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8040101
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Effects of endolymphatic and perilymphatic application of salicylate in the pigeon. I: Single fiber activity and cochlear potentials.
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The effects of salicylate on the mammalian cochlea function are well documented. However, there is a lack of reports on salicylate effects on the avian auditory periphery and it might well be that salicylate is not ototoxic at all in submammalian vertebrates. We therefore recorded single fiber activities, compound action potential (CAP) and endocochlear potential (EP) during application of salicylate (calculated final concentration of about 2-18 mmol/l) into the scala media of pigeons. We furthermore recorded CAP and EP during perilymphatic perfusion of salicylate (2-20 mmol/l). Salicylate applied into the scala media led to an elevation of tip threshold in single fibers ranging from 5 to 35 dB. The characteristic frequencies of the fibers were not changed. This effect on auditory nerve fibers was reflected in an elevation of CAP thresholds. The mean spontaneous discharge rate was either slightly increased or remained unchanged in the majority of fibers. Perilymphatic salicylate perfusion also led to an elevation of CAP thresholds that was reversible following subsequent perfusion with artificial perilymph. The EP remained unchanged in both application modes. The effects of salicylate were dose dependent and more pronounced in the mid- to high-frequency range. These results are consistent with an action of salicylate on the process (electrical or mechanical, or both) responsible for the sensitivity and frequency selectivity in the avian peripheral hearing organ.
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8040100
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Immunohistochemical localization of S-100 protein in auditory and vestibular end organs of the mouse and hamster.
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The distribution of S-100-like immunoreactivity in mouse and hamster auditory and vestibular end organs was determined by the use of immunohistochemistry. Within the organ of Corti, the cytoplasm of cells of Deiter and Hensen were strongly immunoreactive. Inner hair cells and the peripheral processes and cell bodies of the spiral ganglion were weakly immunoreactive for S-100, whereas the supranuclear regions of outer hair cells and cells underlying the basilar membrane were unstained. Immunoreactivity was observed near the base of outer hair cells. In the lateral wall of the cochlea, cellular components of the spiral ligament and a subpopulation of epithelial cells in the stria vascularis, identified as predominantly basal cells, were immunoreactive. For the saccule, utricle, and semicircular canals, S-100 immunoreactivity was observed in vestibular hair cells, types I and II, and the nerve calyces surrounding type I hair cells as well as in nerve fibers underlying the sensory epithelium. Weak S-100-like immunoreactivity was associated with vestibular nerve fibers and cell bodies in the vestibular ganglion. The localization of S-100-like immunoreactivity to the sensory cells and nerve fibers of the peripheral auditory and vestibular end organs is consistent with a functional role for S-100 proteins at these sites.
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8040099
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Temporal modulation transfer functions for AM and FM stimuli in cat auditory cortex. Effects of carrier type, modulating waveform and intensity.
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For 167 single units, recorded from primary auditory cortex in 28 cats, we show that tuning to the modulation frequency (MF) of amplitude-modulated (AM) sound is strongly dependent on carrier type. In general AM noise-bursts and click-trains produce good tuning to MFs with repetition rates around 8-10 Hz. Amplitude- or frequency-modulation of tone-carriers resulted largely in low-pass temporal modulation transfer functions (tMTFs) with a best modulation frequency (BMF) around 4 Hz. Individual BMFs for noise carriers ranged from 3-26 Hz, whereas for tone carriers they were mostly below 6 Hz and rarely above 10 Hz. The sharpness of tuning for broad-band stimuli decreased with increasing duty-cycle of the modulation; it was most pronounced for clicks, next best for exponential sine-AM and broadest for sinusoidal AM. In contrast the reverse was found for tone carriers; the better modulation following was found for sinusoidal modulation and was most likely entirely due to a stronger onset response. Decreasing the modulation depth below 100% showed an increasing influence of onset transients and periodic rebounds, however, the average tMTFs for depths between 50-100% are similar. The optimal intensity level for noise carriers was usually higher than for tone carriers. Overall the modulation-sensitivity of cortical neurons regardless of carrier type and modulating waveform was in the range of modulation frequencies found in music, speech and other complex sounds.
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8040098
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Evidence for electrically evoked travelling waves in the guinea pig cochlea.
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Electrically evoked compound action potentials (EECAP) were produced by the injection of pulsed sinusoidal current through metal electrodes into the basal turn. Plots of current threshold against frequency closely resembled conventional compound action potentials (CAP) audiograms for frequencies represented apically of the electrode location. EECAPs were masked by sound and CAPs were masked by current in a manner consistent with the generation of a propagated travelling wave.
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8040097
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Changes in the cat cochlear nucleus following neonatal deafening and chronic intracochlear electrical stimulation.
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The effects of chronic intracochlear electrical stimulation on the cochlear nucleus (CN) were studied in eight cats that were neonatally deafened by daily intramuscular injections of neomycin. Profound hearing loss was confirmed in each animal by auditory brainstem response (ABR) and frequency following response (500 Hz) testing. Five of the kittens were implanted unilaterally with a scala tympani electrode array at ages 8-16 weeks. These kittens were stimulated daily for four hours at 2 dB above the evoked ABR threshold, over a period of three months, and subsequently euthanized for histological analysis at 26-32 weeks of age. The three remaining deaf kittens were maintained without stimulation over prolonged periods in order to study the long-term consequences of neonatal deafening, and were euthanized at 66-133 weeks of age. This study compares the CN of these deafened experimental animals and the CN of normal adult cats. Three experimental parameters were examined: CN volume, cross-sectional area of spherical cells in the rostral anteroventral cochlear nucleus (AVCN), and spherical cell density in this same region. The CN in animals that received electrical stimulation showed significant bilateral degenerative changes in all three measured parameters. Total nuclear volume was reduced by 35-36%, spherical cell size was reduced by 20-26%, and spherical cell density decreased by 36-42%, as compared to the normal cat CN. Comparisons were also made in the stimulated animals between CN ipsilateral to the stimulated cochlea and the contralateral, unstimulated CN.(ABSTRACT TRUNCATED AT 250 WORDS)
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8040096
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The course and morphology of efferent nerve fibres in the papilla basilaris of the pigeon (Columba livia).
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This paper describes the course and morphology of efferent fibres in an avian cochlea. Horseradish peroxidase stained efferent fibres in the pigeon papilla basilaris were identified by Nomarski optics and camera lucida drawings. There are at least two types of efferent fibres: Large thick fibres take mainly a transversal course and contact short and intermediate hair cells over the free basilar membrane as well as hyaline cells. Large efferent fibres contact both hair cells and hyaline cells. Small thin fibres contact short or intermediate hair cells over the free basilar membrane or tall hair cells over the neural limbus. A physiological consequence of the findings is that efferent activity will concomitantly lead to a contraction of hyaline cells and a hyperpolarization of hair cells.
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8040095
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Discharge pattern in the auditory nerve evoked by vowel stimuli: a comparison between acoustical and electrical stimulation.
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Single channel cochlear implants only transmit the time structure of the electrically coded input signal. All nerve fibres show similar thresholds for monopolar round window stimulation, i.e., activation does not depend on their site of origin. To investigate the fine structure of the firing pattern elicited by stimulation with an analogue coded speech processing system (VIENNA 1-channel implant), cats were electrically stimulated with German steady-state vowels at the round window. Single fibre activity was recorded from primary auditory fibres and period histograms were calculated. The electrically evoked impulse patterns were compared with those from acoustic stimulation with the same vowels. With acoustic stimulation, the response of a fibre depends on the individual characteristic frequency (CF) with regard to the fundamental F0 and the formants F1, F2 and F3 of the vowels, the spontaneous activity of the fibre and the sound level. The evoked firing pattern was used to calculate period histograms, the frequency content of which was analysed by Fourier transformation. With electrical stimulation in the threshold range, an action potential is strongly synchronized to a cathodic peak of the current within one period of F0. With increasing current level 3-5 impulses can be locked to the same period. The timing of the short intervals is determined by the relative refractory period and current peaks (negative or positive) caused by the dominant higher formant F2 or F3. The acoustically evoked patterns are specific for the CF of the neuron and represent the spectral information of the different vowels.(ABSTRACT TRUNCATED AT 250 WORDS)
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8040094
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Preferred intervals in birds and mammals: a filter response to noise?
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Quasi-periodic spontaneous activity (preferred intervals, PIs) has been reported from avian primary auditory afferents. In mammals, PIs have not been reported, as yet. As the length of PIs is close to 1/characteristic frequency, it has been suggested that this type of spontaneous activity indicates particular mechanisms in avian inner ear transduction. However, the present paper shows that pigeon auditory fibres possessing preferred intervals in their spontaneous activity always belong to the most sensitive and the most sharply-tuned fibres recorded. This leads to the assumption that preferred intervals are the response of narrow-band filters to noise. This view is supported by three additional findings: (i) Near-threshold noise provokes PIs in avian fibres that show no spontaneous PIs. (ii) Similarly, PIs can also be evoked in mammalian (gerbil) auditory afferents by low level noise. (iii) Phase-locking of auditory afferents can be achieved by sound stimuli 10-20 dB below rate threshold. It is argued that no conclusions may be drawn from the presence of PIs about the nature of the underlying filter.
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8040093
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Coexistence of calcitonin gene-related peptide and choline acetyltransferase in eel efferent neurons.
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We applied choline acetyltransferase, (ChAT) and calcitonin gene-related peptide (CGRP) immunocytochemistry to the efferent neurons that innervate the lateral line and the ear of the eel. Strong immunoreactivity to the ChAT antiserum was observed in neurons located within the octavolateralis efferent nucleus that could be distinguished, on the basis of their form, location and dendritic organization, from the ChAT-immunopositive motoneurons of the adjacent facial motor nucleus. Both facial motoneurons and efferent neurons were found to be immunopositive for CGRP, although the reaction was always stronger in the motoneurons. Double labelling experiments established the presence of both ChAT and CGRP in many efferent neurons. The results are evidence that cholinergic efferent neurons supplying end organs of different modalities may also produce calcitonin gene-related peptide.
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8040091
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The role of middle ear muscles in the development of resistance to noise induced hearing loss.
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The role of middle ear muscles (MEMs) in the development of increased resistance to noise induced hearing loss (NIHL) was studied using monaural chinchillas. Animals with severed MEMs as well as those with intact MEMs were exposed to an octave band noise (OBN) centered at 0.5 kHz at 95 dB for six hours/day for ten consecutive days. Results indicated that animals with severed MEMs showed greater initial threshold shifts (TS) than the animals with intact MEMs. Both the groups showed a decrease in TS over the ten days of exposure. The subjects were given five days of recovery and then re-exposed to the same noise at 106 dB for 48 h. Permanent threshold shifts (PTS) in each group was compared against those in a control group exposed to the noise only at the higher level. Interestingly, both the 'conditioned' groups incurred substantially less PTS than the control group exposed only to the higher level.
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8040092
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Noise induced hearing loss in fetal sheep.
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The auditory brainstem response (ABR) was recorded in utero from chronically instrumented fetal sheep prior to and following exposure of pregnant ewes to intense broadband noise (120 dB SPL for 16 h). ABRs were elicited by clicks and tone bursts (0.5, 1, 2, and 4 kHz) delivered through a bone oscillator secured to the fetal skull. Latency-intensity functions for most of the four vertex-positive waves (labelled I-IV) were prolonged and ABR thresholds were temporarily elevated by an average of 8 dB following the noise exposure. Results show that exogenous sounds can penetrate the uterus and result in alterations of the fetal ABR.
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8040090
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Lipid peroxidation inhibitor attenuates noise-induced temporary threshold shifts.
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The purpose of this study was to investigate the protective effects of U74389F (Upjohn Co. Kalamazoo, MI), a 21-aminosteroid/lipid peroxidation inhibitor, and a member of the lazaroid drug class, on temporary threshold shifts in animals exposed to prolonged noise stimulation. Animals treated with U74389F and exposed to noise showed attenuated cochlear action potential threshold (CAP) shifts and cochlear microphonic (CM) when compared to non-drug treated noise-exposed subjects. These data suggest that inhibition of FOR induced lipid peroxidation is an important mechanism in noise-induced asymptotic temporary threshold shifts.
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8040089
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Changes in distortion product otoacoustic emissions and outer hair cells following interrupted noise exposures.
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Changes in distortion product otoacoustic emissions (DPOAEs) were examined during and after interrupted noise exposures and compared to the condition of the outer hair cells (OHCs) and inner hair cells (IHCs) as assessed by scanning electron microscopy (SEM). Binaural, adult chinchillas were exposed to a 95 dB SPL, octave band noise centered at 0.5 kHz for 15 days using a 3 h on/9 h off schedule. DPOAEs were measured before, during and after the exposures. DPOAE amplitudes decreased significantly during the first few days of the interrupted noise exposures and then began to recover. At most frequencies, the emission amplitudes recovered completely to pre-exposure baseline values by five days after the last exposure. The results of the present study indicate that the changes in DPOAE amplitude paralleled the recovery in the amplitude and threshold of the compound action potentials as reported previously (Boettcher et al., 1992). Although the DPOAEs completely recovered, considerable OHC loss and stereocilia disarray was evident even four weeks after exposure.
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8040088
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G-proteins coupled to phosphoinositide hydrolysis in the cochlear and vestibular sensory epithelia of the rat are insensitive to cholera and pertussis toxins.
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In the cochlear (CSE) and vestibular sensory epithelia (VSE), phosphoinositides are hydrolyzed in response to stimulation of phospholipase C (PLC) by cholinergic muscarinic and purinergic P2y agonists. Such receptor-mediated activation of PLC is expected to be coupled through guanine nucleotide-binding proteins (G-proteins). Although several classes of G-proteins have been identified in the inner ear, nothing is known about the type of G-proteins associated with the phosphoinositide second messenger system in CSE and VSE. Phosphoinositide hydrolysis was determined by the release of radiolabeled inositol phosphates (InsPs). Ten mM NaF plus 10 microM AlCl3 increased basal InsPs accumulation 2-fold in both CSE and VSE of the rat. Release of InsPs was also enhanced by guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) in saponin-permeabilized tissues. Furthermore, release of InsPs stimulated by both carbamylcholine (CCh) and adenosine 5'-O-[3-thiotriphosphate] (ATP-gamma-S) was significantly inhibited by 100 microM guanosine 5'-O-[2-thiodiphosphate] (GDP-beta-S). These results strongly suggest the involvement of G-proteins in the receptor-PLC coupling in CSE and VSE. ADP-ribosylation in membrane fractions of CSE and VSE in the presence of cholera toxin (CTX) or pertussis toxin (PTX) indicated the existence of Gs- and G(i)-type G-proteins. However, neither CTX nor PTX affected basal or agonist-stimulated release of InsPs. These observations suggest that muscarinic and P2y purinergic receptors are coupled to PLC via CTX- and PTX-insensitive G-proteins in CSE and VSE.
