Short Time Course Research Articles

Spinal cord pharmacology of pain

The transmission of pain from peripheral tissues through the spinal cord to the higher centres of the brain is clearly not a passive simple process using exclusive pathways. Rather, circuitry within the spinal cord has the potential to alter, dramatically, the relation between the stimulus and the response to pain in an individual. Thus an interplay between spinal neuronal systems, both excitatory and in- hibitory, will determine the messages delivered to higher levels of the central nervous system. The incoming messages may be attenuated or enhanced, changes which may be determined by the particular circumstances. The latter state, termed central hypersensitivity [61], whereby low levels of afferent activity are amplified by spinal pharmacological mechanisms has attracted much attention [13, 15]. However, additionally, inhibitory controls are sub- ject to alteration so that opioid sensitivity in different pain states is not fixed [14]. This plasticity, the capacity for transmission in nociceptive systems to change, can be induced over very short time courses. Recent research on the pharmacology of nociception has started to shed some well-needed light on this rapid plasticity which could have profound conse- quences for the pharmacological treatment of pain [8, 13, 15, 23, 24, 35, 36, 41, 62]. The pharmacology of the sensory neurones in the dorsal horn of the spinal cord is complex, so much so that most of the candidate neurotransmitters and their receptors found in the CNS are also found here [4, 32]. The transmitters are derived from either the afferent fibres, intrinsic neurones or descending fibres. The majority of the transmitters and receptors are concentrated in the substantia gelatinosa, one of the densest neuronal areas in the CNS and crucial for the reception and modulation of nociceptive messages transmitted via the peripheral fibres [4]. Nociceptive C-fibres terminate in the outer lamina 1 and the underlying substantia gelatinosa, whereas the large tactile fibres terminate in deeper laminae. However, in addition to the lamina 1 cells which send long ascending axons to the brain, deep dorsal horn cesll aslo gvie rsie to ascendnig axons and respond to C-fibre stimulation. In the case of these deep cells the C-fibre input may be relayed via from the afferents will facilitate spinal excitation. By ; :

Salamander olfactory bulb neuronal activity observed by video rate, voltage-sensitive dye imaging. II. Spatial and temporal properties of responses evoked by electric stimulation.

1. Video imaging of changes in voltage-sensitive dye (VSD) fluorescence was used to analyze spatial and temporal properties of activity patterns in the in vivo salamander olfactory bulb and primordium piriform cortex after electric stimulation. Distribution of activity among and within the neuronal layers was analyzed after orthodromic stimulation of the whole olfactory nerve (ON), isolated fascicles, or local epithelial sites, and after antidromic stimulation of the medial olfactory tract (OT). 2. Optical signals propagated through the bulbar layers with a sequence that correlates with electrophysiological responses. After orthodromic stimulation, VSD responses started in the glomerular layer, spread to the deeper laminae, and, after reaching the region of mitral/tufted somata, were observed as a brief burst of activity in the OT. Compound action potentials in the ON were associated with short-duration, rapidly depolarizing optical responses in the ON layer. Responses in glomerular layer and external plexiform layer (EPL) first showed in some recordings a brief, small-amplitude hyperpolarization, followed by a period of depolarization, followed by a second, longer-lasting hyperpolarization. The periods of optical hyperpolarization could be related to events observed in intracellular mitral/tufted cell recordings. 3. With shocks delivered to the entire ON, depolarizing responses were nonhomogeneously distributed, appearing as multiple foci or bands of activity. Spatial patterns within each bulbar layer had poorly defined borders. Sites showing short-latency responses were often those with the largest and longest-lasting activity. 4. Increasing the intensity of stimulation to the ON enhanced the size and duration of the depolarizing and hyperpolarizing responses. The short-latency, early hyperpolarization was best seen with low-intensity, peripherally placed stimuli. 5. ON stimulation also elicited activity in the contralateral bulb. Activity started at the innermost layers and spread in patches to regions of the EPL just beneath the glomeruli. These had durations similar to ipsilateral responses, but longer latencies. A period of early hyperpolarization, longer than that on the ipsilateral side, was followed by prolonged depolarization and then by a second, later hyperpolarization. 6. Antidromic stimuli applied to the OT evoked optical responses consisting of a period of depolarization followed by hyperpolarization, similar to the components elicited by orthodromic stimuli. These responses had short time courses, began in the deeper layers, and spread to the superficial region of the bulb usually without reaching the glomerular region. 7. Punctate stimulation of the mucosa or nerve elicited depolarizing and hyperpolarizing events that depended on the stimulation site.(ABSTRACT TRUNCATED AT 400 WORDS)

Nearwork-induced transient myopia: a critical review.

