamethasone administration was effective in one case with high serum DHEA-S level in whom clomiphene citrate worsened the psychotic symptoms, and thyroid hormone was effective in one case. In comparison with the pathophysiology of PCOS, a possible relationship was suggested between psychiatric problems and the PCOS-like hormonal abnormalities in these cases.


A clinical approach to help psychiatric patients with smoking cessation. In this paper we briefly review the dynamics of smoking and nicotine dependence, discuss the evaluation of the addicted smoker, and describe interventions to facilitate the attempt to quit smoking. We also discuss the interface of psychiatric illness and smoking, particularly among those chronically hospitalized in psychiatric institutions, and suggest a rational approach to help patients with psychiatric illness stop smoking.


Integrated services for treatment of schizophrenic substance abusers: demographics, symptoms, and substance abuse patterns. We have previously described a model of outpatient integrated treatment for patients with comorbid psychoactive substance use disorders and schizophrenia (PSUD/S)(1). Here we review relevant literature on comorbidity and outline the rationale for integrated services. Further, we describe results from 3 related studies: First, we document the approximate incidence of PSUD among a heterogeneous group of 602 schizophrenic inpatient admissions to our hospital. Second, we describe in greater detail the psychiatric symptoms and patterns of substance abuse among a subsample of 106 inpatients with PSUD/S, contrasting them with 112 patients with PSUD and mixed psychotic disorders, but who are not schizophrenic. Third, we present a prospective research project and describe a sample of 30 patients with PSUD/S, detailing demographic characteristics, psychiatric symptoms and substance abuse history. Attention is given to current issues in the differential diagnosis of patients with PSUD/S using standardized instruments.


Clinical profile of clozapine: adverse reactions and agranulocytosis. The arrival of clozapine has been one of the most significant developments in antipsychotic drug treatment since the advent of chlorpromazine ushered in the psychopharmacologic era. However, its utilization has been significantly limited and complicated by its potential to cause adverse effects and agranulocytosis in particular. It must be emphasized that clozapine has a side effect profile that is in many ways distinct from standard typical antipsychotic drugs. Side effects with clozapine are common and range from the benign to the potentially lethal. The most common side effects include sedation, dizziness, and sialorrhea during sleep; the most serious are agranulocytosis, seizures and respiratory depression. Although side effects from clozapine are not necessarily preventable, they are for the most part manageable. Even with the most serious adverse effects, proper knowledge of the medication's actions, clinical vigilance, and prompt intervention can prevent the occurrence of significant morbidity and mortality as a consequence of clozapine treatment.


Neuropsychiatric rehabilitation for persistent mental illness. The benefits of new knowledge on the psychobiology and neuropsychology of serious mental illnesses have been slow to impact on psychiatric rehabilitation technology. A literature review reveals that, at least in the case of schizophrenia, enough is known about neurobiological deficits and their impact on neurocognitive functioning to justify a more informed approach to psychiatric rehabilitation. Essential elements for a program of research are presented and preliminary data are reported examining the prevalence of executive deficits, correlations between neuropsychological deficits and social adjustment, and the nature of socially stigmatizing neuromotor deficits and their reliable assessment. In addition, early experience with the remediation of executive deficits is described and suggestions are made for future developments in this area. The authors conclude that barriers to the integration of knowledge from biological psychiatry and psychiatric rehabilitation have been largely related to academic "cultural" isolation, and that active cross fertilization of ideas is clearly justified by the present state of knowledge.


The neuropsychiatric manifestations of Lyme borreliosis. Lyme borreliosis (Lyme disease), a tick-borne spirochetal illness, has multisystemic involvement and is rapidly increasing in certain areas of the United States. Although its neurologic manifestations are becoming increasingly well recognized, its psychiatric presentations are not well known. The first section of this paper will provide an overview of Lyme borreliosis and a review of the relevant neuropsychiatric literature. The second section will provide clinical descriptions of some common neuropsychiatric symptoms as well as a discussion of the problems typically faced by patients with this illness. Guidelines to assist the clinician in working with these patients will be presented.


