An open-label safety and drug interaction study of natalizumab (Antegren) in combination with interferon-beta (Avonex) in patients with multiple sclerosis.

In this open-label drug-interaction trial, we studied 38 patients with relapsing-remitting multiple sclerosis (MS) who received 3.0 or 6.0 mg/kg of natalizumab as a single intravenous (i.v.) infusion during stable treatment with intramuscular (i.m.) interferon beta-1a 30 microg (IFNbeta-1a; Avonex). To assess the pharmacokinetic (PK) interaction of natalizumab and IFNbeta-1a, serum concentration-time data for both agents were collected and analysed. Biologic response markers of IFNbeta-1a activity, beta2-microglobulin and neopterin, were also assessed to determine effects of natalizumab on IFNbeta-1a pharmacodynamics (PD). Further, safety and immunogenicity were evaluated. The combination of drug therapies was well tolerated. Although natalizumab serum concentrations (and corresponding PK exposure measures) appeared to be somewhat elevated in the presence of IFNbeta-1a, when compared to the same dose (6.0 mg/kg) administered alone in a concurrent comparator study, the differences were generally small and unlikely to be clinically relevant. In general, natalizumab had no apparent clinically relevant effects on the PK or PD properties of IFNbeta-1a. The presence of antibodies to IFNbeta-1a and natalizumab was relatively low. Overall, the study provided safety, immunogenicity, PK and PD data to support a combination strategy for the use of natalizumab and IFNbeta-1a in the treatment of patients with relapsing-remitting MS. A large clinical study is currently in progress to evaluate the efficacy and long-term safety of this combination drug therapy.

In vivo synaptic transmission in young and aged amyloid precursor protein transgenic mice.

Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cognitive impairment. We examined in vivo alterations in hippocampal neurotransmission in both young and aged PDAPP transgenic mice and nontransgenic littermates. We now report that in vivo abnormal neurotransmission in hippocampal circuits of PDAPP mice precedes beta deposition and neurodegeneration. These in vivo data provide the first evidence that dysfunction in hippocampal neuronal circuits may not be correlated with age-related extracellular beta plaque deposition.

Opioid effects on activation of neurons in the medial prefrontal cortex.

1. The effects of opioids have been characterized in portions of the neural circuitry proposed to underly the development and maintenance of addiction. One possible mechanism is modulation of function of endogenous transmitters. 2. Cells in the prefrontal cortex, a brain area involved in cognitive function and processes relevant to addiction, are described that exhibit morphine-associated attenuation of activation response to glutamate but not acetylcholine. 3. The predominantly excitatory response of prefrontal cortical cells to local application of glutamate and acetylcholine were differentially modified by systemic and local application of opioids. 4. Local mu opioid effects mimic those of systemic morphine to a more limited degree. 5. Morphine attenuates the response of prefrontal cortical cells to activation of excitatory afferents from the mediodorsal thalamus, and to a lesser degree, from the basolateral amygdala and the hippocampus. 6. Morphine modulation of prefrontal excitatory activation is naloxone-reversible.

Systemic morphine and local opioid effects on neuronal activity in the medial prefrontal cortex.

Behavioral studies support the importance of the medial prefrontal cortex in the circuitry of drug-reinforced behavior, yet the neurophysiological correlates of this phenomenon remain unclear. The present study evaluates opioid neuropharmacology in the medial prefrontal cortex of the anesthetized rat. The effects of both systemic and local application of mu agonists on individual neurons in the medial prefrontal cortex were examined. Systemic morphine was found to inhibit (63%), excite (4%) or have no effect on (33%) spontaneous firing. The inhibitory response was reversed by systemic naloxone in 77% of the cases. Electrophoretic application of a mu-selective agonist, [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin, had mixed effects on cell activity. While most cells exhibited no change in firing rate (53%), 38% showed inhibition of spontaneous activity. The [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin-evoked inhibitory responses were antagonized by electrophoresis of naloxone (86%). These results indicate that the medial prefrontal cortex might directly mediate some portion of the overall response to opiates in reinforcement or self-administration paradigms. The naloxone-reversible inhibition of firing seen following both systemic and local application of predominantly mu-selective agonists argues for a direct involvement of medial prefrontal cortical neurons in opiate-induced effects. However, the smaller percentage of cells inhibited by local versus systemic application of mu agonists also supports an influence of other brain circuitry in this response.

Repetitive excitation of bursts of action potentials in the rat hippocampus following single shock stimulation.

1. Post-stimulus time (PST) histograms of rat hippocampal cells were recorded in vivo following single-shock stimulation of the fornix. 2. The PST histograms displayed a series of peaks of decreasing amplitude, similar to damped oscillatory responses previously recorded in cats and rabbits. 3. The effect of increased background activity was investigated by recording histograms with concurrent pulse train stimulation of the contralateral hippocampus. The histograms showed a decreased latency to the onset of the second peak. 4. Damped oscillatory activity seen in the in vivo rat preparation could not be elicited in the in vitro rat slice preparation. Thus species differences cannot account for the absence in slice studies of this type of damped oscillatory activity. 5. We conclude that the level of spontaneous activity is one factor contributing to the genesis of multiple peaks in histograms in the in vivo preparation.

Epileptiform burst activity induced by potassium in the hippocampus and its regulation by GABA-mediated inhibition.