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8040087
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Neural processes in the dorsal cochlear nucleus of the anaesthetised cat investigated from unit responses to electrical stimulation of the auditory nerve.
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Extracellular responses of dorsal cochlear nucleus single units were recorded in response to biphasic, bipolar electrical stimulation of spiral ganglion cells and their peripheral processes using a banded electrode array in the scala tympani of the barbiturate anaesthetised cat. The DCN responses to this stimulus were the result of excitatory and suppressive (including inhibitory) processes. The excitatory responses from DCN units were usually within a range of 1.8-2.8 ms and these responses were probably the result of monosynaptic input from the auditory nerve. Latencies > 2.8 ms were most likely due to activation of di- and poly-synaptic pathways from auditory nerve fibres, except that latencies between 3.5-4.75 in hearing animals could have arisen from electrophonic mechanisms. Suppression of spontaneous activity was usually long acting, lasting > 70 ms following each pulse of the pulse train, but short acting suppression with a latency of 3.5-4.75 ms and a duration of < 10 ms was occasionally observed. These suppressive responses probably resulted from synaptic inhibitory input, but neural membrane properties may have contributed. In hearing animals, excitatory latencies within the range 1.8-5.2 ms were similar for units with different response area types or different PSTH patterns in response to acoustic CF tones or noise.
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8040086
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Peripheral analysis of frequency in human ears revealed by tone burst evoked otoacoustic emissions.
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Otoacoustic emissions were evoked in the same ears with single tone bursts at 1, 2 and 3 kHz and with a complex stimulus consisting of a digital addition of the three tone bursts. Stimuli were presented at 75, 59 and 37 dB SPL to 28 ears of human subjects with normal hearing. The purpose was to determine if comparisons of responses to the complex stimulus with a posthoc addition of responses from single tone bursts could delineate features of cochlear frequency analysis of short-duration signals. For processing of the data, the results from the individual tone bursts were combined offline to form a composite response. This was then compared with the response obtained with the complex stimulus. Results revealed close correspondence between the spectra of the complex and composite responses in all ears despite interindividual differences in response morphology. Correlations between the complex and composite waveforms exceeded 80% for all stimulus levels. Subtractions of the two spectra revealed that the majority of the differences occurred at frequencies on the high-frequency slopes of the 1- and 2-kHz spectral peaks. This was due to a reduction in energy for the responses obtained with the complex stimulus. There was little variation between the two response types in the peak frequencies of their spectra, in the energy at frequencies on the lower frequency sides of the spectral peaks at 1 and 2 kHz, or in the spectral components at 3 kHz. Results reveal characteristics of the analysis of frequency in the preneural stages of cochlear processing.
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8040085
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Representation of interaural level difference in the VLVp, the first site of binaural comparison in the barn owl's auditory system.
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In the avian auditory system, the posterior division of the ventral nucleus of the lateral lemniscus (VLVp) is the first site where the levels of sound arriving at the two ears are compared. VLVp units are excited by sound at the contralateral ear and are inhibited by sound at the ipsilateral ear, and, as a result, are sensitive to interaural level differences (ILD). In this study, we investigate the functional properties of VLVp units and describe the topography of ILD sensitivity along the dorsoventral dimension of this nucleus. The responses of VLVp units were tested with monaural and binaural noise delivered through earphones. Excitatory and inhibitory responsiveness was quantified using several measures that assessed the effect of contra-ear stimulation and the effect of ipsi-ear stimulation on the contra-ear response. On the basis of these measures, we characterize the map of ILD sensitivity in the VLVp. The temporal pattern of unit responses were also analyzed. The discharges of VLVp units were regular and time-locked to the onset of a stimulus, a pattern of discharge reminiscent of the 'chopper pattern' observed in the lateral superior olive (LSO) of mammals. The temporal discharge patterns of a single VLVp neuron often distinguished between equivalent ILDs, resulting from different combinations of contra- and ipsi-ear levels, that were not distinguished by spike count alone. However, the temporal response pattern did not distinguish between all such combinations of contra- and ipsi-ear levels. The additional information was encoded by the pattern of activity across the entire population of VLVp neurons. This study describes similarities in the functional properties of VLVp and LSO units that suggest similar physiological mechanisms in avians and mammals for encoding similar acoustic information.
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8040084
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In vitro pharmacologic characterization of a cholinergic receptor on outer hair cells.
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Acetylcholine (ACh) is the major neurotransmitter released from the efferent fibers in the cochlea onto the outer hair cells (OHCs). The type of ACh receptor on OHCs and the events subsequent to receptor activation are unclear. Therefore we studied the effect of agonists and antagonists of the ACh receptor on isolated OHCs from the guinea pig. OHCs were recorded from in whole cell voltage and current clamp configuration. ACh induced an increase in outward K+ current (IACh) which hyperpolarized the OHCs. No desensitization to ACh application was observed. Cs+ replaced K+ in carrying the IACh. The IACh is Ca(2+)-dependent, time and voltage sensitive, and different from the IKCa induced by depolarization of the membrane potential. When tested at 100 microM, several agonists also induced outward current responses (acetylcholine > suberyldicholine > or = carbachol > DMPP) whereas nicotine, cytisine and muscarine did not. The IACh response to 10 microM ACh was blocked by low concentrations of traditional and non-traditional-nicotinic antagonists (strychnine > curare > bicuculline > alpha-bungarotoxin > thimethaphan) and by higher concentrations of muscarinic antagonists (atropine > 4-DAMP > AF-DX 116 > pirenzepine). Pharmacologically, the ACh receptor on OHCs is nicotinic.
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8040083
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A nicotinic-like receptor mediates suppression of distortion product otoacoustic emissions by contralateral sound.
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The purpose of this investigation was to provide in vivo pharmacologic characterization of a cholinergic receptor mediating the suppressive effects of medial olivocochlear (MOC) efferent activation. MOC neurons were activated by contralateral sound and the resulting suppression of ipsilateral distortion product otoacoustic emissions (DPOAEs) was monitored before and after intracochlear perfusions of cholinergic antagonists. Results revealed a dose-dependent blockade of contralateral suppression of DPOAEs by a wide variety of nicotinic and muscarinic cholinergic receptor antagonists, as well as by non-traditional antagonists of cholinergic activity. The nicotinic antagonists, alpha-bungarotoxin, curare and kappa-bungarotoxin, and the glycine antagonist, strychnine, blocked contralateral suppression at nanomolar concentrations and demonstrated similar potencies. IC50 values were 2.38 x 10(-7), 2.79 x 10(-7), 3.81 x 10(-7) and 2.96 x 10(-7) M, respectively. These agents were followed in potency by the nicotinic antagonist, trimethaphan (1.75 x 10(-6) M), the M3 muscarinic antagonist, 4-DAMP (1.88 x 10(-6) M) and the GABAA antagonist, bicuculline (2.39 x 10(-6) M). Increasingly greater concentrations of the muscarinic antagonists, atropine (9.52 x 10(-6) M), AF-DX 116 (2.72 x 10(-5) M) and pirenzepine (8.24 x 10(-4) M) were necessary to block contralateral suppression of DPOAEs. The in vivo pharmacology of this putative outer hair cell cholinergic receptor suggests that it may be a member of the nicotinic family of receptors.
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8040082
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Endolymph calcium increases with time after surgical induction of hydrops in guinea-pigs.
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The ionized Ca2+ concentration in cochlear endolymph is normally extremely low. Previous studies have shown that endolymph Ca2+ levels become elevated when measured at long intervals after endolymphatic hydrops is surgically induced. The present study was designed to investigate how rapidly endolymph Ca2+ increases following endolymphatic duct ablation. Hydropic animals were tested at either 4 days, 4 weeks, 8 weeks or 16 weeks after surgery. In each animal endolymph Ca2+ and endocochlear potentials were measured in all four cochlear turns using double-barreled Ca(2+)-sensitive electrodes. Cochlear sensitivity was assessed using compound action potential thresholds. Our results confirm that hydropic animals show an elevation of endolymph Ca2+ and a reduction of EP which is initially small, but becomes more pronounced at longer times after surgery. At 16 weeks endolymph Ca2+ was increased by an average factor of 20 in the basal turn and 7.5 in the fourth turn. These findings suggest that endolymph Ca2+ changes may not be the primary factor responsible for hydrops generation, but probably contribute to cochlear dysfunction in later phases of hydrops. For some experimental groups, the elevation of AP threshold was more closely correlated with endolymph Ca2+ level than it was with endolymph volume. Endolymph Ca2+ changes must therefore be considered in order to account for dysfunction in the hydropic cochlea.
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8040081
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Morphology of the cochlear nucleus in CBA/J mice with chronic, severe sensorineural cochlear pathology induced during adulthood.
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The effects of chronic cochlear impairment on morphological features of the adult cochlear nucleus (CN) were assessed in CBA/J mice in which severe sensorineural damage had been induced by exposure to intense noise. Sections from various CN subdivisions, stained for Nissl substance and fibers, were quantitatively evaluated in four groups of noise-exposed mice that differed with regard to the age at noise exposure (2, 6, or 11 months), age at the time the CN was evaluated (6, 11, or 24 months), and the duration (chronicity) of sensorineural impairment (4, 5, 13, or 18 months). Like-aged, non-exposed CBA mice were used as controls, so the effects of peripheral damage and aging could be compared. Cochlear damage produced significant changes in CN subdivisions thought to receive the heaviest input from cochlear afferents (anteroventral CN, octopus cell area, dorsal CN layer III). These changes included a reduction of neuropil volume, reductions in neuron size, and increases in neuronal packing density that were complementary to reduced volume in these subdivisions. Effects on neuron number were minimal in all subdivisions. Central changes in noise-exposed mice were absent or diminished in DCN layers I and II, which receive relatively less input from primary fibers. The age at onset and chronicity of damage had little to do with the severity of central effects of cochlear damage. The effects of cochlear damage were not additive with age-related changes seen in the old controls.
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8040077
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Synthesis and anticandidal activities of optimized analogs of antibiotic Sch 37137.
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Peptide analogues of Sch 37137 the antifungal antibiotic have been synthesized and evaluated in vitro against Candida sp. Di- and tripeptides containing methionine, leucine, norvaline, lysine, glutamic acid and N3-(trans-epoxysuccinamoyl)-L-2,3-diaminopropanoic acid, (EADP) were obtained. Peptides containing (D)-, and (L)-trans-epoxysuccinamic acid were also prepared. All of the analogues examined displayed in general higher anticandidal activity than a mixture of diastereomers of Sch 37137.
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8040076
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Suppressive effect of cyclosporin A on delayed-type hypersensitivity to syngeneic testicular cells.
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We have investigated the immunosuppressive effect of cyclosporin A (CsA) on delayed-type hypersensitivity (DTH) to syngeneic testicular cells (TC). DTH to syngeneic TC was induced by subcutaneous (sc) immunization with viable syngeneic TC and was augmented by a high dose of cyclophosphamide (CY)-pretreatment. DTH was suppressed by administration of CsA in a dose-dependent manner. When the mice were immunized alone or with 100 mg/kg of CY-pretreatment, 30 mg/kg or more of CsA suppressed DTH to TC. In mice immunized with 200 mg/kg of CY-pretreatment, 50 mg/kg of CsA was needed to suppress DTH. DTH is thought to play a key role in the induction and/or maintenance of experimental autoimmune orchitis (EAO). Our data show that DTH to syngeneic TC induced by immunization is suppressed by administration of CsA. Pretreatment of mice with immunization and administration of CsA suppressed DTH significantly when the mice were challenged with immunization with CY-pretreatment. However, DTH was rather enhanced significantly in mice pretreated with administration of CsA alone without preimmunization. Therefore, even though administration of CsA with immunization suppresses DTH, administration of CsA alone might rather eliminate suppressive mechanism resulting in augmentation of DTH.
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8040075
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Pironetin, a novel plant growth regulator produced by Streptomyces sp. NK10958. I. Taxonomy, production, isolation and preliminary characterization.
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A novel plant growth regulator, pironetin, was isolated from the culture broth of Streptomyces sp. NK10958. It was extracted from the culture broth with ethyl acetate and purified by column chromatographies. Pironetin showed 23% inhibition on the growth of rice plants without any loss of crop yield at 10 g/a on 9 days before heading.
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8040074
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Structural studies of new macrolide antibiotics, shurimycins A and B.
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The structures of new antibiotics, shurimycins A and B produced by Streptomyces hygroscopicus A1491, were elucidated from the physico-chemical properties, 2D NMR techniques and chemical degradation experiments to be 36-membered macrolides related to azalomycins, scopafungin and guanidylfungins. Shurimycins were active against fungi and Gram-positive bacteria.
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8040072
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FL-120A-D', new products related to kinamycin from Streptomyces chattanoogensis subsp. taitungensis subsp. nov. I. Taxonomy, fermentation and biological properties.
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Six new kinamycin antibiotics, designated as FL-120A-D' (1-6) were isolated from the culture filtrate of Streptomyces sp. strain IY2-13. Based on its cultural, physiological, morphological and chemical characteristics, this strain was identified as a new subspecies of Streptomyces chattanoogensis and named S. chattanoogensis subsp. taitungensis. These kinamycins have demonstrated a potent activity against Gram-positive aerobic and anaerobic bacteria.
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8040073
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FL-120A-D', new products related to kinamycin from Streptomyces chattanoogensis subsp. taitungensis subsp. nov. II. Isolation and structure determination.
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Six new kinamycin antibiotics have been isolated from the culture filtrate of Streptomyces chattanoogensis. The structures of six related components were determined employing 1D and 2D NMR spectroscopy and mass spectrometry. These structures represent the first reported epoxide kinamycin (2, 3) and propionyl derivative of kinamycin (5), and new isobutyryl derivatives of kinamycin (1, 4, 6).
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8040071
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Novel antibiotics, amythiamicins. I. Taxonomy, fermentation, isolation, physico-chemical properties, and antimicrobial activity.
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Novel antibacterial antibiotics, amythiamicins A, B, C and D, have been isolated from the fermentation broth of Amycolatopsis sp. MI481-42F4. In this paper, the taxonomy of the producing strain, fermentation, isolation, physico-chemical properties and biological activities of amythiamicins are reported. Amythiamicins inhibit the growth of Gram-positive bacteria including multi-drug resistant strains.
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8040070
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Chrymutasins: novel-aglycone antitumor antibiotics from a mutant of Streptomyces chartreusis. II. Characterization and structural elucidation.
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Chrymutasins A, B and C are glycosidic antibiotics produced by a mutant of the chartreusin producer-organism Streptomyces chartreusis. We report here the structure elucidation of these compounds. The sugar moieties involved were determined by comparison with the related chartreusins. The structure of the aglycone, the same in all three compounds, was elucidated by NMR, incorporation studies of labeled compounds and synthesis of derivatives. The chrymutasin aglycone differs from that of chartreusin by a single carbon and an amino group.