[Epidemiology of alcoholism in Voralberg. Comparison of administrative incidence 1967, 1977 and 1987 in a regional psychiatric hospital]. We report on the administrative incidence of alcoholism as registered by admissions for treatment in the regional psychiatric hospital, in Vorarlberg, caring for approximately 330,000 inhabitants. 1967, 1977 and 1987 were chosen as years of observation, thus describing the regional development of alcoholism in the last 20 years. Selected epidemiological data are compared to those of local population. Over the years a vast increase in admissions and treatments was registered--a result of changes in information on the addiction itself and improvement in facilities, staff and medical care in general. Whereas female involvement has sharply risen as compared to earlier decades, it now appears to have studied at a rate of 3:1 (m:f). In 1987 juvenile alcoholism as rated by hospital-admissions had comparatively declined. A greater number of married alcoholics in more qualified positions decided on treatment. Concordant somatic and psychiatric diseases are discussed. The results stress the importance of different approaches to motivation and treatment in this complex phenomenon.


["Endogeniform" affective psychoses and normal pressure hydrocephalus]. Four patients with neuroradiological evidence of normal pressure hydrocephalus and psychiatric diagnosis of affective psychoses with major depression--like characteristics are presented. Three patients underwent shunting operations following an observation period of 2 to 6 years. During the post-operative follow-up of 3 to 7 years, resp., no clinical changes were noted. In our opinion, and following critical evaluation of the available literature, major depression--like affective disorders in normal-pressure hydrocephalus are not influenced by shunting operations, unless they occur simultaneously as an additional symptom in an Adams-Hakim syndrome with definite progression.


[Myasthenia gravis in the frontier of psychiatric diagnosis]. Retrospectively 20% of more than 200 patients with myasthenia gravis reported being initially diagnosed as having a psychiatric disorder. Younger women are significantly most at risk of a psychiatric misdiagnosis whereas men are more often subject to somatic misdiagnoses. The sample's mean duration of the disease was 10 years. Nevertheless misdiagnoses still coincide with higher depression scores. Depression is also related to the dosage of anticholinesteratic medication as well as to the self-reported muscular weakness. Personality assessment through an inventory reveals only slight emotional instabilities and no illness specific profiles.


[Diagnostic inquiries in patients with a theta ground rhythm variant in the EEG]. Basing on the examination of 82.767 EEGs, 118 patients with theta rhythm variant (GRV) were found out. From their case-histories all particulars taken to be important were gathered by means of a questionnaire. In addition to this 70 of these patients were interviewed, mostly in the course of a visit at home, in order to supplement the data by catamnestic informations. Moreover, attending family doctors were asked for informations, and from 14 patients elsewhere recorded EEGs were evaluated. With regard to its cycles per second, the GRV proved to be stable even for long periods, but as to its coming to the fore a slight changeability revealed. Concerning physical complaints, the patients primarily suffered from headache, giddiness, and liability to fainting fits, secondary they frequently were affected with vegetative disorders and stomach complaints. In view of the psychic aspect striking often came to light unrest, lack of vitality, disturbed social contacts, sexual problems, anxiety fits, depressive reactions, and suicidal thoughts. High sensitiveness and insufficient self-sureness in many cases were conspicuous attributes. In particular men often failed in establishing or maintaining intimate human relations, so that many of them remained single, made at best only few friends, and easily became outsiders. Inability to enforce own desires against opposition, liability of mood, ill-humor, discontent, or even jealousy frequently made their appearance. As to gainful employment and professional status several of them were less successful than their siblings and their parents.


[Undetected physical diseases in new psychiatric admission]. We report on clinical observations from a 10-bed psychiatric acute ward where predominantly patients with concurrent physical diseases are treated. Of 287 patients admitted within 18 months we detected serious physical illness previously unrecognized or at least not sufficiently diagnosed in 15 cases (5.2%; age 17-88 years; 4 m, 11 f). Six patients suffered from acute neurological disease. One or more extracerebral disorders were found in nine cases. 14 of the 15 patients presented with organic mental syndromes classified according to ICD-9 (acute organic psychosis: n = 8, chronic organic psychosis: n = 6). The physical diseases unknown at admission were the only cause of the acute organic psychoses while they were contributing to the development of psychiatric symptoms in the majority of the other patients. In 14 patients the diagnosis of the previously unrecognized illnesses led to a significant change of therapy. At discharge 10 patients had improved with regard to their somatic and mental state while in two cases only the physical symptoms had remitted. One patient remained completely unchanged and two patients died from their serious diseases. Our case studies illustrate the fact that a relevant proportion of newly admitted psychiatric patients suffers from life-threatening medical illnesses. These require prompt and specific interventions and can only be detected by early and thorough physical examination.


