First-line gemcitabine versus epirubicin in postmenopausal women aged 60 or older with metastatic breast cancer: a multicenter, randomized, phase III study.

BACKGROUND: This randomized, phase III study compared the efficacy and safety of first-line gemcitabine versus epirubicin in the treatment of postmenopausal women with metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients aged > or = 60 years (median 68 years) with clinically measurable MBC received either gemcitabine 1200 mg/m(2) or epirubicin 35 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. RESULTS: Of 410 patients entered, 397 (198 gemcitabine and 199 epirubicin) were randomized and qualified for the time to progressive disease (TTP) and survival analyses. Total cycles administered in 185 gemcitabine and 192 epirubicin patients, respectively, were 699 (mean 3.5, range 0-12) and 917 (mean 4.6, range 0-10). Epirubicin demonstrated statistically significant superiority in TTP (6.1 and 3.4 months, P=0.0001), overall survival (19.1 and 11.8 months, P=0.0004), and independently assessed response rate (40.3% and 16.4% in 186 and 183 evaluable patients, P <0.001). For gemcitabine (n=190) and epirubicin (n=192), respectively, common WHO grade 3/4 toxicities were neutropenia (25.3% and 17.9%) and leukopenia (14.3% and 19.3%). Of the 28 on-study deaths (17 gemcitabine, 11 epirubicin), three were considered possibly or probably related to treatment (gemcitabine). CONCLUSIONS: Postmenopausal women > or =60 years of age with MBC tolerate chemotherapy well. In this study, epirubicin was superior to gemcitabine in the treatment of MBC in women age > or =60, confirming that anthracyclines remain important drugs for first-line treatment of MBC.

Song development: in search of the error-signal.

Song development provides an opportunity to study the mechanisms of vocal learning dynamically at molecular, cellular and systems levels, and across time scales ranging from minutes to months. To exploit these opportunities one needs to identify appropriate units, types and time scales of vocal change in nearly real time. The previous chapter by Tchernikovski et al. in this volume described techniques that make this research strategy feasible by allowing us to observe the song learning process through a "temporal microscope" with variable degrees of resolution. In this chapter we summarize some of the new observations and raise hypotheses about the learning strategy of the bird. We focus on inferences that can be drawn from behavioral observations to the nature and complexity of the instructive signal that guides the vocal change (error-signal). We examine two effects: i) the emergence of syllable types and ii) changes in features within a syllable type. We found that different features of the same syllable change during different and sometimes disjointed developmental windows. We discuss the possibility that song imitation is achieved by correcting partial errors, and that features of those partial errors change adaptively during development, perhaps concurrently with changes in perception and in motor proficiency. Those hypotheses can be best examined by across levels investigation, starting from identifying critical moments in song development and recording of articulatory dynamics and neural patterns when only a few features of specific syllables undergo rapid changes. Such investigation could relate behavioral events to brain mechanisms that guide song learning from moment-to-moment and across extended periods.

Visual event related potentials. The origin of wave P300. A computer model.

This five-layered model consisting of 180 neurons is aimed at simulating some elementary functions of primary visual cortex of mammals in form detection. Its main achievements are: 1. Detection of points, lines, simple geometric figures in the V1. 2. Abstraction of 19 different qualities of geometric figures. 3. Simulation and rational explanation of processing of peripheral stimuli in the V1, explanation of mechanism of origin of visual ERPs, including P300 wave. 4. Simulation and explanation of the nature and build up of the cognitive function within V1 and its possible relation to long-term memory. 5. The model is based partly on Hebb-type synapses, illustrates the role of neuronal assemblies, sheds light on the functional relationship of excitatory and inhibitory neurons, in their conformity with special tasks of different cortical layers.

Tuberculous skeletal muscle involvement in acute leukemia: report on two cases.

Bacterial infection of skeletal muscle (pyomyositis) is usually followed by abscess formation. The most commonly isolated pathogen is Staphylococcus aureus. Tuberculosis rarely affects patients with acute leukemia. The authors report on 2 patients, one with acute myelogenous leukemia and the other with acute lymphoblastic leukemia whose clinical course was complicated by tuberculous skeletal muscle abscesses. In both instances, musculoskeletal pain was accompanied by evidence of muscle abscesses by imaging studies of the painful areas. Therefore, in patients with acute leukemia and evidence of muscle abscesses with initial cultures negative for bacteria and fungi, one should include tuberculosis in the differential diagnosis.