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8040069
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Chrymutasins: novel-aglycone antitumor antibiotics from a mutant of Streptomyces chartreusis. I. Taxonomy, mutation, fermentation, isolation and biological activities.
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Three novel antibiotics, named chrymutasins A, B and C, were isolated from the fermentation products of a mutant strain obtained by NTG (N-methyl-N'-nitro-N-nitrosoguanidine) treatment. The mutant strain produced the chrymutasins, which differed in the aglycone moiety from chartreusin, and related compounds. The production of these compounds needed a characteristically long fermentation period. The antitumor activity of chrymutasin A is better in vivo than that of chartreusin, the cytotoxic activity against cell lines in vitro is equivalent, and the antimicrobial spectrum is narrower.
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8040068
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Fusarium merismoides Corda NR 6356, the source of the protein kinase C inhibitor, azepinostatin. Taxonomy, yield improvement, fermentation and biological activity.
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Fungal strain NR 6356, Fusarium merismoides Corda, was discovered as the source of the protein kinase C (PKC) inhibitor, azepinostatin. The strain was identified based on its growth on potato sucrose agar, slender conidial shape, characteristic polyphialide and production of abundant chlamydospores. Fusarium aquaeductuum Lagh. IMI 103658 and Fusarium sp. NR 7222 were also found to produce the same inhibitor. After single colony isolation and medium optimization trials, a more than 30-fold increase in the production of azepinostatin over the original culture was achieved. Azepinostatin selectively and potently inhibited rat brain PKC with an IC50 value of 70 nM. Other enzymes utilizing ATP, including hexokinase, were not affected. The Ki of azepinostatin for PKC was 0.5 nM. The inhibition of PKC was competitive with ATP and uncompetitive with histone.
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8040067
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Thielocin B3, a novel antiinflammatory human group II phospholipase A2 specific inhibitor from ascomycetes.
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Evidence accumulated to date suggests that extracellular group II phospholipase A2 (PLA2-II) is involved in the pathogenesis of inflammatory disease. During screening for PLA2 inhibitors, we found a novel PLA2 inhibitor named thielocin B3 in the culture broth of an ascomycetes. Thielocin B3 strongly inhibited human PLA2-II (IC50 = 0.076 microM) in a reversible and noncompetitive manner (Ki = 0.098 microM), whereas it inhibited human group I PLA2 only weakly (IC50 = 18 microM). It also quenched the tryptophan fluorescence of Naja mocambique venom PLA2; almost 100% quenching being attained at a thielocin B3/enzyme molar ratio of 1.0. Its inhibitory activity toward human PLA2-II and Naja mocambique PLA2 was markedly decreased by methylation of its two carboxyl groups, while the quenching observed for Naja mocambique PLA2 was not altered. These results suggest that the two carboxyl groups do not participate in the binding of thielocin B3 to the enzyme, but play a crucial role in the PLA2 inhibition. Furthermore, in the rat carrageenan-induced pleurisy model, thielocin B3 significantly reduced both exudate volume and PLA2 activity in the exudate when coinjected with carrageenan.
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8040066
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WS79089A, B and C, new endothelin converting enzyme inhibitors isolated from Streptosporangium roseum. No. 79089. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities.
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WS79089A, B and C, which are novel endothelin converting enzyme (ECE) inhibitors have been isolated from the fermentation broth of Streptosporangium roseum No. 79089. These inhibitors were purified from an acetone extract of whole culture broth followed by Silicar CC-4 column chromatography and HPLC. WS79089A, B and C showed highly selective ECE inhibition activity with IC50 values of 0.73 microM 0.14 microM and 3.42 microM, respectively. On the basis of spectroscopic and chemical evidence, the tentative structures of WS79089A, B and C have been proposed, they have benzo[a]naphtacen chromophores.
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8040056
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Structure-activity relationship among polyhydro derivatives of tylosin.
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Tetra-, hexa- and octahydro derivatives of tylosin were prepared by the reduction of the conjugated double bond and carbonyl groups. Hydrogenation of the diene did not change the in vitro antimicrobial activity of compounds, while reduction of carbonyls causes small or complete loss of activity.
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8040055
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PF1018, a novel insecticidal compound produced by Humicola sp.
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A new insecticidal compound PF1018 was isolated from the culture broth of Humicola sp. It exhibited insecticidal activity against a wide range of critical pest species. The structure of PF1018 was determined to be (7aS)-2-((2E)-1-hydroxy-3-((1S,3aR,4R,5R,7aR)-3a,4,5,7 a-tetrahydro-1,3,5,7- tetramethyl-5,1-((3S)-(Z)-2,3-dimethylpropeno)-1H-inden-4-yl )-2- propenylidene)pyrrolizidine-1,3-dione, by NMR spectral analyses coupled with X-ray crystallographic analysis and chemical degradation study.
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8040054
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Novel aspartyl protease inhibitors, YF-0200R-A and B.
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Novel pepstatin A-sensitive Candida albicans aspartyl protease inhibitors, named YF-0200R-A and B, were isolated by column chromatography and preparative HPLC from the fermentation broth of Streptomyces sp. YF-0200R. The structures of YF-0200R-A and B were elucidated by spectroscopic analysis as alpha, beta and gamma, delta unsaturated fatty acids with two or three hydroxyl groups. YF-0200R-A and B inhibit aspartyl protease from Candida albicans with IC50 values of 6.5 x 10(-4) M and 6.2 x 10(-4) M, respectively.
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8040053
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Novel retrovirus protease inhibitors, RPI-856 A, B, C and D, produced by Streptomyces sp. AL-322.
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Four kinds of retrovirus protease inhibitors (RPI-856 A, B, C and D) were isolated as white powder from the culture filtrate of a soil isolate, Streptomyces sp. AL-322 by column chromatography using Diaion HP-20, Sephadex LH-20, ODS reversed phase HPLC and SP-2SW ion exchange HPLC. The structures of these inhibitors were elucidated by physico-chemical properties, chemical reactions and spectral analyses, as valyl-ADPAA-leucyl-AOPBA-valyl-valyl-aspartic acid (RPI-856 A and B) and valyl-ADPAA-leucyl-AOPBA-valyl-valine (RPI-856 C and D) [ADPAA = 2-amino-2-(3,5-dihydroxyphenyl)acetic acid, AOPBA = 3-amino-2-oxo-4-phenylbutyric acid]. RPI-856 A and B, and RPI-856 C and D were both determined to be diasteromers each other on the asymmetric carbon in AOPBA. These four inhibitors strongly inhibited in vitro HIV-1 protease and HTLV-I protease both derived from recombinant Escherichia coli with IC50 of 10(-7) approximately 10(-8) M.
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8040052
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New naphthacenecarboxamide antibiotics, TAN-1518 A and B, have inhibitory activity against mammalian DNA topoisomerase I.
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New naphthacenecarboxamide antibiotics, TAN-1518 A and B, were isolated from a culture broth of Streptomyces sp. AL-16012. Their structures were elucidated from their reactions and from spectroscopic analyses. The relaxation of supercoiled pBR322 DNA by calf thymus DNA topoisomerase I was inhibited by these metabolites as potently as by camptothecin. However, the decatenation of kinetoplast DNA by calf thymus DNA topoisomerase II was little affected by these agents. The major metabolite, TAN-1518 A, strongly suppressed the growth of various murine and human tumor cells, inducing apoptosis. Unlike camptothecin, TAN-1518 A did not stimulate cleavable complex formation in the nuclei of CHO-K1 cells and had weak activity in intercalating into DNA strands. This metabolite arrested the growth of human tumor cell lines in G1 phase of the cell cycle. These results suggest that TAN-1518 A and B are novel antitumor agents targeting topoisomerase I.
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8040051
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Cytostatin, a novel inhibitor of cell adhesion to components of extracellular matrix produced by Streptomyces sp. MJ654-NF4. II. Physico-chemical properties and structure determination.
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The structure of cytostatin was determined to be 5,6-dihydro-5-methyl-6-(6-hydroxy,1,5-dimethyl-4-phosphonooxy-7,9, 11-tridecatrienyl)-2H-pyran-2-one sodium salt on the basis of physico-chemical properties and NMR studies.
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8040050
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Cytostatin, a novel inhibitor of cell adhesion to components of extracellular matrix produced by Streptomyces sp. MJ654-NF4. I. Taxonomy, fermentation, isolation and biological activities.
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Cytostatin has been identified as a novel inhibitor of cell adhesion to components of extracellular matrix (ECM) in cultured broth of Streptomyces sp. MJ654-NF4. Though cytostatin did not inhibit EL-4 cell adhesion to ECM components such as laminin and fibronectin; it inhibited the adhesion of B16 melanoma cells to laminin and collagen type IV but not to fibronectin. It exhibited antimetastatic activity on B16 melanoma cells in mice. The cytotoxicity of cytostatin are also reported.
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8040049
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Aselacins, novel compounds that inhibit binding of endothelin to its receptor. II. Isolation and elucidation of structures.
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Three novel compounds, named the aselacins, which inhibit the binding of endothelin to its receptor have been isolated from two related Acremonium species of fungi grown in stationary culture. These compounds are cyclic pentapeptolides with a ring formed by cyclo[Gly-D-Ser-D-Trp-beta-Ala-L-Thr] and an additional exocyclic D-Gln to which is attached a functionalized long chain fatty acid. The aselacins differ in the functionalization of this acid. The structures of the aselacins were determined by amino acid analysis, mass spectrometry and evaluation of 1-D and 2-D homonuclear and heteronuclear 1H, 13C and 15N NMR spectra in protic and aprotic solvents. The stereochemistry of the amino acids present was elucidated by chiral HPLC of hydrolyzed compound.
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8040048
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Aselacins, novel compounds that inhibit binding of endothelin to its receptor. I. The producing organism, fermentation and biological activity.
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A radioligand test to detect inhibitors of endothelin-1 binding to its receptors in bovine atrial and porcine cerebral membranes was used to screen fungal metabolites from stationary fermentations. Inhibitory activity, observed in culture extracts of two Acremonium species, led to the discovery of aselacins A, B and C. Aselacin A inhibits binding to both membrane fractions with IC50s of approximately 20 micrograms/ml.
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8040041
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To treat or not to treat the internal mammary nodes: a possible compromise.
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A method for designing partly wide tangential fields that irradiate the superiorly placed internal mammary nodes, yet exclude the inferiorly placed internal mammary nodes and the cardiac tissue, is described for patients receiving tangential radiation for breast cancer. Patients are immobilized in hemibody foam cradles. A CT study is performed with a series of fiducial markers. The CT data set can then either be transferred to the three-dimensional treatment planning computer for sophisticated treatment planning, or can be viewed to design partly wide tangential fields "by hand." This latter method is far less time consuming and, we believe, usually adequate, given the uncertainties in identifying the location of the internal mammary nodes. This technique has been implemented in our clinic and has been used to treat approximately 15 patients. In four of these patients, a formal dose-volume histogram analysis revealed that these partly wide tangential fields can adequately exclude the cardiac volume and include the superiorly placed internal mammary nodes. Modest reductions in the pulmonary volume that is incidentally irradiated are seen compared to conventional wide tangents that irradiate the entire length of the internal mammary chain. While controversy remains regarding the appropriateness of internal mammary nodal irradiation for patients with breast cancer, the technique described represents an attractive compromise. Selective irradiation of the superiorly placed internal mammary nodes (which are those at greatest risk for involvement) with customized "partly wide" tangential fields is possible. This treatment technique may provide the survival advantage that might be seen with internal mammary node irradiation, yet avoid the possible cardiac morbidity.
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8040040
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Optimizing the time course of brachytherapy and other accelerated radiotherapeutic protocols.
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It is likely that early-responding tissues, such as tumors, repair sublethal damage more rapidly than do late-responding tissues. This difference can be exploited to design protocols with a significantly improved therapeutic advantage for accelerated radiotherapeutic regimens, including brachytherapy. The time course of potential protocols is computer optimized, maximizing the therapeutic difference between tumor-control probability (TCP), and normal-tissue complication probability (NTCP). These quantities are evaluated with the linear-quadratic model, using clinically derived parameters. The optimization is performed by individually adjusting doses in different parts of the treatment, maximizing the therapeutic advantage. In the main calculations, half times for damage repair were T1/2(late) = 4 h, T1/2(early) = 0.5 h. Two component (fast/slow) repair processes were also investigated. Protocols determined by optimization have significantly greater therapeutic advantage than continuous low-dose rate (CLDR) protocols of the same overall dose and time. The optimized protocols are either (a) acute-dose/gap/CLDR/gap/acute-dose; or (b) a series of acute doses separated by 3-4 h. As a typical example, results are given for 60 Gy/120 h CLDR brachytherapy, which is assumed to give NTCP = 0.2 and TCP = 0.8. Under our assumptions, optimized regimes, with the same overall time and dose, produce an NTCP of approximately 0.11 and TCP of approximately 0.83, a significant therapeutic gain over CLDR. Difference in repair rates between early- and late-responding tissues can be exploited to produce clinically practical protocols that are significantly superior to current regimens. Such optimized protocols produce slightly better tumor control than CLDR with the same overall dose and time, significantly less late damage, and similar early normal-tissue sequellae. Temporal optimization, thus, promises to be a powerful tool in designing better treatment protocols.
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8040037
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Optimizing brachytherapy for locally advanced cervical cancer.
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No adequate high dose rate brachytherapy technique exists to cover all known tumor volume by using one type of applicator in patients presenting with a cervix carcinoma extending to the vaginal wall and the parametria. We adapted the existing high dose rate applicator, existing of two ovoids and one intrauterine tube, to achieve adequate irradiation of the uterus, the parametria, and the vaginal wall in these patients. Using the optimization program of the Nucletron Planning System, isodose curves were obtained to apply a specified dose of 8.5 Gy at point A and at 5 mm depth of the vaginal wall by using a single applicator for both fractions. Fractionated high dose rate brachytherapy can be given with both higher dosimetric accuracy and more adequate irradiation of the vaginal and the parametrial tumor component after adapting the existing high dose rate applicator for brachytherapy in cervical cancer.
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8040038
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A simple device to position large/flaccid breasts during tangential breast irradiation.
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It is technically difficult to irradiate large pendulous or flaccid breasts with tangential photon fields because they often lie very high or lateral on the chestwall. We, therefore, designed a device to reposition the breast on the chestwall to facilitate treatment. A device to aid in repositioning the breast on the chestwall has been designed. The device consists of a reinforced polyvinylchloride tube formed into a ring that is placed around the breast. A strap around the patient's chest holds the ring in place. The breast tissue is manually moved to the desired position on the chestwall, whereafter the strap is tightened to maintain the position. Treatment setup marks are placed on the skin peripheral to the breast and on the immobilization mold. Twelve patients with large/flaccid breasts were successfully treated with this device. The technical and physician staff find the reproducibility and acute treatment reactions to be acceptable. Anatomically, the use of this device reduces the volume of lung tissue otherwise included in the tangential fields in patients where the breast lies far lateral. In patients where the breast lies too far cephalad on the chestwall for tangential fields to clear the arm, repositioning of the breast with this device makes tangential fields possible. This repositioning appliance aids in the radiation treatment of patients with large or flaccid breasts and, in some instances, renders otherwise nontreatable patients treatable with radiation therapy.