Plasma cholinesterase isozymes and REM latency in schizophrenia. The relation between electroencephalographic sleep parameters and plasma cholinesterase isozymes was examined in a group of 19 unmedicated schizophrenic patients. Rapid eye movement (REM) latency was found to be significantly inversely correlated with isozyme 3 (mainly acetylcholinesterase). The results are discussed in relation to cholinergic involvement in the regulation of REM sleep and in the pathophysiology of schizophrenia.


Urinary catecholamines and cortisol in parasuicide. A relationship of urinary catecholamines and of urinary free cortisol with violent suicide attempts has been reported. We have reexamined this issue in patients within 24 hours of hospital admission. Suicide attempters had significantly higher norepinephrine (NE: mean +/- SD = 58.3 +/- 27.0 micrograms/24 hours; n = 27) than did control patients with suicidal ideation (mean +/- SD = 37.1 +/- 21.3; n = 10). Among suicide attempters, those who used physical means had the highest NE levels (mean +/- SD = 69.7 +/- 21.3) and those who took overdoses of antidepressants (mean +/- SD = 51.9 +/- 17.3; n = 6), benzodiazepines (mean +/- SD = 65.1 +/- 29.7; n = 5), or miscellaneous drugs (mean +/- SD = 59.1 +/- 36.5; n = 11) had lower NE values. In contrast to NE, urinary dopamine (mean +/- SD = 402.6 +/- 392 micrograms/24 hours, epinephrine (EPI: mean +/- SD = 14.3 +/- 4.0 micrograms/24 hours), the NE/EPI ratio (mean +/- SD = 8.3 +/- 0.9), urinary free cortisol (mean +/- SD = 157.9 +/- 11.5 micrograms/24 hours) and serum cortisol (mean +/- SD = 35.0 +/- 13.1 nM/l) did not differ between groups. There were no group differences in age (mean +/- SD = 36.3 +/- 16.5 years), Beck Depression Inventory score (mean +/- SD = 26.3 +/- 12.9), Beck Hopelessness Scale score (mean +/- SD = 10.0 +/- 5.6), Beck Scale for Suicidal Ideation score (mean +/- SD = 13.6 +/- 9.3), or Hamilton Rating Scale for Depression score (mean +/- SD = 19.5 +/- 9.8). In the four parasuicide groups, there was no difference in suicide intent (mean +/- SD = 13.3 +/- 7.9). These findings indicate that there is increased NE output shortly after suicide attempts. Previous reports of a low NE/EPI ratio in suicidal patients may reflect adaptive changes rather than the acute state of the patient at the time of the attempt.


Sleep in spousally bereaved elders with subsyndromal depressive symptoms. Spousal bereavement in late life frequently leads to major depression. However, many people suffer from "minor" depressive symptoms that entail considerable suffering even in the absence of syndromal major depression. We describe longitudinal electroencephalographic (EEG) sleep and clinical evaluations in 14 elderly, recently spousally bereaved subjects who were experiencing subsyndromal depressive symptoms. While subjects did not meet diagnostic criteria for syndromal major depression, they did have mildly elevated scores on the Hamilton Rating Scale for Depression (mean = 10.6, range = 8-16) at the time of initial sleep studies (T1), which were carried out, on average, 5.5 months after loss of the spouse. Entry into the study was limited to volunteers who did not have a personal history of major depression or psychiatric disorder. Twelve subjects underwent followup clinical and EEG sleep evaluations (T2), 9.9 months after spousal loss. Fifty percent continued to show depressive symptoms at 6-month followup. Test-retest comparisons of sleep and clinical measures were made with a group of sex- and age-matched control subjects who were neither bereaved nor depressed. EEG sleep measures did not significantly correlate with time from loss of spouse, severity of depressive symptoms, or subjective sleep quality. Analysis of variance with repeated measures detected a significant group X time interaction effect for delta sleep ratio (decreasing in controls but increasing in the bereaved).


