Evaluation of Oral Tebipenem as a Step-Down Therapy following Intravenous Ertapenem against Extended-Spectrum ß-Lactamase-Producing Escherichia coli in a Hollow-Fiber In Vitro Infection Model.

Tebipenem is an orally bioavailable carbapenem in development for the treatment of patients with complicated urinary tract infections. Herein, we describe the results of studies designed to evaluate tebipenem's potential as an oral (p.o.) transition therapy from intravenous (i.v.) ertapenem therapy for the most common uropathogen, Escherichia coli. These studies utilized a 7-day hollow-fiber in vitro infection model and 5 extended-spectrum ß-lactamase-producing E. coli challenge isolates. Human free-drug serum concentration-time profiles for tebipenem 600 mg p.o. every 8 h and ertapenem 1 g i.v. every 24 h were simulated in the hollow-fiber in vitro infection model. Samples were collected for bacterial density and drug concentration determination over the 7-day study period. Generally, ertapenem monotherapy resulted in a greater reduction in bacterial density than did tebipenem monotherapy. In the treatment arms in which ertapenem dosing was stopped following dosing for 1 or 3 days, immediate bacterial regrowth occurred and matched that of the growth control. Finally, in the treatment arms in which ertapenem dosing was stopped following dosing for 1 or 3 days and tebipenem dosing was initiated for the remainder of the 7-day study, the intravenous-to-oral transition regimen reduced bacterial burdens and prevented regrowth. Given that transition from intravenous to oral antibiotic therapy has been shown to reduce hospital length of stay, nosocomial infection risk, and cost, and improve patient satisfaction, these data demonstrate tebipenem's potential role as an oral transition agent from intravenous antibiotic regimens within the antibiotic stewardship paradigm.

RFLP patterns and risk factors for recent tuberculosis transmission among hospitalized tuberculosis patients in Rio de Janeiro, Brazil.

Isolates of Mycobacterium tuberculosis from 120 tuberculosis patients seen in the 12 months ending September 1994 at 2 tertiary-care centres in Rio de Janeiro were characterized by IS6110 restriction fragment length polymorphism (RFLP) analysis. Ninety-seven patients (81%) had isolates with unique RFLP patterns, while 23 patients (19%) had isolates that belonged to 11 different RFLP cluster patterns. The strains from the latter patients were distributed among 1 group of 3 patients and 10 groups of 2 patients each. The cluster-pattern strains were not associated with gender, age, HIV infection, type of residence, living in shelter, homelessness or previous history of tuberculosis. However, clustering was strongly associated with multidrug resistance (P = 0.006). These data suggest that recent exogenous transmission may be important for the development of new cases of multidrug-resistant disease in patients attending tertiary-care centres in Rio de Janeiro, Brazil.

Drug resistance patterns among hospitalized tuberculous patients in Rio de Janeiro, Brazil, 1993-1994.

The purpose of this study was to analyze the prevalence and risk factors for drug resistance among hospitalized patients in two tertiary care centers, an acquired immunodeficiency syndrome (AIDS) reference center and a sanatorium, in Rio de Janeiro, Brazil. From 1993-1994, 389 patients were diagnosed as having tuberculosis (TB). Isolates from 265 patients were tested for in vitro susceptibility to rifampin and isoniazid. Resistance to one or more drugs was detected in 44 patients (16.6%) and was significantly more common among recurrent cases in both hospitals (p=0.03 in the AIDS center and p=0.001 in the sanatorium). Twenty seven patients (10.2%) had isolates resistant to both isoniazid and rifampin. Multi-drug resistance was associated with human immunodeficiency virus (HIV) infection among patients who had never been treated for TB. In conclusion, drug-resistant TB is high in hospitalized patients in Rio de Janeiro, especially among HIV infected patients. Therefore, measures to control TB and prevent nosocomial transmission need urgently to be set up in the Brazilian hospitals.

The role of the pedunculopontine tegmental nucleus in relation to conditioned motor performance in the cat. I. Context-dependent and reinforcement-related single unit activity.