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8040036
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Reproducibility of field alignment in difficult patient positioning.
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Quantitative assessment of the accuracy of field alignment in a homogeneous group of patients with difficult positioning (postoperative irradiation after total hip replacement). In 95 patients linear and rotational discrepancies were measured between the simulation and first check film and between five consecutive verification films. For the total group of patients, all deviations were normally distributed with mean values of approximately zero and standard deviations of 4.0-8.0 mm (linear discrepancies) and 3.5-5 degrees (rotational discrepancies). Deviations were similar for the transition from simulator to the treatment machine and for subsequent treatment delivery, with 50% and 95% of absolute differences being less than 5 mm and 15 mm, respectively. Our analysis indicates that statistical fluctuations are considerably more important than errors introduced at start of treatment. Therefore, a first check film seems to be inadequate to predict the expected inaccuracies for the whole course of treatment. In addition, our results should help to prescribe appropriate safety margins for patients with difficult positioning.
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8040034
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Combined external beam radiotherapy and intraluminal high dose rate brachytherapy on bile duct carcinomas.
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The aim of this study was to investigate the effectiveness and complications of combined external beam and intraluminal high dose rate irradiation and various adjuvant biliary drainage techniques on patients with bile duct carcinomas. Eighteen patients with carcinomas of the hepatic duct bifurcation and 12 patients with carcinomas of the choledochus duct or the common hepatic duct were treated with combined external beam radiotherapy and intraluminal high-dose rate brachytherapy. Nine patients received radiotherapy after palliative tumor resection and 21 patients were primarily irradiated. Twenty-five patients completed the full course of radiotherapy. On these patients, the reference doses for the external beam varied from 30 to 45 Gy and for brachytherapy from 20 to 45 Gy. Biliary drainage after radiotherapy was achieved either with percutaneous catheters, endoprosthesis, or stents. The median survival for the entire group was 10 months. The actuarial survival was 34% after 1 year, 18% after 2 and 3 years, and 8% after 5 years. The subgroup with palliative tumor resection exhibit a significantly better survival (median: 12.1 months vs. 7.9 months). Three patients are still living without evidence of disease since 35 to 69 months. Major complications like bacterial cholangitis could be lowered from 37% to 28% through exchange of percutaneous transhepatic catheters to endoprosthesis or stents. The longest lasting drainages were achieved through stents. The frequency of radiogenic ulcera were lowered from 23% to presently 7.6% after the total dose of the high dose rate afterloading boost was reduced to 20 Gy. The present standard treatment schedule 40 Gy for the external beam and 20 Gy (fourfold 5 Gy) for the afterloading boost seems to be appropriate and well tolerated. After radiotherapy, a permanent supply of drainage should be made with a stent.
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8040035
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Fluoroscopic visualization of the prostatic urethra to guide transperineal prostate implantation.
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To describe a novel way to assure proper needle positioning within the prostate during transperineal implantation, using the urethra as the primary radiographic landmark. Preoperative computerized tomography (CT) images through the prostate are used to plan optimal transperineal needle-seed placement. When performing the procedure, a Foley catheter, with radio-opaque wire is used to visualize the prostatic urethra fluoroscopically in anterior-posterior and lateral projections. Proper needle placement is determined by their position relative to the urethra. Sixty patients have been implanted with this method at Memorial Sloan-Kettering Cancer Center from 1990-1992. The method described here is an improvement over previously described CT-based techniques. It could be used to supplement or replace ultrasound imaging.
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8040033
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Hyperfractionated total lymphoid irradiation and cyclophosphamide for preparation of previously transfused patients undergoing HLA-identical marrow transplantation for severe aplastic anemia.
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To assess the immunosuppressive capacity of hyperfractionated total lymphoid irradiation and cyclophosphamide for transplantation of unmodified allogeneic marrow in sensitized aplastic anemia patients. From February 1983 to September 1990, 23 multiply transfused aplastic anemia patients underwent unmodified bone marrow transplantation from HLA genotypically identical sibling donors following preparation with 6 Gy hyperfractionated total lymphoid irradiation and 160 mg/kg cyclophosphamide. Graft-versus-host disease prophylaxis included steroids in one patient, methotrexate in four, cyclosporine in seven, and methotrexate/cyclosporine in 12. There were 17 males and 6 females with a median age of 13 (range: 2.5-32). One patient died early before engraftment of bacterial sepsis. Twenty-two patients were evaluable for engraftment. Three experienced graft failure including one primary, and two late graft failures associated with cyclosporine withdrawal. Acute graft-versus-host disease occurred in 7/22 (> or = grade II in 6), and chronic graft-versus-host disease in 3/17 patients. Except for a patient who received total body irradiation for a second transplant, no patient in this series developed interstitial pneumonia. Fifteen patients are alive with follow-up of 38-125 months (median 68). The overall actuarial survival at 5 years is 69%, at 8 years it is 60%, with one late death. The survival of adult patients was similar to that of younger patients (> or = 16 years old: 63%, < 16 years old: 55%). The development of acute graft-versus-host disease adversely influenced survival (88% with Grade 0-I, 17% with grade II-IV; p = 0.002). No hypothyroidism or secondary malignancies have been documented in this series. Pretransplant immunosuppression with 6 Gy of hyperfractionated total lymphoid irradiation and 160 mg/kg CY reduces but does not eliminate the incidence of graft failure in sensitized aplastic anemia patients. The dose and the mode of administration of total lymphoid irradiation in this trial may be associated with a lower incidence of late side effects. Survival is comparable to that obtained using preparative regimens without radiation.
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8040032
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Distinguishing tumor recurrence from irradiation sequelae with positron emission tomography in patients treated for larynx cancer.
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Distinguishing persistent or recurrent tumor from postradiation edema, or soft tissue/cartilage necrosis in patients treated for carcinoma of the larynx can be difficult. Because recurrent tumor is often submucosal, multiple deep biopsies may be necessary before a diagnosis can be established. Positron emission tomography with 18F-2fluoro-2deoxyglucose (FDG) was studied for its ability to aid in this problem. Positron emission tomography (18FDG) scans were performed on 11 patients who were suspected of having persistent or recurrent tumor after radiation treatment for carcinoma of the larynx. Patients underwent thorough history and physical examinations, scans with computerized tomography, and pathologic evaluation when indicated. Standard uptake values were used to quantitate the FDG uptake in the larynx. The time between completion of radiation treatment and positron emission tomography examination ranged from 2 to 26 months with a median of 6 months. Ten patients underwent computed tomography (CT) of the larynx, which revealed edema of the larynx (six patients), glottic mass (four patients), and cervical nodes (one patient). Positron emission tomography scans revealed increased FDG uptake in the larynx in five patients and laryngectomy confirmed the presence of carcinoma in these patients. Five patients had positron emission tomography results consistent with normal tissue changes in the larynx, and one patient had increased FDG uptake in neck nodes. This patient underwent laryngectomy, and no cancer was found in the primary site, but nodes were pathologically positive. One patient had slightly elevated FDG uptake and negative biopsy results. The remaining patients have been followed for 11 to 14 months since their positron emission studies and their examinations have remained stable. In patients without tumor, average standard uptake values of the larynx ranged from 2.4 to 4.7, and in patients with tumor, the range was 4.9 to 10.7. Positron emission tomography with labeled FDG appears to be useful in distinguishing benign from malignant changes in the larynx after radiation treatment. This noninvasive technique may be preferable to biopsy, which could traumatize radiation-damaged tissues and precipitate necrosis.
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8040031
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A prospective study of short-course radiotherapy in poor prognosis glioblastoma multiforme.
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Older age and poor performance status at presentation are unfavorable prognostic factors for patients with glioblastoma multiforme. Some studies suggest a shorter, palliative course of radiotherapy may confer similar benefits as compared to a radical course in such patients. We report a prospective, single arm trial, describing the use of a short-course of radiation in patients with glioblastoma and poor prognostic features. Twenty-nine patients with pathologically confirmed glioblastoma and age > or = 65 years or with initial KPS < or = 50 were treated with a short-course of whole brain radiotherapy (30 Gy/10 fractions/2 weeks). Computer tomography tumor volume, dexamethasone requirements, Spitzer quality of life index, and Karnofsky performance status were measured pre and 1 month postradiation. Overall survival for the study patients was compared with that of radically treated and supportive care only historical controls. Indices of tumor response were stable or improved in 60% of patients evaluable 1 month postradiotherapy. Median survival for all study patients was 6 months. Median survivals in similar groups of radically treated and supportive care only patients were 10 and 1 month(s), respectively. A survival advantage for the radical vs. short-course treatment was observed for the subset of patients with a pretreatment KPS > 50. Elderly patients with a low pretreatment KPS (< or = 50) may be treated adequately with a short, palliative course of radiotherapy. Elderly patients with a higher pretreatment KPS (> 50), however, may benefit from a higher dose radiotherapy regimen.
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8040030
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Hyperthermia induces doxorubicin release from long-circulating liposomes and enhances their anti-tumor efficacy.
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To examine the possibility that hyperthermia would accelerate drug release from long-circulating liposomes, and enhance their antitumor activity. Liposomes were prepared by thin film hydration technique. Hyperthermia was induced by ultrasound apparatus and a water bath heating system. The antitumor efficacy of treatment against RIF-1 tumor in C3H mice was evaluated by the tumor growth delay assay. In vitro drug release experiments demonstrated that increase in temperature from 37 degrees C to 41 degrees C resulted in about a sixfold increase in doxorubicin (DOX) release in a 1-h period. Increasing the temperature to 43 degrees C, resulted in only a modest additional drug release. Drug uptake studies showed that local hyperthermic treatment immediately following the drug administration dramatically enhanced Stealth liposome-encapsulated doxorubicin (S-DOX) uptake by tumors, but did not do so for free DOX. At 42 degrees C and at a dose of 10 mg/kg, the accumulation of S-DOX was about 10-fold and 2.5-fold higher than that with free drug and S-DOX at 37 degrees C, respectively. The antitumor efficacy study confirmed our hypothesis that the addition of hyperthermia to the treatment of RIF-1 tumors with doxorubicin encapsulated in long-circulating liposomes would enhance antitumor effects. Two hyperthermia treatments given at 24-h intervals appeared to be the most promising method of combining heat and long-circulating liposomes. The increased antitumor activity was not accompanied by increased toxicity, as determined by the body weight of the mice. Local hyperthermic treatment is able to accelerate DOX release from long-circulating liposomes, increase tumor uptake, and enhance their antitumor efficacy. The combination of local hyperthermia and long-circulating liposomes appears to show considerable promise in the treatment of localized diseases.
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8040029
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Influence of elevated temperature on natural killer cell activity, lymphokine-activated killer cell activity and lectin-dependent cytotoxicity of human umbilical cord blood and adult blood cells.
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To determine whether hyperthermia is to the benefit or detriment of host immune function, the effect of hyperthermia was evaluated on various functions of T-lymphocytes from human umbilical cord blood and compared to that of adult blood. Nonadherent mononuclear cells from cord blood or adult blood were used as the effector cells. To generate lymphokine activated killer (LAK) cells, effector cells were kept in culture for 5 days in complete medium containing recombinant human interleukin-2. To activate effector cells to become cytotoxic, cells were kept in culture in complete medium containing Con A. Cytotoxicity was determined in a standard 4-h chromium release assay using K-562 human erythroleukemic cells (in the natural killer cell activity assay) or Daudi cells (in the LAK cell activity or Lectin dependent cytotoxicity assay) as targets. For heat effects, cells in complete medium were heated at the desired temperature in a water bath for 1 h. Lymphokine-activated killer cell activity, lectin-dependent cytotoxicity and T-cell proliferative capacity were not deficient in human cord blood. Cytotoxic activities of T-cells from adult blood as well as from cord blood can be enhanced at febrile range (< or = 40 degrees C), and were significantly decreased by exposure to 1 h at 42 degrees C. The febrile responses (< or = 40 degrees C) to infection, in the course of malignant disease and with biological response modifiers treatment, may all be related to host defense mechanisms. Based on these observations, whole body hyperthermia (< or = 40 degrees C), in combination with the appropriate cytokines, may have therapeutic potential in the treatment of neonatal infections and malignancies under certain circumstances. Hyperthermia in febrile range may, therefore, confer an important immunoregulatory advantage to the host. In contrast, tumor killing therapeutic temperature (> 42 degrees C) which inhibits host immunocompetence should probably be used only for local hyperthermia.
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8040028
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Altered expression of epidermal growth factor receptor and estrogen receptor in MCF-7 cells after single and repeated radiation exposures.
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Studies on radiation-induced changes in gene expression are likely to be very important in developing a better understanding of cellular responses to ionizing radiation. While there is some information on the activation of cellular signal transduction pathways after radiation, few late reacting target genes have been identified. This study focuses on the characterization of expression modulation of two critical growth regulatory genes, estrogen receptor and epidermal growth factor-receptor in malignant mammary epithelial cells in response to single and repeated ionizing radiation exposures. MCF-7 cells were used for single radiation exposure (2-50 Gy) experiments and MCF-IR-3 cells, generated by exposure to cumulative doses of 60 Gy in 2 Gy fractions, respectively, were used to study the effects of repeated exposures. Steady-state messenger ribonucleic acid levels for estrogen receptor, epidermal growth factor-receptor, and transforming growth factor-alpha were determined by ribonucleic acid protection experiments. Estrogen receptor and epidermal growth factor-receptor protein expression was quantitated by competitive binding studies with 3H-estradiol and 125I-EGF. MCF-IR-3 cells showed a permanent three-fold down-regulation of the estrogen receptor messenger ribonucleic acid and protein, while epidermal growth factor-receptor was upregulated about nine-fold. Epidermal growth factor-receptor was substantially up-regulated in MCF-7 cells, at both the mRNA and protein levels, within 24 h of a single 2 Gy exposures, while there was a two-fold concomitant increase in transforming growth factor-alpha messenger ribonucleic acid expression. A decrease in estrogen receptor messenger ribonucleic acid and protein was suggested only after higher doses of single radiation exposures. Single and repeated radiation exposures modulate the expression of two critical growth promoting genes, estrogen receptor and epidermal growth factor-receptor, in MCF-7 cells. The inverse expression of estrogen receptor and epidermal growth factor-receptor established for estrogen receptor-positive malignant mammary epithelial cells is maintained in MCF-7 cells after single and repeated exposures suggesting that radiation acts through common regulatory circuits and may modulate the cellular phenotype.
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8040027
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Interleukin 1 increases thymidine labeling index of normal tissues of mice but not the tumor.