Electroretinography in seasonal affective disorder. Retinal mechanisms have been hypothesized in the pathophysiology of seasonal affective disorder (SAD). Electroretinography (ERG) is a noninvasive electrophysiologic test that provides an objective measure of photoreceptor and retinal function. We conducted dark-adapted ERG examinations with a bright white light stimulus in a group of depressed, drug-free patients with seasonal affective disorder (6 men, 18 women) diagnosed by DSM-III-R criteria, and a group of sex- and age-matched control subjects (6 men, 16 women) during the winter. A significant difference was found between SAD patients and controls, but female SAD patients had lower ERG b-wave amplitudes than female controls, while male SAD patients had higher amplitudes than the matched controls. The ERG b-wave implicit times (times from onset of stimulus to peak of b-wave) were significantly longer in the left eyes of the male control subjects. These data may indicate subtle retinal changes in patients with SAD, but the results must be considered preliminary because of the small number of subjects studied and the large intersubject variability in the ERG procedure.


Functional interrelationship of serotonin and norepinephrine: cortisol response to MCPP and DMI in patients with panic disorder, patients with depression, and normal control subjects. The relationship between norepinephrine (NE) and serotonin (5-hydroxytryptamine; 5HT) functioning was explored in a neuroendocrine challenge paradigm. Ten normal control subjects, 17 patients with major depression, and 22 patients with panic disorder volunteered to participate in this study. Each subject received a challenge with meta-chlorophenylpiperazine (MCPP; 0.25 mg/kg, p.o.), a 5HT agonist, and desmethylimipramine (DMI; 75 mg, i.m.), an indirect NE agonist, in randomized order. The peak-minus-baseline cortisol response to MCPP was used as an indicator of 5HT function, and cortisol response at 75 minutes-minus-baseline to DMI was used as an indicator of NE function. The cortisol responses to DMI and MCPP were found to be highly negatively correlated in the total sample, in particular in the patients with major depression and panic disorder. This finding suggests that the functions (or dysfunctions) of the NE and 5HT systems may not be separate as is usually believed, and that the NE and 5HT disturbances observed in major depression and panic disorder may not be independent. Rather, there may be a joint disturbance of NE-5HT in these disorders.


Disengagement of attention in chronic schizophrenia. Posner et al. (1988) recently found a lateralized impairment in the shift of covert visual attention to the right visual field in acute schizophrenic patients. Strauss et al. (1991) did not find this lateralized attentional deficit in remitted neuroleptic-treated chronic schizophrenic outpatients. The present study examined the covert shifting of visuospatial attention in clinically ill inpatients with chronic schizophrenia and in nonpsychotic control subjects. Although patients with schizophrenia were slower in all conditions, no lateralized attentional abnormalities were found. Taken together, these studies suggest that neuroleptic treatment may affect a lateralized attentional impairment in chronic schizophrenia.


Disruption of saccade production during oculomotor tracking in schizophrenia and the use of its changes across target velocity as a discriminator of the disorder. A clear measure of eye movement disorder (EMD) that reliably separated schizophrenic individuals from others would both give insight into the brain control of the disorder and provide an aid in diagnosis. In the present study, a detailed analysis was carried out of the interactions between the pursuit and saccadic components of eye movements at different target velocities. The subjects comprised schizophrenic patients, unipolar depressed patients, and normal controls. The speed of the slow pursuit component did not differ among the groups, but schizophrenic subjects made more saccadic movements at low target velocities, though they started further away from the target at high target velocities. On the basis of these differences, a slope was computed of the linear function that related the number of saccadic eye movements to the velocity of a ramp visual target. Slope direction was negative for schizophrenic subjects but positive for unipolar depressive and normal subjects, and the correct classification rate for subjects was 84%.


Negative symptoms and the early course of schizophrenia. To determine the usefulness of including a duration criterion in the definition of "negative" symptoms, the prognostic significance of a longitudinally obtained measure of negative symptoms was compared with a cross-sectionally obtained measure. As predicted, the presence of negative symptoms based on longitudinal observation was associated with most aspects of 18-month course in a group of "first-episode" schizophrenic individuals, whereas cross-sectional levels of negative symptoms were not. The findings suggest that negative symptoms, when operationalized as a trait-like phenomenon, help to portend a poor course of illness.


