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.

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.

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.

Thalamic projections of the vestibular nuclei in the cat as revealed by retrograde transport of horseradish peroxidase.

Vestibulo-thalamic projections were studied in the cat by injecting horseradish peroxidase in different parts of the nucleus ventralis lateralis thalami (VL) and analyzing the distribution of the tracer in the vestibular nuclei: when it was injected in the dorsal part of VL, cells in the contralateral superior and medial vestibular nuclei were labeled, thus confirming the existence of a vestibulo-thalamic pathway.

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.

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.

[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.

Observations on the orthograde and retrograde transport of horseradish peroxidase in the cat.

Horseradish peroxidase (HRP) was applied to the precruciate cortex of the cat. The peroxidase was either applied directly to the surface or injected by glass micropipettes in single or multiple injections. Retrograde as well orthograde transport was observed by light and electron microscopy in different areas: in the thalamus: the nucleus ventralis lateralis and the nucleus centrum medianum, in the red nucleus and in the spinal cord. The distribution of HRP within the nervous elements of the nuclei: axon terminals and/or perikarya and dendrites, was observed by light and electron microscopy. HRP was present in dendrites and perikarya, indicating retrograde transport, in experiments where damage to the injected nervous tissue could be suspected. However HRP appeared restricted to the nerve endings, indicating orthograde transport, when the damage seemed to be minimal. This effect of injury on retrograde transport of HRP was further confirmed by experiments using bilateral HRP injections and unilateral lesions of the spinal cord to label rubro-spinal cells. Thus retrograde transport of HRP could be induced by lesion in systems where it does not occur normally. The normal intra-axonal transport of HRP appears to be from the perikaryon to the nerve endings. This orthograde transport can be seen under the light microscope and can be confused with faint retrograde labeling.

Activity of ventrolateral thalamic neurons in relation to a simple reaction time task in the cat.

Unrestrained cats performed ballistic forelimb flexion movements triggered by an auditory stimulus (CS) on a simple reaction time (RT) paradigm. During the variable foreperiod the subject was required to hold down a lever and to release it on presentation of the CS. The RTs ranged from 200 to 300 ms. The activity of single neurons of the ventrolateral nucleus of the thalamus (VL) was recorded bilaterally. More than 40% of the 166 units recorded in the VL contralateral to the performing limb presented, after the CS, changes of activity with a latency less than 100 ms and were classified into three types: (1) Twenty-five units had a short latency transient increase of activity 10 to 30 ms after the CS, followed by a longer increase or decrease in activity. Short latency increase as well as subsequent increase of the firing rate were not correlated to the RTs. (2) Twenty-nine units showed a 40-60 ms latency increase of activity which lasted long enough to continue during the forelimb movement. These units displayed a correlation between the RTs and the mean firing rate measured in the 40-100 ms period after the CS. The more the cells were activated, the shorter the RTs. (3) Fifteen units presented a reciprocal pattern of discharge with respect to the type (2) units. The firing rate decreased with latencies ranging from 20 to 90 ms after the CS. Only 14,5% of the 96 units recorded in the VL ipsilateral to the performing limb presented changes of activity starting in the 100 ms period following the CS. Background firing levels as well as phasic activity were rather low compared to those observed contralaterally. Sixteen units showed burst activity while the cat was performing but burst pattern was not time-related to the task. In an unconditioned animal, a very low level of activity and an absence of modulations were observed in both VLs.

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.

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.