The literature on nearwork-induced transient myopia (NITM) is reviewed, with NITM being defined as the short-term myopic far point shift immediately following a sustained near visual task. A majority of these investigations demonstrated the presence of NITM for a variety of test parameters, e.g., visual acuity, contrast sensitivity and far point. Overall, these studies reported relatively small myopic shifts, with a mean of approximately 0.40 D and a range from 0.12 to 1.30 D. The subsequent decay is characterized by an exponential function with a relatively short time course. While the precise etiology and implications of NITM remain unclear, speculations regarding its origin and relevance to clinical myopia are discussed. Studies that did not demonstrate NITM are also reviewed.

Effects of timing and duration of cognitive activation in [15O]water PET studies.

The multiple injection [15O]water method offers unique opportunities for studying cognitive processing by the human brain. The influence of the duration and temporal placement of an activation task, in relation to the arrival of the radiotracer in the brain, is a fundamental methodologic question for cognitive activation studies. A quantitative positron emission tomography (PET) study of five normal volunteers was performed in which the stimulation consisted of a visual activation task (alternating checkerboard pattern) superimposed on an auditory baseline task (syllable monitoring). Ten injection conditions, with varying duration and timing of the visual activation, were used. Regional CBF (rCBF) in visual cortex was measured quantitatively using the autoradiographic method. A 20-s stimulation, centered on the bolus arrival in the brain, produced significant changes in rCBF. Because varying the duration and timing of the activation task technically violates the temporal homogeneity assumption of the autoradiographic model, a mathematical simulation was formulated to evaluate the potential influence of these variations. Results of the simulation are consistent with the PET data and suggest that activation can be limited to a narrow temporal window centered on the radiotracer uptake. The ability to observe significant changes in rCBF with short stimulation intervals is of particular interest in the use of [15O]water PET for studies of cognitive processes with a short time course.

The kinetics and mechanism of repair of UV induced DNA damage in mammalian cells. The use of 'caged' nucleotides and electroporation to study short time course events in DNA repair.

Using 'caged' DNA break trapping agents as well as the equivalent uncaged reagents and an automated apparatus, we have measured time courses of incorporation of radiolabelled nucleotides into HL60 cellular DNA in the early stages after 248 UV laser damage. These time courses show two distinctive phases, one between 0 and 120 seconds and another after 120 secs following damage. The first phase consists of a transient which shows a rapid initial incorporation of radiolabel followed by a sharp fall in incorporated label. This occurs with TTP as well as ddATP, which suggests that an excision activity which results in removal of recently incorporated bases is not solely provoked by the incorporation of an unnatural base, but also by the incorporation of an incorrectly paired base in a phase of what may be low fidelity repair. The second phase consists of a more steady state of incorporation. Both phases are dose dependent and show higher incorporation at higher doses. The transient is most apparent at does which cause some lethality. It may represent a form of emergency or 'panic' repair where it seems that there may be an immediate effort to maintain strand continuity in the damaged DNA. Results of experiments with polymerase inhibitors suggest that a polymerase which is sensitive to aphidicholin and which shows some sensitivity to dideoxythymidine is active during the transient phase of repair. Since excision of newly incorporated radiolabel takes place very rapidly during the first phase this would imply that a polymerase with an associated proof-reading nuclease is active at this stage. Polymerases alpha, delta, and epsilon all have this property but delta and epsilon have a higher sensitivity to dideoxythymidine than does alpha. Since the transient burst phase shows significant inhibition by dideoxythymidine, it is more likely that delta or epsilon are active at this stage. The putative panic response discussed in relation to proof reading mechanisms in aminoacyl-tRNA and DNA synthesis.