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This study was conducted to investigate the action of human recombinant interleukin 1 as a radioprotector for different mouse normal cells other than bone marrow cells. Semi-continuous injections of tritiated thymidine were administered every 6 h, over 24 h to determine thymidine labeling index. Mice were injected with recombinant human interleukin 1 24 h prior to tritiated thymidine and were compared to control animals that did not receive interleukin 1. Mice were killed 1 h after the last thymidine injection. The 24 h thymidine labeling index for normal tissues and RIF-1 tumor was determined. Labeling indices were also determined 1-14 days after a series of fractionated irradiations with or without pretreatment with a single dose of interleukin 1 administered 24 h prior to the first radiation. The thymidine labeling index of normal tissues was higher following the injection of recombinant human interleukin 1 24 h before radiolabeling. This was found in all normal tissues tested, including the lip and tongue mucosal basal cell layers, crypt cells of the duodenum, alveolar cells of the lung, hepatocytes, and basal skin cells. The thymidine labeling index of RIF-1 fibrosarcoma was not affected by interleukin 1 injection. A single interleukin 1 injection 24 h before the first radiation fraction also increased the thymidine labeling indices of normal tissues after localized fractionated irradiation. The thymidine labeling index of RIF-1 tumor was not increased by interleukin 1 administration except after relatively high radiation doses (20 Gy in five fractions). The ability of interleukin 1 to enhance the thymidine labeling index declined after the first day following the completion of fractionated irradiation. Recombinant human interleukin 1 increased the 24 h thymidine labeling index in normal tissues in mice, but not in RIF-1 tumor. Fractionated irradiation could maintain the effect of a single dose of interleukin 1, administered 24 h prior to the first fraction, up to 24 h after the end of radiation.
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8040026
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Morphological correlates of fractionated radiation of the mouse lung: early and late effects.
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The definition and quantitation of radiation-induced morphologic alterations in murine lungs is presented. The extent of injury to the lung, which is the dose-limiting organ in the thorax, may be reduced by fractionating the total radiation exposure to permit partial repair of radiation-induced damage between fraction administration and also to permit a larger total exposure to be administered. We previously reported that, following fractionated radiation exposures, as the dose/fraction decreases, the total dose to reach an isoeffect increases, with an alpha/beta ratio of 3.2 and 3.0 for breathing rates and lethality, respectively. In the present report, we provide comparative morphologic evaluation of the effects of weekly fractionated (three doses at one dose/week), daily fractionated (15 doses at 1/diem), and hyperfractionated (30 doses at 2/diem) radiation exposures. The doses administered within each group were uniform. To determine morphologic alterations, LAF1 mice were irradiated with 3, 15, and 30 fractions delivered in 19 days overall treatment time. In the hyperfractionation schedule, the two fractions per day were separated by a 6-h time interval. Total doses were as follows: 15-21 Gy for weekly fractionation, 30-41.5 Gy for daily fractionation, and 30-49.5 Gy for hyperfractionated schedules. Lung tissue, recovered either 24 or 72 weeks following the final exposure, was evaluated by transmission and scanning electron microscopy and light microscopy. Using a series of morphologic parameters, a total dose of 15 Gy in the weekly treatment schedule was found to be equivalent to a total dose of 30 Gy in the daily fractionation schedule and 37 Gy in the hyperfractionated treatment regimen at 24 weeks postirradiation. Measured at 72 weeks postirradiation, total exposures of 15 Gy on the weekly fractionation regimen corresponded to total exposures of approximately 30 Gy in both the daily fractionated and hyperfractionated regimens. Morphological damage was not uniform throughout the exposed lung and tended to be concentrated in lobes or portions of lobes. In the three fractionation regimens studied, there is progressive sparing of the lung with increased fractionation (i.e., weekly < daily < twice daily) during the pneumonitic stage (24 weeks postirradiation). Both daily and twice daily fractionations provide increased sparing over weekly fractionation during the fibrotic stages (72 weeks postirradiation), but were not markedly different from each other (i.e., weekly < daily = twice daily).
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8040024
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Ketoconazole attenuates radiation-induction of tumor necrosis factor.
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Previous work has demonstrated that inhibitors of phospholipase A2 attenuate ionizing radiation induced arachidonic acid production, protein kinase C activation and prevent subsequent induction of the tumor necrosis factor gene. Because arachidonic acid contributes to radiation-induced tumor necrosis factor expression, we analyzed the effects of agents which alter arachidonate metabolism on the regulation of this gene. Phospholipase A2 inhibitors quinicrine, bromphenyl bromide, and pentoxyfylline or the inhibitor of lipoxygenase (ketoconazole) or the inhibitor of cyclooxygenase (indomethacin) were added to cell culture 1 h prior to irradiation. Radiation-induced tumor necrosis factor gene expression was attenuated by each of the phospholipase A2 inhibitors (quinicrine, bromphenyl bromide, and pentoxyfylline). Furthermore, ketoconazole attenuated X ray induced tumor necrosis factor gene expression. Conversely, indomethacin enhanced tumor necrosis factor expression following irradiation. The finding that radiation-induced tumor necrosis factor gene expression was attenuated by ketoconazole suggests that the lipoxygenase pathway participates in signal transduction preceding tumor necrosis factor induction. Enhancement of tumor necrosis factor expression by indomethacin following irradiation suggests that prostaglandins produced by cyclooxygenase act as negative regulators of tumor necrosis factor expression. Inhibitors of tumor necrosis factor induction ameliorate acute and subacute sequelae of radiotherapy. We propose therefore, that ketoconazole may reduce acute radiation sequelae such as mucositis and esophagitis through a reduction in tumor necrosis factor induction or inhibition of phospholipase A2 in addition to its antifungal activity.
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8040025
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Late effects of intraoperative radiation therapy on retroperitoneal tissues, intestine, and bile duct in a large animal model.
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The late histopathological effects of intraoperative radiotherapy (IORT) on retroperitoneal tissues, intestine, and bile duct were investigated in dogs. Fourteen adult foxhounds were subjected to laparotomy and varying doses (0-45 Gy) of IORT (11 MeV electrons) delivered to retroperitoneal tissues including the great vessels and ureters, to a loop of defunctionalized small bowel, or to the extrahepatic bile duct. One control animal received an aortic transection and reanastomosis at the time of laparotomy; another control received laparotomy alone. This paper describes the late effects of single-fraction IORT occurring 3-5 years following treatment. Dogs receiving IORT to the retroperitoneum through a 4 x 15 cm portal showed few gross or histologic abnormalities at 20 Gy. At doses ranging from 30-45 Gy, radiation changes in normal tissues were consistently observed. Retroperitoneal fibrosis with encasement of the ureters and great vessels developed at doses > or = 30 Gy. Radiation changes were present in the aorta and vena cava at doses > or = 40 Gy. A 30 Gy dog developed an in-field malignant osteosarcoma at 3 years which invaded the vertebral column and compressed the spinal cord. A 40 Gy animal developed obstruction of the right ureter with fatal septic hydronephrosis at 4 years. Animals receiving IORT through a 5 cm IORT portal to an upper abdominal field which included a defunctionalized loop of small bowel, showed a few gross or histologic abnormalities at a dose of 20 Gy. At 30 Gy, hyaline degeneration of the intestinal muscularis layer of the bowel occurred. At a dose of 45 Gy, internal intestinal fistulae developed. One 30 Gy animal developed right ureteral obstruction and hydronephrosis at 5 years. A dog receiving 30 Gy IORT through a 5 cm portal to the extrahepatic bile duct showed diffuse fibrosis through the gastroduodenal ligament. These canine studies contribute to the area of late tissue tolerance to IORT.
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8040023
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Protective effects of glutathione on cisplatin neurotoxicity in rats.
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Different attempts have been made to minimize the neurotoxicity of cisplatin (DDP) and the use of "neuroprotective" drugs seems to be a promising strategy. In rats we compared the effects on the dorsal root ganglia neurons and peripheral nerves of the administration of DDP alone or in combination with glutathione (GSH), a putative "neuroprotective" drug. Twenty-four Wistar rats were treated with DDP alone (2 mg/kg/week) or with the same dose of DDP plus GSH (300 mg/week) for nine cycles and they were compared to 12 untreated age-matched rats. All the animals underwent either neurophysiological examination of the tail nerve or pathologic examination of the dorsal root ganglia. Analytical determination of the platinum concentration in dorsal root ganglia was also performed. Morphologic and morphometric evaluations demonstrated a reduced incidence of pathologic changes in DDP plus GSH-treated rats with respect to DDP-treated ones. In agreement with the morphological findings, the platinum concentration in the dorsal root ganglia was lower and sensory nerve conduction velocity in the tail nerve less markedly decreased in the animals treated with DDP plus GSH with respect to those treated with DDP alone. We conclude that the administration of GSH is effective in reducing the neurotoxic effects of DDP, thus supporting the preliminary results obtained in clinical trials in humans.
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8040022
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A new model of radiation-induced myelopathy: a comparison of the response of mature and immature pigs.
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The development of an experimental model of radiation-induced myelopathy in the pig which would facilitate the study of the effects of clinically relevant treatment volumes. The effects of local spinal cord irradiation, to a standard 10 x 5 cm field, have been evaluated in mature (37-42.5 weeks) and immature (15.5-23 weeks) pigs. Irradiation was with single doses of 60Co gamma-rays at a dose-rate of 0.21-0.65 Gy/min. The incidence of paralysis was used as an endpoint. Irradiation of mature animals resulted in the development of frank paralysis with animals showing combined parenchymal and vascular pathologic changes in their white matter. These lesions, in common with those seen in patients, had a clear evidence of an inflammatory component. The latency for paralysis was short, 7.5-16.5 weeks, but within the wide range reported for patients. However, it was shorter than that reported in other large animal models. The ED50 value (+/- SE) for paralysis was 27.02 +/- 0.36 Gy, similar to that in rats taking into account dose-rate factors. The irradiation of immature pigs only resulted in transient neurological changes after doses comparable to those used in the mature animals, ED50 value (+/- SE) 26.09 +/- 0.37 Gy. The reasons for these transient neurological symptoms are uncertain. A reliable experimental model of radiation-induced myelopathy has been developed for mature pigs. This model is suitable for the study of clinically relevant volume effects.
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8040021
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Neoadjuvant hormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy.
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To determine the extent of reduction of volume of normal tissue structures exposed to high doses of radiation therapy (RT) after administration of neoadjuvant hormonal therapy (NHT) in patients with bulky, geometrically unfavorable prostatic cancers. Twenty-two patients with bulky prostatic cancers were treated with a 3 month course of neoadjuvant leuprolide acetate and eulexin prior to three-dimensional (3-D) conformal radiotherapy. Patients were included if 3-D treatment planning revealed that either > 30% of the rectal wall would receive 95% of the prescription dose (D95) (n = 13); > or = 50% of the bladder wall would receive D95 (n = 10); or that any volume of small bowel would receive > or = 65% of the prescription dose (n = 16). All patients underwent simulation and conformal treatment planning before and after NHT. Pre and posthormone cumulative dose volume histogram (DVH) calculations for all normal tissue structures were analyzed and compared for each patient. The median percentage of target volume reduction after NHT was 25% (range: 3-52%). Ten of 13 patients (78%) whose prehormone rectal DVH demonstrated > 30% of the rectal wall receiving D95 responded to NHT with a median 25% (range: 16-48%) reduction of rectal volume receiving the D95. A median reduction of 50% (range: 6-64%) of the bladder volume receiving D95 was observed in nine of ten patients (90%), while 13 of 16 (81%) showed a reduction of small bowel volume to a median percentage of 88% (range: 67-100%) of the prehormonal values. Neoadjuvant hormonal therapy is an effective method for decreasing the size of bulky prostatic tumors as well as for optimizing the geometry of the target volume in relation to the adjacent normal tissue structures prior to radiation therapy. Such an approach allows for reduction of the volume of normal tissues exposed to high doses in the majority of treated patients. Currently, studies are underway to determine whether NHT will lead to a decreased likelihood of long-term complications associated with radiotherapy of bulky, geometrically unfavorable prostatic tumors, and permit the safe delivery of escalated dose levels using conformal treatment techniques.
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8040020
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Preliminary results of a pilot study using WR-2721 before fractionated irradiation of the head and neck to reduce salivary gland dysfunction.
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Based on in vivo evidence of radioprotection of the salivary glands using WR-2721, a pilot study was undertaken to determine the feasibility, toxicity, and salivary function of patients receiving WR-2721, while undergoing radiation therapy to the head and neck. Patients undergoing radiation therapy for cancer of the head and neck were eligible if the major salivary glands received more than 45 Gy. WR-2721 was administered over 6 min IV, 10-15 min prior to each dose of radiation five times per week. Saliva was collected and measured prior to radiation therapy, weekly during radiation therapy, 1 month postradiation therapy, and every 3 months thereafter. Flow rates of unstimulated whole saliva, stimulated whole saliva, and stimulated parotid saliva were measured using standard techniques. 99mTc salivary scintiscans were performed prior to radiation therapy, 1 month postradiation therapy and every 3 months thereafter. Nine patients are presently enrolled on the first dose level (100 mg/m2) of this study. Eight completed per protocol, two with minor decreases of total WR-2721 doses. Two patients progressed with distant metastases soon after completion of therapy. All available data are included in the analysis. Median follow-up for all patients is 18 months. Flow rates of unstimulated whole saliva decreased significantly during radiation therapy reaching 5.6% of baseline at 9 months postradiation therapy, subsequently recovering to 20% of baseline, then remaining stable over time. Stimulated whole salivary flow rate similarly decreased during radiation therapy and reached its nadir (11% of baseline) at 3 months postradiation therapy, improving to 27% of baseline by 2 years. The stimulated parotid flow rate decreased during radiation therapy to 1.4% of pretreatment levels. Significant recovery took place 6 months postradiation therapy and by 18 months values had recovered to 54% of baseline. 99mTc salivary scintiscans confirmed this rebound of parotid function postradiation therapy. Toxicity was minimal with the exception of one patient who received only 27% of the planned total drug dose due to grade 3 hypotension after the eighth treatment. No recovery of salivary function has been seen in this patient; flow rates remain zero in all three areas tested 21 months after radiation. Administration of WR-2721 prior to each dose of radiation was feasible and without significant toxicity at 100 mg/m2. Salivary gland function improved over time after completion of radiation, particularly the parotid. Future directions include escalation of WR-2721 dose to 200 mg/m2 and then 300 mg/m2, and a Phase III randomized trial will be undertaken once the optimal dose is established.
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8040019
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Sarcomas of the hand and foot: analysis of local control and functional result with combined modality therapy in extremity preservation.