Neuronal plasticity induced by neonatal monocular (and binocular) enucleation.

Monocular (ME) and binocular enucleation has become a useful experimental tool for analyzing the mechanisms of neural plasticity. ME when performed during an early postnatal period (up to 15 days after birth) initiates a series of adaptive reactions in the visual (and other sensory) system(s) which tend to compensate for the lost sensory capacity. Extirpation of one eye (usually the right) destroys afferents to both lateral geniculate bodies dorsal nucleus (CGLd) and superior colliculi (CS), being severely impaired by the degeneration of retino-geniculate and collicular synapses. The sprouting of retinogeniculate fibers coming from the remaining eye replaces these synapses in both CGLds. Ipsilateral representation of the remaining eye (usually of minor significance) becomes extended in the left CGLd and consequently in the left visual area, just as in the superior colliculi. A similar but somewhat smaller extension takes place in the contralateral CGLd and visual cortex. The strengthening of commissural connections results in a remarkable extension of callosally connected stripes and patches in both hemispheres. After ME in the critical period, the control over behavior is taken over by the remaining eye. Its power of resolution is improved because of the higher survival of (mainly ipsilaterally projecting) ganglion cells. Therefore, both hemispheres are still available for storing visual information. In ME rats the learning of visual tasks requires both hemispheres, but relearning is still possible after extirpation of the contralateral one. The possible two main mechanisms of adaptive plastic changes are: (i) replacement of degenerated synapses by sprouting collaterals of ingrowing foreign fibers, and (ii) neurons having morphologically intact but inactive synapses establishing connections with afferent fibers other than the usual. The same mechanism is seen operating in cross-modal adaptive reactions as well.

A computer model of the visual cortex.

A three-layered simulation of the visual cortex was constructed, receiving inputs from 252 retinal photoreceptors. Lateral geniculate body was taken as a simple relay station. In the cortical module afferent neurons with circular receptive fields, orientation selective simple cells, tuned complex cells, excentricity neurons and different kinds of inhibitory neurons were included. The model reproduces neuronal and network responses recorded in experiments and some sensory illusions, of which one is here demonstrated.

A computer model of processes of binocular vision in the cerebral cortex.

Fundamentals and options of modeling cortical processes of binocular vision are dealt with in this paper. Physiologically characterized cell types of the visual cortex are modelled and used as basis of a network implementing a simulation of the binocular vision. An attempt is made to establish correlations between typical activity patterns of visual cortical cells and the network incorporating them.

T-cell large granular lymphocytic leukemia following orthotopic liver transplantation.

Aggressive T-cell neoplasms are an infrequent complication of allogeneic organ and bone marrow transplantation. To date, chronic T-cell lymphoproliferative malignancies have not been described. The present case documents the occurrence of a T-cell large granular lymphocytic leukemia (T-LGL) in a patient following orthotopic liver transplantation. Genotype studies showed a clonal T-cell receptor beta-chain gene rearrangement. A unique feature was the detection of a specific chromosomal deletion at 1p32 involving the tal-1 gene, an abnormality previously described only in aggressive T-cell neoplasms.

Neonatal monocular enucleation-induced cross-modal effects observed in the cortex of adult rat.

The cortices of neonatally enucleated rats were explored for somatosensory responses with special reference to an extension into the occipital cortex. Monocular enucleation was performed on rats at birth. The animals were raised and from the age of three months the activity evoked by either electric stimulation of the vibrissa pad or bending of the vibrissae was tested in the contralateral cortex by electric recording and autoradiography. It was found that early enucleation caused an expansion of the somatosensory responses, among others into the visual area. Neurons responsive to visual and somatosensory stimuli were demonstrated in the anterior part of the primary and secondary visual areas, contralateral to the enucleation. Electrophysiological and autoradiographic studies unambiguously proved that early enucleation exerted a significant cross-modal effect on the somatosensory responsive area.

Rapid synthesis of a glycine-rich protein in the cerebral cortex of the rat during activity.