Application of morphine prior to noxious stimulation differentially modulates expression of Fos, Jun and Krox-24 proteins in rat spinal cord neurons

The expression of Fos, Jun and Krox-24 proteins was investigated in spinal cord neurons of the rat 2, 4 and 8 h following noxious thermal stimulation of one hind-paw and pre-treatment with morphine. The number of neurons expressing c-Fos, c-Jun, Jun B and Krox-24 were maximal after 2 h and thereafter declined. The number of Fos B and Jun D immunoreactive neurons increased constantly for up to 8 h with Jun D showing expression above baseline only after 4 h following stimulation. Intravenous application of morphine (5 and 10 mg/kg) 20 min before noxious heat stimulation decreased the expression of all six proteins at any time-point with a predilective effect on neurons of deeper laminae of the dorsal horn. The suppressive effects of morphine were more pronounced with the higher dose of morphine and completely reversed by intravenous naloxone (1 and 10 mg/kg). The temporospatial patterns of expression following morphine were similar to those seen without morphine, but in a much smaller number of neurons and with a shorter time-course. However, despite the high dose of morphine and continuous halothane anaesthesia during the whole experimental procedures, a considerable number of neurons expressing the various genes remained in all laminae of the spinal cord. At 2 h following noxious heat stimulation morphine had decreased the number of labelled neurons for c-Fos, Fos B, Krox-24, c-Jun and Jun B to 30–60% of control levels in laminae I-II and to 10–30% in laminae III-VII,X of the spinal cord. At 4 h the level of reduction had further increased while Jun D was only moderately reduced to 75% in all laminae of the spinal cord. Eight hours following noxious heat plus morphine application we did not detect noxious evoked immunoreactivity for c-Fos, Krox-24, c-Jun and Jun B, while there was residual labelling for Fos B in the superficial dorsal horn and for Jun D in laminae I-VII and X of the spinal cord. The different temporospatial pattern of immediate early gene expression in neurons of the spinal cord dorsal horn following noxious stimulation suggest that variable transcription complexes may interact with DNA regulatory sequences and could thus activate alternative secondary response genes, even under protection of a high dosage of morphine applied before noxious stimulation.

Impulse-response functions for chromatic and achromatic stimuli

Thresholds were measured for detecting pairs of briefly flashed stimuli displayed successively at variable onset asynchronies. The stimuli were 1 cycle/deg vertical sinusoidal gratings, modulated either in luminance (yellow–black) or in color (red–green). The successive presentations were either of the same contrast (positive) or of opposite contrast (negative), yielding four separate summation curves: positive and negative summation for color and for luminance. Both the positive and the negative curves followed a shorter time course for luminance than for color, implying a faster response at threshold. To calculate impulse response functions from the summation data, we assumed that the neural impulse response from two successive stimuli sum linearly at threshold, that thresholds are determined by probability summation of the combined impulse response over time, and that the impulse response can be described by an exponentially damped frequency-modulated sinusoidal function with four free parameters. The predicted impulse responses for luminance and for color are quite different, being biphasic for luminance and monophasic for color. Fourier transform of these functions yielded estimates of the amplitude and the phase functions of hypothetical visual detectors: the amplitude functions predicted well the contrast sensitivity of counterphased gratings (as a function of temporal frequency) both for luminance and for chromatic stimuli.

The isolated heart-lung preparation in the cat an in situ model to study the role of the lungs in the disposition of drugs

In the search for drugs with an extreme short time course of action, compunds should be developed that are rapidly distributed to and temporarily stored in well-perfused organs. Since the lungs receive the complete cardiac output and have the ability to temporarily store drugs, we have developed an in situ, isolated lung preparation in the cat to study the contribution of the lungs to the disposition of drugs. The cat's own heart perfuses the lung in situ with autologous blood. The circulation between the left ventricle and the right atrium is short-circuited via an aorta-caval shunt. The right forelimb is added to study pharmacodynamics simultaneously (only for muscle relaxants). Validation of the model for 180 min of perfusion showed complete isolation of the organs without major biochemical changes or edema and a stable muscle response. In pilot experiments with two structurally related muscle relaxants, initial muscle relaxation was followed by spontaneous recovery of neuromuscular function and a gradually decreasing plasma concentration, indicating partial disposition by the lungs. This was confirmed by direct concentration measurements in the lung. The present model may provide a powerful experimental tool to elucidate the role of the lungs in the disposition of drugs.