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The records of 28 patients with sarcomas of the hand and foot treated at the National Cancer Institute (NCI) between 1977 and 1992 were reviewed to assess local control and functional results. Histologic types included 15 cases of the Ewing's sarcoma family of tumors, 7 cases of alveolar rhabdomyosarcoma, and 6 cases of nonrhabdomyosarcoma soft tissue sarcomas. Median age of all patients was 18 years (range 4-61), with a median potential follow-up of 114 months following diagnosis. Surgery varied from incisional biopsies for Ewing's Sarcoma and rhabdomyosarcoma lesions to complete excision when possible for nonrhabdomyosarcoma soft tissue sarcoma lesions. Amputation was not primarily performed, except in two patients who underwent ray resections of hand lesions (patients 13 and 24). Radiotherapy generally consisted of 50 Gy/25 fractions (fx)/5 weeks for Ewing's Sarcoma, 54 Gy/30 fx/6 weeks for rhabdomyosarcoma, and 63 Gy/35 fx/7 weeks for nonrhabdomyosarcoma soft tissue sarcomas. Chemotherapy was administered on various NCI protocols. Actuarial local control for Ewing's Sarcoma was 84% at 5 and 10 years. All but one survivor are capable of hand/foot function for routine activities without orthotic requirements. Five of six patients (83%) who died of metastatic disease had functional distal extremities. Actuarial local control for rhabdomyosarcomas was 100%, with equivalent function. No patient developed a second malignancy in the treatment field. Although equivalent local control may be achieved in these lesions with either amputation or radiotherapy, a prudent management course would be to defer amputation for management of local recurrences. Many patients with these lesions fail in distant sites only and die without local failure. For these patients and for those who remain long-term survivors, we believe a functional hand and foot provides a better quality of life than a prosthesis.
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8040017
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Patterns of recurrence of glioblastoma multiforme after external irradiation followed by implant boost.
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To study patterns of recurrence in patients with focal primary glioblastoma treated on Northern California Oncology Group protocol 6G-82-2 including surgery, focal external beam radiotherapy (59.4-60 Gy) with oral hydroxyurea followed by temporary brain implant with high-activity iodine-125 sources (50 Gy), and six cycles of chemotherapy with procarbazine, lomustine, and vincristine. Serial brain imaging scans were available for review in 25 of 34 patients with glioblastoma who underwent brain implant boost. Of 381 scans performed between the date of diagnosis and the date of death or last follow-up, 362 (95%) were re-reviewed. Disease progression was scored as local (within 2 cm of the implant site), separate within the brain parenchyma (> or = 2 cm from the implant site), subependymal, or systemic. Both initial and subsequent failures were scored. Three patients are 5-year survivors, without evidence of disease, at 267, 292, and 308 weeks. Of the 22 initial sites of failure, 17 (77%) were local, three (14%) were separate brain lesions (one of which was due in retrospect to multicentric disease at diagnosis), one (5%) subependymal, and one (5%) systemic. Five patients with local failure later had other sites of failure, including a separate brain lesion in 1, subependymal spread in 3, and both in 1. One patient with separate brain failure later had local progression and then subependymal spread. Although there was a significant risk of separate brain lesions or subependymal spread over time, local tumor progression was the predominant pattern of failure.
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8040018
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Trilateral retinoblastoma--incidence and outcome: a decade of experience.
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This report examines the incidence and outcome of trilateral retinoblastoma in children treated for retinoblastoma. A group of patients who are at highest risk for the development of trilateral retinoblastoma is defined. Between 1979 and 1990, 117 children were treated with external beam radiation therapy for retinoblastoma, (97/117, bilateral). Median follow-up time was 68 months. The median age at diagnosis was 7 months. Six cases of trilateral retinoblastoma were identified. The incidence of trilateral retinoblastoma in children with bilateral retinoblastoma was 6% (6/97) and 10% in those with a family history of retinoblastoma. The median age at diagnosis of RB in the children with trilateral retinoblastoma, was 3 months, younger than the median age of the entire retinoblastoma group. In all cases, the pineal region was excluded from the radiotherapy fields. Treatment for the trilateral retinoblastoma consisted of craniospinal axis radiation therapy and chemotherapy in three patients, chemotherapy alone in two, and no treatment in one. All patients died from this disease. Overall, of the 117 children treated at our institution for retinoblastoma with a median follow-up of 68 months, 12 have died. Trilateral retinoblastoma was the major cause of death, accounting for 50% (6/12) of deaths. Trilateral retinoblastoma is a major and under-appreciated cause of mortality in the first 5 years after the diagnosis of bilateral retinoblastoma. A more aggressive approach toward screening a defined population of childhood retinoblastoma survivors may be warranted.
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8040016
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The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age.
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To determine if in patients with single brain metastasis the addition of neurosurgery to radiotherapy leads to lengthening of survival or to better quality of life. From 1985 to 1990, 66 patients with single brain metastasis from a solid tumor were entered in a randomized trial of neurosurgery plus radiotherapy vs. radiotherapy alone. Patients were stratified for lung cancer vs. other sites of cancer and for progressive vs. stable systemic cancer. Radiotherapy was given to the whole brain by a novel scheme of two fractions of 2 Gy per day for a total dose of 40 Gy in 2 weeks, to obtain a relatively high total dose and short overall time, with minimal risk of late damage to normal tissue in long-term survivors. In the whole group of 63 evaluable patients, both with lung cancer as with other tumors, the combined treatment led to a better duration of survival (median 10 vs. 6 months; p = 0.04). The largest difference between both treatment arms was observed in patients with inactive extracranial disease (median 12 vs. 7 months; p = 0.02). Patients with active extracranial disease had an equal median survival of only 5 months, irrespective of given treatment. Age proved to be a strong and independent prognostic factor: patients older than 60 years had a hazard ratio of dying of 2.74 (p = 0.003) compared with younger patients. Following treatment, most patients remained functionally independent until a few weeks before death. In the majority of patients the cause of death was systemic tumor progression. Patients with single brain metastasis and with controlled or absent extracranial tumor activity should be treated with surgery and radiotherapy, especially when they are younger than 60 years. For patients with progressive extracranial disease, radiotherapy alone seems to be sufficient. The accelerated radiotherapy scheme of 40 Gy in 2 weeks to the whole brain is tolerated well and should also be considered for patients in a good performance status with surgically unaccessible single metastasis or even with multiple brain metastases.
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8040015
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Radiotherapy for nasopharyngeal carcinoma: shielding the pituitary may improve therapeutic ratio.
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Nasopharyngeal carcinoma (NPC) is well known for its invasiveness and erosion of the base of the skull is not uncommon. Before the advent of computed tomography, the evaluation of the base of the skull was by plain radiography. Because of the low sensitivity of these investigations, traditional teaching has included the sphenoid sinus in the volume of irradiation. Increase in longevity of patients allows the manifestation and documentation of the long-term sequelae of irradiating the hypothalamic-pituitary axis and the temporal lobes. This study is an attempt to evaluate whether the hypothalamic-pituitary axis can be shielded from the target volume in a proportion of NPC patients. One hundred fifty-two NPC patients with no evidence of erosion of the base of the skull and sphenoid, nor extension to the nasal fossa and ethmoid sinuses were randomized to receive standard radiotherapy covering the whole sphenoid sinus or radiotherapy using a modified technique that shields the pituitary and the anterior part of the hypothalamus. This modified technique also shields a large part of the lower temporal lobes that are otherwise covered by standard treatment portals. The characteristics and treatment of the two subgroups of patients were otherwise comparable. At a median follow-up of 31.5 months, the tumor control between the two subgroups of patients were comparable (p = 0.3928). However, 8 of the 71 patients in the unshielded group had developed symptomatic neuroendocrine complications, while none of the other group did (p = 0.0061). Two patients developed secondary hypothyroidism, one patient developed oligomenorrhoea associated with raised prolactin, and five patients developed temporal lobe necrosis. The protective effect on neuroendocrine complication of this shield was demonstrated at median follow-up of 31.5 months, and the local control was not jeopardized. Modification of treatment technique as presently described, which is applicable to one-third of NPC patients to improve the therapeutic ratio, is recommended for general use.
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8040014
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High-dose reirradiation of head and neck cancer with curative intent.
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This study evaluates the response of new or recurrent head and neck cancers and the response of associated normal tissues to high dose reirradiation with curative intent. From 1964 to 1991, 15 patients with in-field new second head and neck cancers and 85 patients with recurrent head and neck cancers have had high-dose reirradiation that overlapped with previously irradiated volumes. Reirradiation was given only to patients with no more than apparent minimal clinical radiation effects from the first radiation course. The reirradiation consisted of external beam only in 82 patients, external beam plus intracavitary or interstitial implant irradiation in 14 patients, and interstitial implant irradiation only in four patients. The combined overlapping dose from both the initial and subsequent irradiation (including brachytherapy) was 69-89 Gy in 14 patients, 90-99 Gy in 15 patients, 100-119 Gy in 27 patients, and 120 Gy or greater in 44 patients. Four patients had areas of overlap that received greater than 180 Gy. The actuarial 5-year survival was 37% for patients with new second primary cancers and 17% for patients with recurrent cancers. Loco-regional tumor control was achieved in 60% of the patients with new tumors and in 27% of the patients with recurrent tumors. Nine of the 100 patients developed severe adverse normal tissue effects from the reirradiation. High-dose reirradiation of head and neck cancers can be successful curative treatment in a significant proportion of patients. It is associated with substantial but acceptable risks in properly selected patients.
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8040013
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Salvage irradiation by brachytherapy of velotonsillar squamous cell carcinoma in a previously irradiated field: results in 73 cases.
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The salvage brachytherapy performed in patients presenting velotonsillar carcinoma in a previously irradiated field is evaluated in terms of local control, complications and survival. Between 1976 and 1990, 73 patients presenting with velotonsillar squamous cell carcinoma in a previously irradiated area were treated at Center Alexis Vautrin with brachytherapy along using an 192Ir implant (afterloading technique) with curative intent. According to the UICC 1987 TNM classification, there were 45 T1 N0, 20 T2 N0, one T3 NO, one T3 N2 and six Tx Nx. The 5-year actuarial local control for T1 N0 and T2 N0 are 80% and 67% respectively. The regional relapse rate was 10% in both groups. Grade 2 complications occurred in 13% of patients and these were neither related to the volume treated nor the dose rate. There were no Grade 3 or 4 complications. The 5-year specific survival is 64%, with a plateau after the 5th year, but the 5-year overall survival is only 30%. Fourty-two percent of the patients in this series died from another carcinoma. All but two of these were related to continued alcohol and tobacco intoxication. We conclude that brachytherapy alone (60 Gy) is optimal treatment for patients presenting with velontonsillar carcinoma in a previously irradiated field. The greatest challenge is the screening of these patients and the prevention of subsequent head and neck cancers. Recognizing the fact that these patients are at high risk for subsequent malignancies of upper aerodigestive tract, lung and esophagus, close surveillance is necessary for: (a) early diagnosis and prompt treatment; and (b) development of prevention strategies of field cancerization.
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8040012
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The study of tumoral, radiobiological, and general health factors that influence results and complications in a series of 448 oral tongue carcinomas treated exclusively by irradiation.
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Our aim was to study the different factors that influence the results and complications in a series of 448 carcinomas of the oral tongue treated from January 31, 1972 to December 31, 1986, by brachytherapy (Br) +/- neck dissection (181 cases) or combination of external beam irradiation and brachytherapy (EBI + Br) (267 cases). The patients distribution (TNM classification 1979) was: 125 T1, 186 T2, 128 T3, 9 T4Tx, 78% N0, and 22% N+. We used guide gutter or plastic tubes technique (Paris system dosimetry). Results at 5 and 10 years are: local control 68% and 64%, locoregional control 58% and 53%, specific survival 45% and 39%, and overall survival 44% and 27%. In the univariate analysis for local control (LC) and overall survival (OS), we considered the tumoral factors. At 5 years, the LC for T1, T2, T3 are 93%, 65%, and 49%, and the OS 69%, 41%, and 25%, respectively (p < 0.002). The lesions of the undersurface of the tongue have a better LC (77%) than other localizations (64%) (p = 0.02). For general factors, the index of general health condition, age, and sex were not significant for LC, but proved significant for OS (p = 0.01). Significant radiobiological factors: the safety margin (expressed by the ratio treated surface on tumoral surface > or = 1.2) is significant for LC and OS. This is the same if the interval between EBI and Br is < or = 20 days. Neither the dose rate, the spacing between the sources, the total dose, nor Br dose were significant, but the last two were adapted according to the infiltration. In the univariate study for grade 2 and 3 complications (tissue and bone), the surface treated (> 12 cm2), and the dose rate > 0.7 Gy/h were significant. The multivariate study showed that the small size of the lesion is the most important factor for local control, with brachytherapy alone for T1T2N0 and the number of days between EBI and brachytherapy < or = 20 days. For the complications, the most important factors are the total dose > 80 Gy and a treated surface > 12 cm2.
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8040010
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Experience in charged particle irradiation of tumors of the skull base: 1977-1992.
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To review the experience at University of California Lawrence Berkeley Laboratory in using charged particles to irradiate primary neoplasms of the skull base and those extending to the skull base from the nasopharynx and paranasal sinuses. During the period from 1977 to 1992, 223 patients were irradiated with charged particles at the Lawrence Berkeley Laboratory for tumors either arising in or extending to the skull base, of whom 48 (22%) had recurrent lesions, either post previous surgery or radiotherapy. One hundred twenty-six patients had lesions arising in the cranial base, mostly chordoma (53), chondrosarcoma (27), paraclival meningioma (27) with 19 patients having other histologies such as osteosarcoma or neurofibrosarcoma. There were also 31 patients with primary or recurrent squamous carcinoma of the nasopharynx extending to the skull base, 44 patients with major or minor salivary gland tumors, mostly adenocarcinoma, and 22 patients with squamous carcinoma of the paranasal sinuses, all with cranial base extension. Local control and survival appeared improved in tumors arising in the skull base, following the ability with charged particles to deliver high doses (mean of 65 Gy-equivalent) with relative sparing of the adjacent normal tissues. The Kaplan-Meier 5-year local control was 85% for meningioma, 78% for chondrosarcoma, 63% for chordoma and 58% for other sarcoma. Follow-up ranged from 4-191 months with a median of 51 months. Charged particle radiotherapy is highly effective in controlling cranial base lesions which have have been partially resected. Better tumor localization with CT and MRI, improved 3-D treatment planning and beam delivery techniques have continued to reduce the level of serious complications and increase local control and survival.
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8040011
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Does prolonged treatment course adversely affect local control of carcinoma of the larynx?
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The purpose of this paper is to present local control rates of carcinoma of the larynx in relation to the total treatment course after radical radiation therapy. A total of 1350 patients with laryngeal carcinoma treated at the Massachusetts General Hospital for the past three decades were available for analysis. Treatment courses were divided into two groups: 45 days and > 45 days. The local control rates were compared and evaluated for statistical differences. The data indicated that prolonged treatment course adversely affects local tumor control of both advanced glottic and supraglottic lesions, but to a lesser degree for the early tumors. The study indicated that for optimal local control, radiation treatment should be completed as soon as possible, preferably within 6.5 weeks, either by once- or twice-daily accelerated programs. The local control of early T1 glottic cancer has been exceedingly satisfactory by conventional once-daily radiation therapy. Further improvement by shortening of treatment time for such early lesions will be difficult to assess without a prospective randomized trial.