The activity of the pedunculopontine tegmental nucleus (PPTg) neurons was recorded in three unrestrained cats operantly conditioned to perform a lever-release movement. The movement had to be initiated either rapidly after a (click) stimulus in a simple reaction-time paradigm or had to be delayed after the same stimulus in trials identified by a tone cue. Successful trials were rewarded by a food pellet. A total of 107 neurons were recorded with microelectrodes. Brief spike neurons (mean duration: 0.7 ms) and broad spike neurons (mean duration: 2 ms) presumed to be cholinergic were detected. Of the 73 neurons localized in the PPTg area, 53 had brief spikes and 20 broad spikes. Changes in activity most commonly occurred very early after the stimulus or during the reinforcement process. Most neurons with brief spikes exhibited very early excitation after the stimulus and reinforcement-related activity. These neurons had a mean activity of 23.7 impulses/s in the period preceding the stimulus. The onset of activation after the stimulus had a latency of 8.6+/-6.9 ms (mean+/-SD), with a range of 4-35 ms. In trials where the movement had to be delayed after the stimulus, the early activation disappeared or was considerably reduced, showing that it was context-dependent. A small proportion of neurons with brief spikes initially decreased activity after the stimulus, but with a latency >9 ms. All the neurons with broad spikes, except one, had reinforcement-related activity. Half of them showed exclusively reinforcement-related activity, the other half also early activation after the stimulus. These neurons were about half as active in the period preceding the stimulus occurrence than the neurons with brief spikes. The early context-dependent activation is discussed in relation to the excitatory projection of PPTg neurons on the subthalamic nucleus. The reinforcement-related activity, preferentially evidenced in broad spike neurons presumed to be cholinergic, is speculated to be associated with cholinergic projection of PPTg neurons to the dopaminergic neurons of the substantia nigra. Finally, the role of PPTg in the ongoing control of motor performance and reinforcement processes is discussed in relation to the basal ganglia circuitry.

The role of the pedunculopontine tegmental nucleus in relation to conditioned motor performance in the cat. II. Effects of reversible inactivation by intracerebral microinjections.

The effects of reversible pharmacological manipulation of the neuronal activity in the pedunculopontine tegmental nucleus (PPTg) on the performance of a conditioned movement was studied in two freely moving cats. The microinjections were given in regions where, in the same subjects, we had previously identified neurons with context-dependent early activity after a trigger stimulus and with reinforcement-related activity. The subjects were conditioned to perform a forelimb-flexion movement controlled by a simple reaction-time task. In addition, one subject was trained to execute the same flexion movement, but delayed after the trigger stimulus. Food pellets were used as the reinforcer. Lidocaine injections (1 microl of 2% solution, injected over a 6-min period) induced a transient arrest of performance within minutes. The cessation of performance could be preceded by behavioral signs such as meowing, attempt to escape from the experimental booth, licking, or stereotyped posture. No rotational behavior could be observed. The effects of lidocaine could be mimicked in one subject by an extinction procedure. Muscimol injections (two injections of 0.2 microg in 1 microl, tested in one subject) also induced arrest of performance, but the return to pre-injection level of performance could not be obtained within the time of the test session. The quantitative analysis of reaction times and of inter-trial intervals showed that altering PPTg activity affected inter-trial intervals, but only slightly affected the reaction times. It is speculated that the PPTg is involved in the reinforcement process related to selecting the appropriate motor program.

Correlations between activity of pallidal neurons and motor parameters.