Renin expression in rat testis is controlled by gonadotropin

The effect of human chorionic gonadotropin (HCG) on renin concentration and renin mRNA was studied using the testis and kidney of rats. Forty-five rats were divided into three groups. The first group (25 rats) was used for short time course study with single injection of 150 IU HCG and the second group (10 rats) for long term injection of 150 IU HCG daily for 3 weeks. In both groups, serum and testicular sample were taken after 24 hours both nephrectomy in order to exclude the influence of renal renin and angiotensin. The third group (10 rats) was used to find the effect of HCG on renal renin. Plasma and testicular renin concentration were measured by radioimmunoassay of angiotensin I. The specificity of renin concentration was determined using a specific renin antibody. Renin mRNA of the kidney and testis were measured by a sensitive RNAase protection assay method. Testicular renin mRNA increased and reached the maximum level at 8 hrs after 150 IU HCG single injection. And also testicular renin concentration significantly increased and it showed the maximum levels at day 3. However long term HCG administration in rats showed higher in levels in testicular renin concentration, however renin mRNA level was not increased. Non-nephrectomized rats showed low levels of plasma renin concentration and no changes in mRNA after HCG administration. The results suggest that renin angiotensin results suggest that renin angiotensin system independently exists in the testis and testicular renin mRNA is increased by HCG administration.

A Model Circuit for Cortical Temporal Low-Pass Filtering

We propose that the low-pass characteristics in the temporal and velocity domain of area 17 cells are generated by the abundant excitatory connections between cortical neurons. We have incorporated this anatomical feature in a model circuit in which simple cells' firing is initiated by geniculocortical excitatory synaptic input, with a short time course, and firing is maintained by feedback corticocortical excitatory synapses, which have a longer time course. The low-pass performance of the model is demonstrated by computing the model simple cells' velocity response curves (VRC) elicited by moving bars, and comparing these to those of its LGN (lateral geniculate nucleus) inputs. For the same parameter set, the VRCs of sustained and transient LGN cells are transformed into VRCs typical of central area 17 and central area 18 cells, respectively.

Membrane properties and synaptic responses of Golgi cells and stellate cells in the turtle cerebellum in vitro.

1. Intracellular recordings from anatomically identified Golgi cells and deep stellate cells were obtained in a slice preparation of the turtle cerebellar cortex. 2. Golgi cells and stellate cells had very similar firing patterns, which differed from those of Purkinje cells. In the interneurones, a short time constant and a high input resistance ensured a short response time. A pronounced spike after-hyperpolarization (spike AHP) participated in the rapid repolarization following a depolarizing input. The active and passive membrane properties of the interneurones ensured a very tight temporal coupling between input and output. 3. TTX abolished both the action potentials and a subthreshold depolarizing response. The Na+ excitability was increased by addition of Mn2+ or Co2+ to block calcium channels, or by addition of potassium channel blockers. 4. Ca2+ spikes and a Ca2+ plateau could be evoked following addition of potassium channel blockers. A partly 4-aminopyridine (4-AP)-sensitive transient hyperpolarization was found to control Ca2+ excitability in Golgi cells. It is suggested that this hyperpolarization is due to an A-like conductance. 5. A strong anomalous rectification was activated just below spike threshold, and dominated the subthreshold membrane potential at time scales longer than ca 100 ms. The anomalous rectification was partly blocked by Cs+. 6. Temporal integration over time scales up to ca 25 s was provided by activity-dependent adaptation in firing frequency and a long-lasting after-hyperpolarization (AHPL), which had both TTX-sensitive, Ca(2+)-independent, and Ca(2+)-dependent components. 7. Spontaneous IPSPs and EPSPs were abundant. The IPSPs were abolished by bicuculline. EPSPs were easily evoked by parallel fibre stimulation, had a shorter time course than in Purkinje cells, and were suppressed by the spike AHP. 8. Due to a short response time and a relatively short overall time frame for temporal integration, cerebellar interneurones operate on a faster time scale than the Purkinje cells, the output neurones of the cerebellar cortex. 9. It is suggested that information from shared sources, e.g. the parallel fibres, is distributed onto dynamically different cellular populations based on differences in the intrinsic membrane properties of the postsynaptic neurones.