Dysphoria: a major symptom factor in persons with disability or chronic illness. Depression frequently is diagnosed in persons with chronic illness or following the onset of disability. The overlap of symptoms of many chronic illnesses and disabling conditions with depression may lead to an overestimation of depression in such populations. Some investigators have proposed revised criteria for diagnosing depression in these conditions without an understanding of the contribution of diagnostic criteria in disabling conditions. This study investigated the nature of depressive symptom criteria constellations by individually factor analyzing the Inventory to Diagnose Depression (based on DSM-III diagnostic criteria) in spinal cord injury (n = 134), rheumatoid arthritis (n = 78), student (n = 140), and community (n = 150) groups. A four-factor solution emerged, with the first factor labeled "dysphoria" being represented by symptoms of negative self-evaluations, depressed affect, and suicidal ideation. The results indicate that a core element of the syndrome of depression is dysphoria, which suggests that the contribution of somatic items may be less important to the identification of the depressive syndrome in chronic illness.


Smoking in patients with panic disorder. We compared smoking prevalence in 217 patients with panic disorder with that in 217 age- and sex-matched control subjects who were obtained by telephone survey from the same neighborhoods. Data were obtained for current smoking habits and smoking status at either the onset of illness (patients) or 10 years previously (control subjects). Patients had been ill for 10.6 (SD = 10.0) years. Female patients with panic disorder had a significantly higher smoking prevalence at the onset of their illness than did control subjects 10 years previously (54% vs. 35%). The current smoking prevalence for female patients was also significantly higher than that of control subjects (40% vs. 25%). Male smoking rates did not differ between patients and control subjects. Caffeine use did not appear to explain these findings. These data suggest a link between smoking behavior and panic disorder in women.


Neuroendocrine responses to challenge with dl-fenfluramine and aggression in disruptive behavior disorders of children and adolescents. Prolactin (PRL) and cortisol (CORT) responses to a single oral administration (1.0 mg/kg) of the indirect serotonin agonist dl-fenfluramine were assessed in unmedicated prepubertal and adolescent males with disruptive behavior disorders (DBD). Neuroendocrine responses were correlated with scores on aggression rating scales in prepubertal and adolescent DBD patients and compared with those of matched adolescent normal control subjects. Net dl-fenfluramine-induced PRL and CORT release was not correlated with aggression rating scores in prepubertal and adolescent DBD patients and did not differ significantly between adolescent DBD patients and normal control subjects. Although the present study does not demonstrate a serotonergic abnormality in aggression or DBD, this may be more a reflection of limitations of the neuroendocrine challenge test procedures or the methods used than evidence that serotonergic function in the central nervous system is normal in aggression.


Pupillary constriction during haloperidol treatment as a predictor of relapse following drug withdrawal in schizophrenic patients. It has been proposed that the autonomic nervous system is dysregulated in schizophrenia. We hypothesized that measures of autonomic function, even during neuroleptic stabilization, might predict relapse following withdrawal of medication. Previously, shorter latencies to maximum pupillary constriction have been reported to differentiate acutely hospitalized schizophrenic patients from control subjects. Pupillary light reactions were recorded weekly from 19 chronic schizophrenic inpatients who were initially maintained on haloperidol and subsequently were withdrawn from medication under double-blind, placebo-controlled conditions. Patients were then classified as either relapsed or nonrelapsed (clinically stable) during the drug-free period. During the treatment phase, a shorter latency to maximum pupillary constriction significantly distinguished patients who were later to relapse from the nonrelapsers. The potential use of autonomic activity as an indicator of prodromal sensitivity was supported. In addition, these findings emphasize the need for classification of drug-free patients according to clinical status.