The relationships between the activity of 87 pallidal neurons and parameters characterizing motor performance were analysed quantitatively in six unrestrained cats performing a forelimb flexion movement controlled by a reaction-time paradigm. Three motor variables were considered: the static force exerted when the trigger stimulus occurred, the latency of the force change initiating the liver-release movement and the velocity of the force change. For all the cats, the latency of the change in force was the prevalent parameter in determining the movement onset occurrence. The single-unit activity was quantified on a trial-by-trial basis by measuring the mean firing rate in windows of fixed duration. Both normal (total) and partial linear correlation coefficients were used. Partial correlation coefficients were calculated between the mean firing rate during selected windows and each of the motor parameters. A total of 17% and 9% of all partial correlation coefficients tested (n = 1566) was found to be significantly different from zero, respectively with p < 0.05 and p < 0.01. The mean percentages of explained variation, measured by the square of the correlation coefficient, were 17% (p < 0.05) and 21% (p < 0.01). The 46 pallidal neurons presenting an increase in discharge after the trigger stimulus could be classified in homogeneous subgroups with respect to the signs of the correlations. Representations of the motor programme underlying reaction-time performance evidenced at the pallidal level further substantiate a specific involvement of the basal ganglia in the latency of motor triggering.

[Retinal involvement in Gaucher's disease]. / La participation rétinienne dans la maladie de Gaucher.

Gaucher's disease, a storage disease, causes storage of the sphingolipid glucosylceramide in the reticulo endothelial system. The manifestations of such deposits within the retina consist of the appearance of numerous whitish spots, such as preretinian infiltrates. Several authors have noticed the higher frequency of appearance of such spots in splenectomized patients, with marked extrasplenic infiltration. In our case, the systemic infiltration was massive at the time of the ophthalmoscopic examination, as confirmed by the bone-marrow biopsy and computerized axial tomography study, in spite of the fact that the spleen had not been removed. Our hypothesis is that the appearance of the whitish preretinian deposits in the course of the disease is connected with the degree of systemic infiltration, stressing the importance of examination of the eye fundus in Gaucher's disease.

Organization and physiology of the substantia nigra.

A comprehensive review of the literature on the anatomy, electrophysiology and pharmacology of the substantia nigra is presented. A diagram is developed taking into account the interneuronal interactions of neurotransmitters and receptors that control firing rates and neurotransmitter releases. The central features of the diagram are a positive dopaminergic feedforward process and a positive feedback mechanism mediated by extrasynaptic substance P diffusing from striatal terminals to dopaminergic dendrites of the zona compacta neurons. This loop can enhance the transmission of information from the striatum through the pars reticulata output neurons. The loop is controlled at the level of zona compacta neurons by a negative feedback supported by the dendritic release of dopamine and boosted by pedunculopontine activation mediated by muscarinic receptors. The output of the loop is controlled by two negative feedforward processes, both involving GABAergic striatonigral afferents. Application of the model to pharmacological studies of diverse behaviors including seizures, turning, and conditioned behaviors reveals unforseen relationships and may offer insights into, and directions for, further analysis of the mechanisms and functions involved.

The possible use of a spallation neutron source for neutron capture therapy with epithermal neutrons.

Spallation is induced in a heavy material by 72-MeV protons. The resulting neutrons can be characterized by an evaporation spectrum with a peak energy of less than 2 MeV. The neutrons are moderated in two steps: first in iron and then in carbon. Results from neutron fluence measurements in a perspex phantom placed close to the moderator are presented. Monte Carlo calculations of neutron fluence in a water phantom are also presented under some chosen configurations of spallation source and moderator. The calculations and measurements are in good agreement and show that, for proton currents of less than 0.5 mA, useful thermal-neutron fluences are attainable in the depth of the brain. However, the dose contribution from the unavoidable gamma background component has not been included in the present investigation.

The production by 72 MeV protons of keV neutrons for 10B neutron capture therapy.

Fast neutrons, produced in a spallation process by 72 MeV protons hitting heavy nuclei, can be moderated down to keV energies, suitable for 10B capture therapy. Measurements of neutron flux from copper and lead targets, after moderation by water and hydrocarbons, have been performed, together with measurements of the fast neutron and gamma-backgrounds. The comparisons with Monte Carlo calculations show good agreement. As neutron fluences up to 10(12) to 10(13)n/cm2 can be produced within a few hours in about 0.5 m target distance the technique seems to be suitable for clinical experiments.

Participation of the red nucleus in motor initiation: unit recording and cooling in cats.