The protective effect of damaging eccentric exercise against repeated bouts of exercise in the mouse tibialis anterior muscle.

Using a damaging eccentric exercise regime of the mouse tibialis anterior (TA) muscle we have investigated the extent and time course of protection afforded by one bout of exercise against damage resulting from a second bout of activity. Maximal force and fibre morphology were preserved if the exercise was repeated within 21 days, but by 84 days muscles once again became susceptible to damage. Low-frequency force loss had a shorter time course of protection against repeated exercise, lasting less than 21 days. The results provide evidence for different mechanisms contributing to the development of muscle damage following eccentric exercise and provide a basis for characterizing the adaptive response of muscle to damaging exercise.

Activation of normal and inflamed fine articular afferent units by serotonin

In cats anesthetized with alpha-chloralose, extracellular recordings were made from fine afferent units belonging to the medial articular nerve (MAN) of the knee joint. The excitatory and sensitizing effects on articular afferents of serotonin (5-HT) applied intra-arterially close to the joint were examined. The joints were either normal or an experimental arthritis had been induced some hours before the recording session. Bolus injections of 1.35–135 μg 5-HT excited about 43% of group III (CV: 2.5–20 m/sec) and 73% of group IV units (CV: < 2.5 m/sec) from normal joints. The latency was usually between 10 and 30 sec, and the duration and size of the responses were dose-dependent. Fast group III units (CV: > 16 m/sec) and group II units (CV: > 20 m/sec) were never excited by 5-HT. Repetitive administration led to pronounced tachyphylaxis of the 5-HT response. Inflammation induced an enhanced sensitivity of group III articular afferent units to close intra-arterial application of 5-HT. In particular the total duration of each response was considerably prolonged (4–10 min against 1–2 min under normal conditions). At the same time the tachyphylaxis seen under normal conditions was greatly reduced. In contrast, group IV articular afferent units did not become sensitized to 5-HT in the course of inflammation. In normal joints 5-HT did not sensitize fine afferent units for movement-induced responses. However, after inflammation, a distinct sensitization to such movements by 5-HT application could be observed both in group III and group IV fiber ranges. The sensitization had a short time course not exceeding 7 min. The tonic component of the movement-induced response was more enhanced than the phasic one. The bolus application of 5-HT led to temporary vasoconstriction of the knee joint vessels. This vasoconstriction was especially pronounced in inflamed joints and impeded the access of subsequently applied substances to the terminal regions of the afferent units under observation. It is concluded that the present results support the notion that 5-HT may participate in the mediation of pain from inflamed tissue such as an arthritic joint by exciting and sensitizing fine afferent units. During inflammation group III units are particularly sensitive to 5-HT and, thus, may carry the bulk of the 5-HT-induced nociceptive messages.

A comparison of the effects of mesencephalic injections of neurotensin(1–13) and neuromedin N on brain electrical self-stimulation

Neuromedin N (NM-N), a hexapeptide that shares a four amino acid C- terminal homology with the tridecapeptide, neurotensin (NT), has been suggested as a potential neurotransmitter or neuromodulator that could interact with the NT-sensitive receptors. In this experiment, we compared the effects of an equimolar concentration of NM-N and NT(1–13) injected in the ventral tegmental area (VTA) on brain electrical self-stimulation (SS), a behavior previously shown to be potentiated by VTA injections of NT(1–13). Rats implanted with a stimulating electrode in the mesencephalic central gray and a guide cannula in the VTA were trained to lever press to obtain rewarding electrical stimulations. Functions relating the rate of lever pressing to the stimulation frequency were determined, on separate daily tests, before and after the injection of 3 nmol of NM-N, NT(1–13), or an equal volume of saline vehicle. At this concentration, both NM-N and NT(1–13) produced a significant facilitation of SS when compared to saline vehicle, an effect that was not seen when the peptides were injected outside the VTA. The facilitation of SS by NM-N, however, was much weaker and of a shorter duration than the one produced by NT(1–13). The shorter time course and the weaker behavioral effect of NM-N compared to NT(1–13) are consistent with its lower potency at the NT receptor and its faster rate of enzymatic degradation in the VTA, and suggest that NM-N potentiated the reward-relevant neural signal by acting on mesencephalic NT receptors.

Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial

Thrombolysis of acute pulmonary embolism can be accomplished more rapidly and safely with 100 mg of recombinant human tissue-type plasminogen activator (rt-PA) (Activase) than with a conventional dose of urokinase (Abbokinase) given as a 4,400-U/kg bolus dose, followed by 4,400 U/kg per h for 24 h. To determine the effects of a more concentrated urokinase dose administered over a shorter time course, this trial enrolled 90 patients with baseline perfusion lung scans and angiographically documented pulmonary embolism. They were randomized to receive either 100 mg/2 h of rt-PA or a novel dosing regimen of urokinase: 3 million U/2 h with the initial 1 million U given as a bolus injection over 10 min. Both drugs were delivered through a peripheral vein.To assess efficacy after initiation of therapy, repeat pulmonary angiograms at 2 h were performed in 87 patients and then graded in a blinded manner by a panel of six investigators. Of the 42 patients allocated to rt-PA therapy, 79% showed angiographic improvement at 2 h, compared with 67% of the 45 patients randomized to urokinase therapy (95% confidence interval for the difference in these proportions [rt-PA minus urokinase] is −6.6% to 30.4%; p = 0.11). The mean change in perfusion lung scans between baseline and 24 h was similar for both treatments. Three patients (two treated with rt-PA and one with urokinase) had an intracranial hemorrhage, which was fatal in one.The results indicate that a 2-h regimen of rt-PA and a new dosing regimen of urokinase exhibit similar efficacy and safety for treatment of acute pulmonary embolism.

Pulsatile release of acetylcholine by nerve terminals (synaptosomes) isolated from Torpedo electric organ.

1. Electrophysiological detection of acetylcholine (ACh) release by synaptosomes from the electric organ of Torpedo was searched for by laying the isolated nerve terminals on a culture of Xenopus embryonic muscle cells (myocytes), and by recording the ACh-induced inward currents in the myocytes. 2. Whole-cell recording in one of the myocytes revealed rapid inward currents that where generated soon after synaptosome application. These pulsatile events strongly resembled those occurring normally during the early phase of synaptogenesis after nerve-muscle contact in Xenopus cell cultures. They were called spontaneous synaptic currents (SSCs). 3. The SSCs produced by the synaptosomes had a rapid time course, with mean time-to-peak and half-decay times of 2.6 +/- 0.4 ms and 6.0 +/- 1.1 ms, respectively. Most events had a falling phase that could be fitted with a single exponential. The mean time constant of decay was 6.2 +/- 1.1 ms. More than half of the SSCs (approximately 60%) constituted a rather homogenous population in which the time-to-peak versus amplitude showed a positive relationship, the smallest events displaying a shorter time course. The rest of the SSCs had a more variable and slower time course. Such events are also observed in young and mature junctions in situ. 4. The amplitudes of SSCs had a wide distribution which was skewed towards the smallest values. The mean amplitude was 65.2 +/- 16.1 pA. 5. During the minutes following an application of synaptosomes, the frequency of the SSCs tended to decrease, but their mean amplitude remained constant. Such behaviour could be reproduced during several successive additions of synaptosomes while recording in the same myocyte. 6. Just after synaptosome application, the SSCs were superposed to a noisy inward current that lasted for 20-60 s. Noise analysis of this current gave the values of 0.7 +/- 0.1 pA for the mean amplitude of the elementary event, and 4.7 +/- 0.2 ms for its mean duration, values that compare well with those reported for the activation of frog embryonic nicotinic receptor. This suggests that the noisy current was due to ACh molecules set free by synaptosomes which were either damaged or which released ACh at some distance. This view was strengthened by biochemical analysis of ACh release by synaptosomes in vitro. 7. Tubocurarine reversibly abolished the appearance of both the noise and the synaptosome-generated SSCs, showing that these currents were due to the action of ACh.(ABSTRACT TRUNCATED AT 400 WORDS)

Androgen responses to acutely increased endogenous insulin levels in hyperandrogenic and normal cycling women