A glycine-rich protein was previously discovered (Rojik and Fehér, 1976) in the nervous system, which proved to be neuron-specific and in its appearance highly dependent on the actual intensity of neural activity. It was named by us neuragin. Time relations and regulation of neuragin synthesis were examined by the glycine labelling method in the cerebral cortex of the rat. During activation of the somato-sensory area, 2 min stimulation sufficed to provoke the appearance of neuragin in the neurons. The newly synthesised protein persisted in the nerve cells at least for 6 hours after stimulation. Phorbol-12-monoacetate strongly enhanced, sphingosin depressed the synthesis of neuragin. It is concluded, that neuragin is an immediate early gene product, similar to proteins encoded by genes c-fos and c-jun.

Deep sensibility of the mystacial pad in the rat and its cortical representation.

The cortical representation of the rat's mystacial pad was examined with the aid of evoked field potentials and recording of single cell activity. Mechanical bending of the vibrissae activated the well-known area within the somato-sensory cortex. Electrical stimulation of the mystacial pad with inserted needle electrodes, bi- and monopolarly, caused a widespread activation extending practically to the whole exposed cortex, including visual, acoustic and motor areas (MSS potentials). The evoked field potentials were accompanied by well-recordable unit activity, mainly in the upper 1000 microns of the cortical depth. Capsaicin, injected into the mystacial pad on the 8th-10th postnatal day heavily impaired the MSS potentials as recorded at 2 months of age, and only moderately acted on the mechanically evoked potentials. So did also the acutely injected capsaicin. Peak latency of the MSS potentials seemed to be in correlation with the distance from the punctum maximum. The latencies of unit potentials, however, did not show such dependence, they were between 8 and 10 ms. MSS potentials are thought to represent cortical projection mainly of thermo- and nociceptive fibers, which play an important role in the early postnatal life.

Modification in primary visual cortical activity of rat induced by neonatal monocular enucleation, an electrophysiological and autoradiographic study.

Mononuclear enucleation was performed in rats at birth. The animals were raised and from the age of 3 months the evoked activity was tested in the contralateral visual cortex both by mapping of evoked potentials and autoradiography. It was found that monocular enucleation changed the distribution of evoked activity characteristically. The focus of activity shifted laterally and restricted itself to the binocular part of the primary visual cortex (Oc1B), while, in the medial part of it (Oc1M) hardly any evoked activity or labelled neurons were found

A computer model of the convulsive membrane.

A computer model of the convulsive membrane was built up by combining the H-H equations of normal ionic currents with a pathological current flowing through calcium channels and carrying sodium ions. Thus any form of paroxysmal depolarization shift could be simulated, by varying two rate constants and potassium conductance. The simulated PDSs are initiated by a minimal conductance pulse and terminate spontaneously according to the inherent rules of the model system. The program is written in Turbo-Pascal language and can be run on any PC.

Neonatal enucleation induces correlated modification in sensory responsive areas and pial angioarchitecture of the parietal and occipital cortex of albino rats.

This study was carried out to investigate whether correlations existing in normal adult rats (Ambach et al., '86) between functional characteristics of neocortical areas and their pial angioarchitecture can be correspondingly modified under pathological conditions. The right eyes of albino rats were enucleated on the 1st, 8th, 15th and 30th day after birth, respectively. At the age of 3 to 4 months, the responsiveness of the parieto-occipital cortex to sensory stimuli was studied in enucleated animals and age matched controls. After the mapping of visually and somatosensorily evoked potentials, the vascular system was filled with dye. Monocular enucleation at birth induced bilateral modifications in sensory responsiveness and corresponding changes in pial angioarchitecture, especially in the venous drainage fields. In comparison with the controls, a considerable expansion was observed in the overlapping zone between visually and somatosensorily responsive areas. In contrast, borders of the visual cortex toward the auditory and retrosplenial areas were essentially stable. Corresponding changes were found in the pial distribution patterns of cerebral veins but not of arteries. The major effect of neonatal enucleation on angioarchitecture was a change in the subdivision of the parieto-occipital veins drainage fields. This was due to a significant enlargement of the anterior accessory occipital (O3) vein, which compressed the drainage fields of the parietal and occipital veins and completely separated them from one another. The results suggest that during ontogenesis: (1) alterations in the formation of sensory input may interfere with neocortical angiogenesis, especially the structuring of veins, (2) after monocular enucleation this influence is prominent in parietal and occipital cerebral veins, and (3) these angiogenetic processes are vulnerable only during the perinatal and early postnatal period.