Cats were trained to release (Go) or not to release (No-go) a lever after a brief auditory signal, depending on the presence of an additional tone (No-go cue). Unit recording and cooling were made in the red nucleus (RN) contralateral to the performing limb. Three major results were found: (1) in the Go condition, we observed phasic increases of rubral firing, with a constant latency after the auditory signal and with an amplitude correlated to the latency of motor triggering (i.e. reaction time, RT); the tonic activity preceding the auditory signal could also be correlated to the RTs for some units; (2) in the No-go condition, there was no phasic increase of rubral firing after the auditory signal; the tonic activity during the presentation of the No-go cue was markedly decreased compared to the Go trials; (3) cooling of the RN increased the RTs and could also block the motor triggering. These results suggest that the RN is involved in setting and triggering a conditioned motor response according to sensory cues.

Activity of caudate nucleus neurons in cat performing a reaction time task.

During a reaction time task, single units were recorded in the caudate nucleus of freely moving cats. Neuronal changes of activity were related to CS, to initiation of movement or to reinforcement. It is suggested that these changes of activity are involved in a process in which informations on the CS and on the on-going movement are associated with information on the occurrence of reinforcement.

Cat red nucleus changes of activity during the motor initiation in a reaction time task.

Unit recordings were made in the posterior red nucleus of 4 freely moving cats, performing a conditioned forelimb flexion in response to a sound, in a simple reaction time (RT) paradigm. More than 50% of the recorded neurons (154) were found to be task-related, with marked changes of firing (mostly increases) time-locked with the go-signal (mean latency: 40.8 ms +/- 12 ms SD) and frequency-correlated with the duration of the RT. These RT-correlated changes of firing disappeared or were markedly decreased when the movement was not triggered. Most of the task-related neurons also displayed late changes of firing during the force change, time-locked with the movement. Furthermore, a clear relation was observed between the rubral firing before and after the go-signal and the sensorimotor field of the recorded neuron: the neurons preferentially related to limb or trunk movements discharged with the highest frequency throughout the conditioned sequence and exhibited the best RT-correlated increases of firing during the movement initiation. In contrast, rubral neurons apparently related to head-movements generally discharged with low frequency and commonly exhibited decreases of firing in the initiation period. The changes of rubral firing prior to the motor activity, correlated to the RTs, suggest a command function for the RN, in the triggering of the conditioned motor response.

The rubro-olivary tract in the cat, as demonstrated with the method of retrograde transport of horseradish peroxidase.

The rubro-olivary projection in the cat was investigated by means of the retrograde transport of horseradish peroxidase. After injections in the inferior olive, more than a thousand labelled neurons were found in the ipsilateral red nucleus. These neurons had triangular-shaped cell bodies with an average diameter of 26.4 +/- 7.7 microns (mean +/- S.E.M.) and had few dendrites. Between 85% and 95% of the rubro-olivary neurons were found in the rostral third of the red nucleus (between A 5.5 and A 7). Morphologically, the rubro-olivary neurons are similar to rubro-thalamic neurons. Previous studies with retrograde transport of horseradish peroxidase have failed to demonstrate an extensive projection from the red nucleus to the inferior olive. These results are discussed in relation to our own findings.

Motor command in the ventrolateral thalamic nucleus: neuronal variability can be overcome by ensemble average.

The variability and stationarity of single unit activity and reaction times in a simple reaction time task were investigated by means of unit recordings from the ventrolateral thalamic nucleus in the cat. The study was carried out on eight neurons recorded over many trials and displaying an increase in activity correlated with the performed reaction time. The stationarity of the correlation appeared to be better than that of the unit activity or reaction time taken alone. In this stationary process the neuronal variability is considerable, and the investigator has to use time averages over many trials to be able to extract information from the single unit data. Since the nervous system does not required repeated presentations of a stimulus to trigger a movement, it must be using parallel processing of information throught ensemble averages. A simulation of an ensemble average based upon the data from these eight neurons showed that such a process can be efficient. An evaluation of the number of neurons required to obtain a quasi deterministic neuronal command of the reaction time value, gave the speculative figure of 70. This figure could represent the dimension of the set of neurons with the same characteristics involved in the motor command.