We examined androgen responses in hyperandrogenic (polycystic ovarian disease [PCOD]) and normal women after an acute endogenous insulin elevation. Standard intravenous glucose tolerance tests (IVGTTs), modified to include a tolbutamide injection 20 minutes after IVGTTs, were performed. Polycystic ovarian disease patients were studied in the untreated state, after 6 weeks of ovarian androgen suppression with leuprolide acetate, after a 6-week rest period, and after 6 weeks of antiandrogen therapy with spironolactone. Normal menstruating women were studied during the early follicular, midcycle, and luteal phases of a single cycle. An acute rise in insulin did not alter serum testosterone or androstenedione levels in PCOD or normal women. A significant rise in dehydroepiandrosterone sulfate after modified IVGTTs was found in both hyperandrogenic and normal cycling women. Although these results are not supportive of the theory that insulin acts on the ovary to stimulate androgen production, they may be because of the short time course of insulin elevation that occurs during an IVGTT.

Parametric determinants in pre-stimulus modification of acoustic startle: interaction with ketamine

Prepulse inhibition of the acoustic startle response is a form of reflex modification known to be sensitive to drugs and to subtle procedural manipulations. The present study examined the importance of prepulse length and prepulse-pulse interval in the expression of prepulse inhibition and its modification by the noncompetitive N-methyl-D-aspartate antagonist, ketamine. In contrast to a previous report, ketamine disrupted prepulse inhibition at doses of 5.6 and 10 mg/kg when its short time course was taken into consideration. In a second experiment, the amount of prepulse inhibition was found to be directly related to prepulse length, with prepulse inhibition produced by shorter prepulse durations slightly more sensitive to disruption by ketamine. A third experiment examined prepulse-pulse time intervals (30-2000 ms). While prepulse inhibition produced by prepulses occurring 60-500 ms before the startle stimulus was disrupted by 10 mg/kg of ketamine, prepulses preceding the startle stimulus by only 30 ms produced either no effect or slight prepulse facilitation under control conditions, and significant prepulse facilitation when ketamine was administered. A fourth experiment examined the time course of prestimulus modification by continuous lead stimuli, ranging in onset from 15 to 75 ms before the startle stimulus. Prepulse facilitation, when observed, tended to occur in earlier portions of the session and was enhanced by ketamine. These results suggest that prestimulus modification of the startle reflex has important parametric and experiential determinants that may influence the effects of drugs. Some of these temporal determinants may have relevance to sensorimotor function in schizophrenia.

Pseudomonas pseudomallei resistance to beta-lactam antibiotics due to alterations in the chromosomally encoded beta-lactamase

Pseudomonas pseudomallei, the causative agent of melioidosis, is generally susceptible to some of the newer extended-spectrum cephalosporins or to combinations of a beta-lactam and clavulanic acid, a beta-lactamase inhibitor. Resistance to these agents may, however, emerge during treatment. We report on alterations in the chromosomal beta-lactamase associated with the development of resistance. Three resistance patterns resulted from three different mechanisms in the strains investigated. Derepression of the chromosomal enzyme resulted in a general increase in the MICs of all of the beta-lactams tested. The second mechanism observed was an insensitivity to inhibition of the beta-lactamase by clavulanic acid. In this case, the level of susceptibility to beta-lactams as independent entities remained unchanged. The final "resistance" pattern occurred in a patient treated with ceftazidime and resulted in a beta-lactamase that was capable of hydrolyzing this antibiotic at detectable levels, but with reduced efficacy against other beta-lactams. The net result was a strain that was generally susceptible to all of the beta-lactams tested except ceftazidime. In all cases, the level of susceptibility to antibiotics other than beta-lactams remained unchanged. Such variability found within one genus over a relatively short time course suggests that treatment of infections caused by this organism should be carefully monitored to detect susceptibility alterations to the chosen therapy.

Syndromes lympho-prolifératifs après transplantation cardiaque et traitement immunosupresseur par Ciclosporine. À propos de 4 cas

Cyclosporine is associated with and increase incidence of lymphoproliferative disorders. In heart transplantation non-Hodgkin's lymphomas (NHLs) are frequent, with a short time course for onset. Three NHLs and one multiple myeloma are reported.