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8040009
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Cellular distribution of CD63 antigen in platelets and in three megakaryocytic cell lines.
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CD63 is a 53 kDa lysosomal membrane glycoprotein that has been identified as a platelet activation molecule. We investigated the localization of CD63 antigen in platelets and in three megakaryocytic cell lines (K562, HEL and CMK11-5) using flow cytometry and immunoelectron microscopy. Flow cytometry showed that a monoclonal antibody directed against CD63 bound to 8.1% of unstimulated platelets and 59.2% of thrombin-stimulated platelets. Immunoelectron microscopy demonstrated that CD63 antigen was distributed randomly inside unstimulated platelets, while it was localized in the open canalicular system of washed platelets and on the cell membranes of thrombin-stimulated platelets. Flow cytometry detected CD63 on 16.4% of HEL cells, 31.2% of K562 cells, and 43.2% of CMK11-5 cells. Immunoelectron microscopy demonstrated that CD63 was localized in the granules and on the surface membranes of HEL cells, in the vesicles and on the membranes of K562 cells, and in the granules and vesicles as well as on the membranes of CMK11-5 cells. Thus, the distribution of CD63 differed markedly among these three megakaryocytic cell lines.
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8040008
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Immunolocalization of alpha-transforming growth factor in the developing rat mammary gland in vivo, rat mammary cells in vitro and in human breast diseases.
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Immunoreactive alpha-transforming growth factor (alpha-TGF) was shown by immunocytochemistry to be present in the rat mammary gland at various stages of development, the staining being most intense in mature myoepithelial cells. Alpha-TGF was also detected in the secretions of the mammary glands of pregnant and lactating rats. alpha-TGF in the extracts of rat mammary glands at each stage of development, and in several rat mammary cell lines and in culture medium in which they had been grown, was shown by Western blotting to consist primarily of a protein of molecular weight 50 kDa. The amount of this protein was greater in the mammary gland of the lactating rat than in resting or involuting glands. alpha-TGF was also found in some, but not all, human breast carcinomas, and in benign hyperplastic breast diseases.
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8040007
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Quantification in immunohistochemistry: the measurement of the ratios of collagen types I and II.
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Quantitative techniques in immunohistochemistry are needed, but they are rarely applied because of doubtful reproducibility. We have developed a method for the detection of collagen types I and III in situ. The method applied was a two-step immuno-alkaline phosphatase technique with visualization of the end-product with Fast Red. The staining intensity was measured with a microdensitometer and the results expressed as ratios. The method yielded results that were unaffected by variations in tissue section thickness but which were proportionally related to time and antigen concentrations. Leiomyoma tissue, with a ratio of collagen types I and III of approximately 1.0, was used to establish the appropriate dilutions of the antibodies, thus assuring identical optical densities. By having the leiomyoma tissue sections incubated together with the heart tissue specimens, leiomyoma tissue was also helpful in correcting deviations from the 1.0 ratio. Accurate measurements of collagen type I/III ratios in normal human heart specimens were obtained with the present quantitative immunohistochemical technique.
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8040006
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The importance of fixation procedures on DNA template and its suitability for solution-phase polymerase chain reaction and PCR in situ hybridization.
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Conventional solution-phase polymerase chain reaction (PCR) and in situ PCR/PCR in situ hybridization are powerful tools for retrospective analysis of fixed paraffin wax-embedded material. Amplification failure using these techniques is now encountered in some centres using archival fixed tissues. Such 'failures' may not only be due to absent target DNA sequences in the tissues, but may be a direct effect of the type of fixative, fixation time and/or fixation temperature used. The type of nucleic acid extraction procedure applied will also influence amplification results. This is particularly true with in situ PCR/PCR in situ hybridization. To examine these effects in solution-phase PCR, beta-globin gene was amplified in 100 mg pieces of tonsillar tissue fixed in Formal saline, 10% formalin, neutral buffered formaldehyde, Carnoy's Bouin's, buffered formaldehyde sublimate, Zenker's, Helly's and glutaraldehyde at 0 to 4 degrees C, room temperature and 37 degrees C fixation temperatures and for fixation periods of 6, 24, 48 and 72 hours and 1 week. DNA extraction procedures used were simple boiling and 5 days' proteinase K digestion at 37 degrees C. Amplified product was visible primarily yet variably from tissue fixed in neutral buffered formaldehyde and Carnoy's, whereas fixation in mercuric chloride-based fixatives produced consistently negative results. Room temperature and 37 degrees C fixation temperature appeared most conducive to yielding amplifiable DNA template. Fixation times of 24 and 48 hours in neutral buffered formaldehyde and Carnoy's again favoured amplification.(ABSTRACT TRUNCATED AT 250 WORDS)
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8040005
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Localization of blood-group-related linear poly-N-acetyllactosamine structure in different human tissues by Griffonia simplicifolia agglutinin-II staining following endo-beta-galactosidase digestion.
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Endo-beta-galactosidase from Escherichia freundii cleaves polylactosaminyl structures as follows: R-GlcNAc beta I-3Gal beta I-4GlcNac beta I-R' + H2O-->R-GlcNAc beta I-3Gal + GlcNAc beta I-R'. By staining with Griffonia simplicifolia agglutinin-II following the enzyme digestion, the distribution of R-GlcNAc beta I-3Gal beta I-4GlcNAc can be demonstrated in tissue sections. This carbohydrate chain is one of the backbone structures carrying the blood-group-related antigens and, thus, localization of this structure may provide detailed information about the distribution of variants with different backbone structures. Various formalin-fixed, paraffin-embedded tissue sections were stained by Griffonia simplicifolia agglutinin-II with or without prior enzyme digestion and the reactivity of the agglutinin imparted by enzyme digestion was studied in the following tissues and cells: pancreatic acinar cells, gastric surface mucosae, duct cells and mucous cells of salivary glands and tracheal glands, surface epithelium of trachea, goblet cells of large intestine, columnar epithelium of uterine cervical glands, distal and collecting tubules of kidney, certain cells of anterior lobe and colloid of middle lobe of pituitary glands, epithelial reticular cells and Hassall's corpuscles of thymus and Kupffer cells of liver. In gastric surface mucosae, the reactivity of the agglutinin appeared in non-secretor individuals but not in the secretor individuals, and in mucous cells of salivary and tracheal glands the reactivity appeared in Le(a- b-) non-secretor individuals but not in Le(a + b-) non-secretor or secretor individuals.(ABSTRACT TRUNCATED AT 250 WORDS)
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8040004
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Ultrastructural localization of carbonyl reductase in mouse lung.
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The immunocytochemical localization of tetrameric carbonyl reductase in the mouse lung was determined by an electron-microscopical immunogold procedure using monospecific antibodies against the enzyme. The labelling of carbonyl reductase was observed within the mitochondria of the ciliated and non-ciliated cells of the bronchioles and the type II alveolar pneumocytes, and the density of labelling in the non-ciliated cells was higher than those in the other cells. No significant labelling was detected over other compartments of the epithelial cells. The labelling was undetectable in the type I alveolar cells, alveolar macrophages and connective tissue cells of the lung. These results clearly indicate the localization of carbonyl reductase to the mitochondrial matrix of these epithelial cells, of which the non-ciliated bronchiolar cells contained particularly high amounts of the enzyme.
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8040003
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Immunolocalization of ubiquitin in degenerating insect flight muscle.
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Ubiquitin was localized by immunofluorescence microscopy during post-mating histolysis of fibrillar flight muscle in female fire ants, Solenopsis spp. Normal muscles, as well as histolysing muscles from artificially inseminated and haemolymph-injected females contained ubiquitin in association with nuclei, Z-lines, myofilaments and mitochondria. However, the density of the ubiquitin immunoreaction was markedly increased in the nuclei, Z-lines and mitochondria of degenerating tissues 6, 12 and 24 h posttreatment. At these times the heaviest immunoreactivity for ubiquitin was seen in association with the nuclei, Z-lines and mitochondria. Immuno-controls, incubated in the absence of the primary antibody, showed no similar immunostaining. When insemination was preceded by the injection of actinomycin D, muscle degradation was significantly depressed after a 24-h period. Also, ubiquitin immunofluorescence was markedly reduced in tissues pre-treated with actinomycin D. These observations suggest that insemination increases the ubiquitination of specific myofibrillar proteins destined for degradation.
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8040002
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The diverse Michaelis constants and maximum velocities of lactate dehydrogenase in situ in various types of cell.
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The kinetics of lactate dehydrogenase in mouse cardiac muscle fibres, skeletal muscle fibres, gastric parietal cells, parotid gland ductal and acinar cells, oocytes and mouse and human hepatocytes were studied as a function of substrate concentration in sections of unfixed mouse and human tissues incubated at 37 degrees C on lactate agarose gel films. The absorbances of the final reaction products deposited in single cells of various types were measured continuously as a function of incubation time using an image analysis system. The initial velocities (vi) of the dehydrogenase were calculated from two equations deduced previously by us, vi = a1 zero A (equation 1) and vi = v + a2 zero A (equation 2), where v and zero A are, respectively, the gradient (steady-state velocity) and intercept of the linear regression line of absorbance on time for incubation times between 1 and 3 min, and a1 and a2 are constants characteristic for each cell type. Hanes plots using vi calculated from equation 2 gave more consistent estimates of the Michaelis constant (Km) and the maximum reaction velocity (Vmax) than those employing either steady-state velocity measurements or vi calculated from equation 1. The Km thus found for mouse skeletal muscle fibres (10.4-12.5 mM) and hepatocytes (14.3-16.7 mM) agreed well with values determined previously in biochemical assays. However, the Km for cardiac muscle fibres (13.4 mM) was higher. The Km of the enzyme in gastric parietal cells, parotid gland cells and oocytes was in the range 7.6-9.7 mM.(ABSTRACT TRUNCATED AT 250 WORDS)
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8040001
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The initial reaction velocities of lactate dehydrogenase in various cell types.
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The initial reaction velocities (vi) of lactate dehydrogenase in hepatocytes, cardiac muscle fibres, skeletal (gastrocnemius) muscle fibres, gastric parietal cells, ductal epithelial and acinar cells of the parotid gland, and oocytes were determined, by computer-assisted image analysis, in unfixed sections of these tissues incubated at 37 degrees C on substrate-containing agarose gel films. They were found to fit the equations vi = a1 zero A (equation 1) and vi-v = a2 zero A (equation 2) reported previously for mouse hepatocytes (Nakae & Stoward, 1993a, b), where v and zero A are, respectively, the gradients (or steady-state velocities) and the intercepts on the absorbance axis of the linear regression lines of the absorbance (A) of the final reaction product on incubation times between 1 and 3 min, and a1 and a2 are constants. Both equations 1 and 2 fitted the observed vi closely for mouse (a1 = 2.7, a2 = 2.2) and human (a1 = 3.0, a2 = 1.9) hepatocytes. However, equation 2 fitted the observed vi better than equation 1 for mouse cardiac muscle fibres (a1 = 1.5), skeletal muscle fibres (a2 = 1.2), gastric parietal cells (a2 = 1.7), acinar (a2 = 1.4) and striated ductal (a2 = 2.2) epithelial cells of the parotid gland, and oocytes (a2 = 1.6). The values of vi calculated from the two equations agreed with the observed vi to within about 11%. They ranged from 105 mumole hydrogen equivalents/cm3 cell/min units in hepatocytes to 24 units in parotid acinar cells, but for other cell types they were between 46 and 61 units. These are all considerably higher than values reported previously.
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8039997
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Klebsiella pneumoniae splenic abscess.
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Splenic abscesses may be solitary or multiple and are unusual infections. Signs and symptoms are variable and do not always include left upper quadrant pain or tenderness, as the Case Report illustrate. Abscesses of the spleen may occur as a result of endocarditis or from hematogenous seeding from a distant focus of infection. Computed tomographic scan of the spleen is the diagnostic method of choice. We report a case of multiple splenic abscesses caused by Klebsiella pneumoniae that resulted from a Klebsiella urinary tract infection and was successfully managed with antibiotic therapy and splenectomy.
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8039995
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Cerebrally induced cardiac arrhythmias (CICA).
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Cerebrally induced cardiac arrhythmias pose a challenge in the care of the intensive care patient. Although prognosis is based mainly on the neurologic status, treatment of the arrhythmia should be instituted promptly especially where cardiac function is impaired. Correct diagnosis is of prime importance because delay of surgical intervention or inadequate choice of anticoagulants or antiarrhythmic drugs may be deleterious. Although descriptions of this phenomenon have appeared in the literature for decades, with the increasing capability of better and more successful management and the recognition of the significance of these on cardiac function, new attention should be focused on the subject. A review of the literature, diagnosis, and management of cerebrally induced cardiac arrhythmias is presented. Examples are given of patients without antecedent heart disease in whom cardiac arrhythmias secondary to neurologic compromise later manifested.
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8039996
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Aminoglycoside dosing in the critical care patient: a case report of tertiary pharmaceutical care.
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To describe special dosage considerations for aminoglycoside antibiotics in critically ill patients from a pharmaceutical care perspective. Case report and discussion. A nontertiary care regional medical center. A 21-year-old male college student involved in a moving vehicle accident who sustained a closed head injury and collapsed right lung with subsequent development of nosocomial pneumonia. Resolution of pneumonia and discharge from hospital. Tertiary level pharmaceutical care. Pneumonia resolved and patient was transferred to rehabilitation center. Tertiary pharmaceutical care provided by the pharmacist includes appropriate choice and monitoring of pharmacotherapy and pharmacokinetic drug dosing to promote good patient outcome.
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8039994
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Development and testing of the Pulmonary Functional Status and Dyspnea Questionnaire (PFSDQ).
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To develop and test the Pulmonary Functional Status and Dyspnea Questionnaire (PFSDQ) that measures both intensity of dyspnea with activities and changes (reductions or improvements) in the ability of patients with chronic obstructive pulmonary, disease to perform daily activities. Instrument development and initial testing for validity and reliability. Hospital-based pulmonary rehabilitation program. One hundred thirty-one adult male patients with chronic obstructive pulmonary disease. Mean age was 63.7 +/- 6.2 years. Pulmonary Functional Status and Dyspnea Questionnaire, pulmonary function and exercise parameters. The PFSDQ is a 164-item paper and pencil self-administered questionnaire and consists of two components measuring dyspnea intensity with activities and changes in functional ability related to 79 activities of daily living. Activities are grouped into scales of self-care, mobility, eating, home management, social, and recreational. The dyspnea component measures the level of dyspnea patients report with these activities. The functional abilities component evaluates the degree to which the performance of activities has changed as the result of chronic obstructive pulmonary disease. The activities are relevant for adults of both sexes and reflect various energy workload requirements. Normative data for both components were described. Content and initial construct validity of the PFSDQ was supported by clinical experts and findings related related to expected theoretical relationships. Internal consistency reliability for both the dyspnea and functional abilities components was 0.91. The alpha coefficients for the scales ranged from 0.88 to 0.94. A case study was used to describe the clinical application of the PFSDQ. The PFSDQ can be used clinically and in research studies to assess dyspnea and changes in the functional ability of patients with pulmonary disease. Although further testing is warranted, initial evaluation supports the validity and reliability of the PFSDQ.