Modification induced in visual cortical activity of rat by neonatal monocular enucleation.

Monocular enucleation was performed on rats at birth. The animals were raised and from the age of 3 months the evoked activity was tested in the contralateral visual cortex both by mapping of evoked potentials and by autoradiography. It was found that monocular enucleation changed the distribution of the evoked activity characteristically. The focus of activity shifted laterally and was restricted to the binocular part of the primary visual cortex, while hardly any evoked activity or labelled neurons were found in its medial part.

Strongyloides hyperinfection in two patients with lymphoma, purulent meningitis, and sepsis.

Strongyloides stercoralis hyperinfection syndrome is a rare complication of strongyloidiasis that occurs in immunosuppressed patients. It is caused by increasing autoinfection of the host by the nematode, leading to serious superimposed enterobacterial sepsis. Once established, it has a high fatality rate. Two cases are reported of Strongyloides hyperinfection in patients with lymphoma who presented with purulent meningitis. Both were receiving combination chemotherapy that included high-dose corticosteroids, and neither was granulocytopenic at infectious onset. The patients had respiratory insufficiency that required mechanical ventilation and serious septic episodes. Both were treated with thiabendazole, and one survived with clearance of the larvae. These cases illustrate the possibility of strongyloidiasis hyperinfection as an underlying diagnosis of purulent meningitis and serious septic episodes in lymphomatous patients. It may occur even without granulocytopenia.

Cytomegalovirus and other herpesviruses infections in heart and bone marrow transplant recipients.

From January 1988 to January 1989 all the heart transplant and bone marrow recipients at the Instituto do Coração of the Hospital das Clínicas of the University of São Paulo Medical School were studied for the incidence and morbidity associated with herpesviruses infections after transplantation. Five bone marrow and 5 heart transplant recipients were followed for a mean of 4.2 months post-transplantation. All the patients were seropositive for cytomegalovirus (CMV) before admission and 80% experienced one or more recurrences during the observation period. Of the 12 episodes of CMV infection, that were identified in this study, 83% were accompanied by clinical or laboratory abnormalities. However, there was only one case of severe disease. The overall incidence of infection for herpes simplex (HSV) was 50%. Although most of HSV reactivations were oral or genital, one case of HSV hepatitis occurred. One of the 6 episodes of HSV infections that were treated with acyclovir showed an unsatisfactory response and was successfully managed with ganciclovir. All the individuals had anti-varicella zoster virus antibodies, but none of them developed infection. The study emphasizes the importance of active diagnostic surveillance of herpesvirus infections in transplant patients. Both CMV and HSV reactivations showed high incidence and important morbidity and thus, deserve prophylactic therapy.

Properties of the slow inward current induced by pentylenetetrazol in Helix neurons.

The slow inward current (SIC) induced by 50 mM pentylenetetrazol was studied on central neurons of Helix pomatia in view of its ionic dependence and sensitivity to channel blockers in the presence of 30 mM TEA. A single electrode voltage clamp was used to measure currents evoked by ramp pulses and voltage steps. Sodium withdrawal had variable effects on this current while TTX had no influence on it. Inorganic and organic calcium channel blockers, on the contrary, always produced a partial or total block of the SIC. It is concluded that the slow inward current is mediated by Ca channels impaired by PTZ. Various ions--Na, Ca, and even Tris--may participate in it in variable proportions.

Sodium bromide treatment influences the plasticity of somatosensory responses in the rat cortex as induced by enucleation.

Effects of sodium bromide were studied on central neuroplasticity induced by early binocular enucleation. It has previously been found that enucleation on the day of birth, but not later than the first postnatal week, resulted in changes in the occipital cortex, such as the invasion of somatosensory evoked activity into the visual cortex areas. The present results showed that sodium bromide treatment extended at least up to 15 days after birth, the critical period during which somatosensory projections could be modified by visual deafferentation. Together with observations of Frost [J. comp. Neurol. (1981) 203, 227-256; Devl Brain Res. (1982) 3, 627-636], the present results suggest a mutual dependency of visual and somatosensory projection development. The present study is the first demonstration that the critical period of development, during which a specific type of neural plasticity can be induced, may be prolonged by pharmacological means, i.e. by chronic treatment with sodium bromide.