Sadomasochism and complementarity in the interaction of the narcissistic and borderline personality type. The narcissist and borderline personality types complement one another's defensive style providing needed defensive externalization of disavowed and split-off feelings. One is exploitative, grandiose, and dominant, forever seeking admiration and exhibiting an aggrandized self; the other experiences humiliation, neediness, helplessness, and terror of aloneness. They form a powerful complementary dyad wherein each identifies with disavowed emotional experiences displayed in the other. They can coexist for lengths of time, defensively discharging unwanted feelings. In the first case presented above, the transference was split initially, with the masoborderline patient being victimized and humiliated by her sadonarcissistic lover. In the second case, a male sadonarcissist enacted disavowed feelings through relationships with masoborderline women. In both cases, defensive enactment was fed by a complementary, intense, and symbiotic relationship. Complementary dynamics can be subtle and difficult to analyze. They involve defensive identification that draws on projection, enactment, and externalization--all difficult defenses to analyze. Enactment rather than remembering is inimical to the development of insight into transference and genetic connections and must be worked through for the analysis to progress. More than the usual analytic patience and resolve is needed to work through the difficult entrapments caused by these dynamics.


Frustration theory--many years later.

Frustration theory--many years later. The role of frustration in learning theory, in the invigoration of behavior and in the development of learned persistence and discrimination learning, is conceptualized. This and other phenomena are facets of the larger explanatory domain of what has come to be known as frustration theory, a theory that has guided the author's own research--from behavioral to developmental to psychobiological --until the present time and has had some influence on the research of other investigators. This is a commentary on the 1st of several published theoretical papers on frustration theory.


On the fit of models to covariances and methodology to the Bulletin. It is noted that 7 of the 10 top-cited articles in the Psychological Bulletin deal with methodological topics. One of these is the Bentler-Bonett (1980) article on the assessment of fit in covariance structure models. Some context is provided on the popularity of this article. In addition, a citation study of methodology articles appearing in the Bulletin since 1978 was carried out. It verified that publications in design, evaluation, measurement, and statistics continue to be important to psychological research. Some thoughts are offered on the role of the journal in making developments in these areas more accessible to psychologists.


The generation of visual images: a review of neuropsychological research and theory. Since the advent of the view that mental imagery is a subdividable process, claims have been made that the generation of images is the domain of the left posterior hemisphere. This article examines theory and data about the neuropsychology of image generation by focusing on the main contributors to the debate. An attempt is made to make the theory and beliefs associated with each of the key figures explicit, because these have influenced the structure of research and the development of new theories. Support is found for the involvement of the left hemisphere, although many researchers claim that the posterior regions of both hemispheres contribute to image generation but that they do so in different ways. The nature of this difference remains the subject of ongoing research.


Forgetting of stimulus attributes: methodological implications for assessing associative phenomena. Differential responding to changes in the stimulus situation, long central to the concept of stimulus control, also provides the implicit conceptual basis for assessing the nature of a variety of associative relationships. However, there is substantial evidence that the perception of stimulus similarity is not a static property. Generalization gradients to contextual as well as discriminative stimuli flatten over time, and this increase in perceived similarity presumably reflects forgetting of the detailed characteristics or attributes of stimuli. Methodologically, the flattening of the gradient imposes an important constraint: The effect of a stimulus shift will be highly sensitive to the length of the delay interval between training and testing. Conceptually, the loss of memory for stimulus attributes also implies that the sources of interference in retention can increase over time.


Social blushing.

Social blushing. This article reviews theory and research regarding the physiology, situational and dispositional antecedents, behavioral concomitants, and interpersonal consequences of social blushing and offers a new theoretical account of blushing. This model posits that people blush when they experience undesired social attention. Puzzling questions involving blushing in solitude, the phenomenology of blushing, types of blushing, and blushing in dark-skinned people are discussed.


Depressed mothers as informants about their children: a critical review of the evidence for distortion. The claim that depressed mothers have distorted, inflated, perceptions of their children's problems has been made with increasing frequency in recent years. This review explicates the significance of the depression-->distortion controversy, introduces a set of standards for evaluating distortion claims, and uses these standards to evaluate the key characteristics of 22 studies that have published data directly relevant to the distortion question. None of the studies that claimed evidence for a depression-->distortion influence on mothers' ratings of their children met the necessary and sufficient criteria for establishing distortion. This review challenges the empirical foundation for the widely held assumption that depressed mothers have distorted perceptions of their children's problems. Issues that will require reckoning in future efforts to explore the depression-->distortion question are considered.