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8039993
|
Abdominal aortic aneurysm surgery, Part I: An overview and discussion of immediate perioperative complications.
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An overview of abdominal aortic aneurysm surgery and the immediate perioperative problems are described. Cardiovascular complications are discussed, with the underlying theme being one of prevention. Clinical nursing algorithms are presented and the salient points of nursing care are summarized.
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8039992
|
Silent myocardial ischemia and nursing implications.
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Silent myocardial ischemia is a common occurrence that affects millions of Americans with coronary artery disease. Although the cause of painless angina is unknown, the consequences are well documented and mimic that of patients who have symptoms. Patients with silent myocardial ischemia, as evidenced by painless ST segment changes on the electrocardiogram, demonstrate increased ventricular ectopy and are at increased risk for sudden cardiac death. The treatment for asymptomatic ischemia is the same as that for patients who exhibit angina. Thus nurses must be proactive in recognizing ST segment changes in their patients with coronary artery disease. This article reviews the pathophysiology of silent myocardial ischemia and the nursing implications.
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8039990
|
Directional coronary atherectomy: a new treatment for coronary artery disease.
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Directional Coronary Atherectomy (DCA) was developed to overcome the deficiencies and limitations of conventional balloon angioplasty. Now with FDA approval, DCA has been proved to be a safe and effective treatment alternative for coronary artery disease in a select group of patients. To provide critical care nurses with a comprehensive overview of DCA and the associated nursing implications. Patients selected to receive DCA were those who showed evidence of myocardial ischemia (positive exercise stress test or symptoms), were free of significant peripheral vascular disease, and were candidates for coronary artery bypass graft surgery. Additional selection criteria was based on the detailed coronary anatomy. A review of one direct experience of more than 200 patients treated with DCA in a university-affiliated hospital. DCA appears to be a valuable alternative for the treatment of select coronary lesions. DCA appears to have a low incidence of dissection and abrupt closure and a restenosis rate slightly lower than conventional balloon angioplasty.
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8039991
|
Implantable cardioverter defibrillators: a guide for clinicians.
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More than 30,000 patients in the United States have implanted devices that cardiovert, shock, or pace their hearts during a dangerous ventricular arrhythmia. This number grows daily as these devices are increasingly able to provide effective treatment for dangerous ventricular arrhythmias. In the past 5 years, the technology surrounding these devices has grown dramatically, going from a single "shock box" made by one vendor to a sophisticated group of devices with multiprogrammable functions. Clinicians who provide care to these patients must be able to understand the purpose of the device and validate its function. A guide to each of the implantable cardioverter defibrillator systems and to the various therapies available in each is presented.
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8039988
|
Accuracy of infrared ear thermometry and traditional temperature methods in young children.
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To compare the accuracy of ear-based, rectal, and axillary temperature measurements in comparison to bladder temperature as a core reference. Repeated-measures comparison study. Pediatric critical care settings in two tertiary care hospitals. Thirty children, 1 to 45 months old (mean 16.6 months), who required bladder catheters for their care. Correlation and agreement (mean offset +/- SD) of ear-based, rectal, and axillary temperature measurements with bladder temperature. Ear-based measurements were made with three infrared thermometers in the core mode, both with and without an ear tug. All six readings were made in the same ear in randomized order. Bladder, rectal, and axillary temperatures were read from continuous digital displays immediately after each ear-based measurement. Ear-based readings correlated relatively well with bladder temperature (r = 0.80 to 0.87), but were lower by means of -0.3 degrees to -0.7 degrees C with moderately high variation (SD = 0.4 degrees to 0.5 degrees C) between children. Use of an ear tug did not affect the readings. Rectal temperature correlated well with bladder values (r = 0.93 to 0.97) and was usually slightly higher (mean offset = 0.2 +/- 0.2 [SD] degrees C), while axillary temperature correlated rather poorly (r = 0.59 to 0.64), with much lower and more variable readings (mean offset = 0.9 degrees +/- 0.6 degrees C). In regard to sensitivity, specificity, and predictive value in screening for fever, rectal readings performed very well, ear-based readings moderately well with some variation, and axillary readings poorly. The findings suggest that the additive core-mode adjustments in infrared ear thermometers are too low for young children, an ear tug is not an essential part of measurement technique, rectal temperature closely reflects bladder temperature, and axillary temperature is low and highly variable.
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8039989
|
Fentanyl-induced chest wall rigidity in a neonate: a case report.
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Fentanyl-induced chest wall rigidity occurred in an 8-week-old infant girl recovering from surgical repair of coarctation of the aorta. The neonate received 30 minutes of a moderate dose continuous infusion of fentanyl before chest wall rigidity developed. Association of the chest wall rigidity with the fentanyl infusion resulted in the appropriate intervention of narcotic reversal and prevented irreversible hypoxic sequelae. Patients receiving fentanyl, even at moderate doses, are at risk for the development of chest wall rigidity.
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8039985
|
Dental health findings in a Native American settlement.
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In 1951, A. Dahlberg took casts of 82 children aged 8-17 who lived in the Sac-Fox Settlement near Tama, Iowa. In 1990, the Indian Health Service supported a survey of 44 survivors from the 1951 study. All were contacted and 23 were examined. The findings from this study were compared with findings from similar aged Sac-Fox residents surveyed in 1982, and with the residents of Iowa of a similar age surveyed in 1980. The DMFS score of the 1990 Sac-Fox samples was larger (92.4) than that for the Iowa Survey (75.3). The periodontal findings were similar in the three samples, with one exception, the category 6+mm pockets were seen more frequently in the 1990 Sac-Fox sample (13.0%) than in the 1982 Sac-Fox (8.7%) and 1980 Iowa (2.9%) samples. Mucosal lesions were observed much more frequently in the Sac-Fox 1990 (69.6%) and 1982 (65.2%) samples, compared to the 1980 sample (8.6%). The frequency of totally edentulous persons was also much greater in the Sac-Fox samples, as compared to the Iowa Sample. It appears that the 1982 recommendations for making preventive procedures available to Sac-Fox adults is still appropriate in 1990.
|
8039979
|
Perforating lichen nitidus.
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A 32-year-old man with no particular family history nor past history visited our clinic in September 1992, with papules that he claimed had developed approximately 3 years earlier. No subjective symptoms accompanied then. On examination, numerous, discrete, pinhead-sized or half-ricecorn-sized, flesh-colored papules were observed on the dorsolateral side of his left hand and fingers. No central dimple or scaling were noticed clinically (Fig. 1). Laboratory tests revealed no abnormal findings. The histopathology of the biopsied specimen showed a circumscribed nest of infiltrating cells closely attached to the epidermis (Fig. 2). These infiltrating cells consisted of mononuclear lymphoid cells and histiocytes. The overlying epidermis was stretched and atrophic. A transepithelial perforation channel existed in direct contact with the surface. Amorphous debris containing cell nuclei lay within the channel (Fig. 2). Lymphoid cells were also observed above the keratin layer overlying the channel. At the lateral margin of the infiltrate, rete ridges extended downward in the manner of a claw clutching a ball. In a periodic-acid-Schiff (PAS)-stained section, a basement defect was observed around the channel.
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8039978
|
Histologic grading system for psoriasis vulgaris.
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Psoriasis vulgaris is a disease of substantial clinical and microscopic diversity and the histologic diagnosis depends upon an aggregate of histologic criteria, some characteristic of psoriasis and others shared with other dermatoses. While involved in drug testing with micromolar concentrations of active agents on small psoriatic plaques, this grading system was developed to quantify as objectively as possible the degree of psoriatic change present at the time of biopsy. Using established references of dermatopathology and a review of the pertinent literature, the salient histologic features of psoriasis were listed and assigned value scores from 1 to 3. The highest score was given to those microscopic criteria most characteristic of the disease. The cumulative score of all features present then gives a mathematical score for each biopsy. This paper presents an uncomplicated mathematically weighted system of grading biopsy specimens from a disease process that shows a spectrum of microscopic features, but is often not diagnostic. The schema offers a method of grading change that can be especially important in studies of therapeutic agents.
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8039977
|
Leukocyte-extracellular matrix interactions in psoriasis.
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The basic phenomenon in psoriasis appears to be a directed leukocyte migration that in a great part, depends on the cell-extracellular matrix (ECM) interactions. To evaluate the leukocyte-ECM interactions in psoriasis, we investigated the adherence of peripheral blood mononuclear cells (PBMC) and polymorphonuclear leukocytes (PMNL) to ECM components (collagen type I, IV, laminin, and fibronectin), using crystal violet staining and measuring absorbance at 570 nm. In the most active cases of psoriasis (pin-point and guttate type) of short duration, we found a decreased adherence of PBMC to collagen type IV. In a majority of cases of actively spreading plaque psoriasis of large extent and longer duration, there was decreased adherence to all ECM components, especially to collagen type IV and laminin. The adhesion of PMNL to collagen type IV (but not to other ECM components) was increased only in cases of short duration. Preliminary data suggest that etretinate treatment may modulate leukocyte adherence to the ECM components in patients with psoriasis. The decreased in vitro adherence of PBMC to ECM components, especially those of the basement membrane, may reflect their in vivo activation and migration to the epidermis, which is a basic phenomenon in psoriasis that could be affected by etretinate therapy.
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8039976
|
Mast cell tryptase and chymase are potential regulators of neurogenic inflammation in psoriatic skin.
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Tryptase and chymase are proteinases present only in mast cells. In psoriatic lesions, mast cells are increased in number. Certain neuropeptides are also more abundant in lesional than nonlesional psoriatic skin. Based on some earlier results as well as the results of the present study, a hypothesis is presented concerning the regulatory action of mast cell tryptase and chymase on neuropeptides in psoriatic inflammation. Forty patients were biopsied, 13 for a mature psoriatic plaque and 9 patients of 27 for a developing (1-3 weeks) psoriatic lesion induced by tape stripping (Koebner reaction). Each lesion had its nonlesional control from the same patient. Mast cell tryptase and chymase, and the neuropeptides Substance P (SP) vasoactive intestinal polypeptide (VIP), and calcitonin-gene-related peptide (CGRP) were stained by enzyme- and immunohistochemical methods. Morphological contacts between mast cells and neuropeptides were visualized using double stains and quantitated in the upper dermis. As the lesion aged, MCTC mast cells displaying tryptase activity increased in number, whereas chymase activity in these cells decreased. All neuropeptides showed some increase along with the development of the lesion, but SP was most abundant in mature lesions. Substance P-positive nerves had also more contacts with mast cells compared to VIP- or CGRP-containing fibers, the contact count being highest in mature lesions. Tryptase is known to degrade VIP and CGRP, but not SP. Chymase is capable of cleaving both SP and VIP, but is rendered partially inactive in psoriatic skin. These data together with the results of the present study strongly suggest that SP has potency to act as an important mediator in different stages of the psoriatic inflammation.
|
8039975
|
Senile dry skin type Sjögren's syndrome.
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Elderly patients may show asteatotic dermatitis complicating Sjögren's syndrome (sjs) that we have named "senile dry skin type sjs." To define the condition further, we have examined a group of patients with sjs and have recorded clinical and laboratory findings in these patients. Of the 36 patients, 11 were men and 25 were women, with a mean age of 72 years. In addition to the subjective sensation of dryness of the eyes and oral cavity and objective signs of dryness revealed by the Schirmer test, the rose bengal test, minor labial gland biopsy, and sialography were carried out, as well as other hematologic and immunologic tests. The following abnormal laboratory tests were found: elevated erythrocyte sedimentation rate (85%), mild hepatic dysfunction (50%), and anemia (45%), leukopenia (42%), and thrombocytopenia (16%). Immunologic abnormalities were also observed, such as: positive antinuclear antibody (55%), an increase in gamma globulin (28%), and a positive rheumatoid factor (20%). In 11 of the 36 patients (30%), the subjective sensation of dryness was absent and only objective signs of dryness were present. The present study suggests that dry-skin-dermatitis associated with sjs is rather common in the elderly.
|
8039974
|
Expression of class II major histocompatibility antigens by keratinocytes in cutaneous T cell lymphoma.
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Expression of various class II MHC antigens by lesional keratinocytes may play an important role in the pathophysiology of a wide variety of human dermatoses including cutaneous T cell lymphoma (CTCL). Nevertheless, there is relatively little information available concerning the concurrent expression of HLA-DR, -DP, and -DQ class II MHC antigens in CTCL. Therefore, our aim in this study was to determine the prevalence, localization, extent, temporal sequence, and consistency of class II MHC antigen expression by lesional keratinocytes in CTCL. We used a semiquantitative immunohistologic analysis to analyze HLA-DR, -DP, and -DQ expression by lesional keratinocytes in 66 skin biopsies obtained from 39 patients with CTCL. Class II MHC antigen expression by keratinocytes was observed in 77% of cases. Expression was detected on the cytoplasmic membrane and within the cytoplasm. It varied among cases from focal to confluent. There was a hierarchy of antigen expression in terms of both extent and time course. HLA-DR was expressed first and most extensively, followed by HLA-DP and then HLA-DQ. Comparative studies of multiple serial or concurrent active lesions from 13 cases indicated that the overall pattern and extent of antigen expression was relatively constant within individual patients. There was no apparent correlation between class II MHC antigen expression and the clinical stage of disease, the type of CTCL skin lesion, or the overall density of the lesional T cell infiltrate. The hierarchy of keratinocyte class II MHC antigen expression observed in this study paralleled that noted in earlier studies of cultured keratinocytes exposed to recombinant interferon-gamma in vitro. This suggests that lesional cytokine levels may be the critical factor governing class II MHC antigen expression by lesional keratinocytes in CTCL.
|
8039973
|
Proliferative actinic keratosis.
|
Solar/actinic keratoses (AKS) are premalignant lesions, usually less than 1 cm in diameter, that appear on chronically sun-damaged skin. We describe four patients with a form of AK that enlarged and recurred despite standard treatment. Histologic examination revealed a single and multilayered sheet of anaplastic cells along the undersurface of the epidermis extending down hair follicles and present over a large area. Three of the patients developed either a squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) within the area encompassed by the AK. These cases represent an insidious, proliferative form of AK with an increased tendency to develop into skin cancer.
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