Intracellular and extracellular recordings were made from pyramidal neurons in hippocampal slices in order to study spontaneous paroxysmal bursting induced by raising the extracellular potassium concentration from 3.5 to 8.5 mM. Extracellular recordings from all hippocampal subfields indicated that spontaneous bursts appeared to originate in region CA3c or CA3b as judged by burst onset. Burst intensity was also greatest in regions CA3b and CA3c and became progressively less toward region CA2. Intracellular recordings indicated that in 8.5 mM potassium, large spontaneous excitatory postsynaptic potentials (EPSPs), large burst afterhyperpolarizations, and rhythmic hyperpolarizing-depolarizing waves of membrane potential were invariably present in CA3c neurons. High potassium (8.5 mM) induced a positive shift (+9 mV) in the reversal potential of GABAergic inhibitory postsynaptic potentials (IPSPs) in CA3c neurons without changing input resistance or resting potential. This resulted in a drastic reduction in amplitude of the IPSP. Reduction of IPSP amplitude occurred before the onset of spontaneous bursting and was reversible upon return to normal potassium. A new technique to quantify the relative intensity of interictal-like burst discharges is described. Pentobarbital, diazepam, and GABA uptake inhibitors, which enhance GABA-mediated synaptic inhibition, reduced the intensity of potassium-induced bursts, whereas the GABA antagonist bicuculline increased burst intensity. Diphenylhydantoin and phenobarbital, anticonvulsants that have little effect on GABAergic inhibition, were without effect on spontaneous bursts. Burst frequency was reduced by bicuculline and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol but was unaffected by other drugs. Reduction of slice temperature from 35 to 19 degrees C dramatically reduced burst intensity but did not markedly affect burst frequency. We hypothesize that high potassium induces a rise in intracellular chloride concentration, possibly by activating an inward KCl pump or by a passive Donnan effect, which results in a decreased IPSP amplitude. With inhibition suppressed, the large spontaneous EPSPs that appear in high potassium cause individual CA3c neurons to fire. A combination of synaptic and electrical interactions among CA3c cells then synchronizes discharges into interictal spike bursts.

Evidence implicating dentate granule cells in development of entorhinal kindling.

Kindling is an animal model of epilepsy induced by periodic focal electrical stimulation of the brain. The network of brain structures responsible for this permanent abnormal excitability is unknown. We hypothesized that the hippocampal formation serves a facilitatory role in lateral entorhinal cortex kindling. We therefore investigated the effect of dentate granule cell destruction induced by the neurotoxin, colchicine into entorhinal cortex kindling development. We found that injection of colchicine into the hippocampal formation, but not frontal cortex, resulted in a 31% increase in the number of stimulations required to establish kindling in comparison with vehicle-injected controls. The effect of intrahippocampal colchicine was due to a 95% increase in the number of stimulations required to attain a class 2 seizure. Based on these and other data, we propose that elimination of granule cells reduces activation of CA2/3 neurons, thereby impairing development of entorhinal kindling.

Interstitial ion concentrations and paroxysmal discharges in hippocampal formation and spinal cord.

This chapter contains a summary of previous work, as well as some new data concerning the roles of potassium and calcium in electrically and chemically induced seizures. During tonic-clonic seizure discharges, the extracellular concentration of potassium, [K+]o, increases from its resting level of 3.0 to 3.5 mM to between 8.0 and 12.0 mM. The time course of the [K+]o increase is such that it cannot play a part in causing either the onset or termination of paroxysmal firing, but its magnitude is in the range where K+ ions have a profound influence on the functions of excitable membranes and synapses. During nonparoxysmal activation of central nervous system (CNS) tissue, [Ca2+]o may decrease, increase, or remain unchanged. When the same stimulus train is repeated every few seconds, in time the [Ca2+]o response may change polarity even if the experimental conditions have not deliberately been altered. Changes in cerebral pH can cause small changes in the level of free Ca2+ ions in the CNS interstitium, possibly contributing to the variability of its response. At the site of origin of seizure discharges, however, [Ca2+]o does decrease in most or all cases. Paroxysmal firing provoked in hippocampal formation by repetitive stimulation of an afferent pathway and recorded with extracellular microelectrodes in a cell-body layer consists of "giant" population spikes riding on a sustained negative shift of the baseline potential. The paroxysmal sustained potential (SP) shift appears to be generated by intense and sustained depolarization of the cell bodies of dentate granule cells, and of hippocampal pyramidal cells. This is different from spinal cord and cerebral neocortex, where paroxysmal SP shifts are generated mainly by depolarization of neuroglial cells. The giant population spikes are probably the result of lockstep firing of granule cells and of pyramidal cells.

Abnormal neuronal excitability in hippocampal slices from kindled rats.

To determine if electrophysiological properties of hippocampal pathways are altered in kindled rats, extracellular recordings were made from hippocampal slices of rats kindled in the lateral entorhinal cortex and compared with those from implanted but unstimulated controls. Studies were made either 24 h or 28 days after the last kindled seizure and done in normal (3.5 mM) or elevated (7 mM) K+. The preparation of slices, data accumulation, and data analyses were done blind. One day or 28 days after the last kindled seizure, the proportion of slices with spontaneous epileptiform bursts recorded from the CA2/3 region in elevated K+ was significantly (P less than 0.001) increased in the kindled animals. The frequency of spontaneous burst firing was also increased and reached significance (P less than 0.02) at 28 days following the last kindling stimulus. One day after the last kindling stimulus, paired-pulse (GABAergic) inhibition in the CA1 region was decreased (P less than 0.001). Several measures suggested an increased synaptic inhibition in the dentate gyrus of slices from the kindled groups 1 day after kindling. Paired-pulse inhibition was increased (P less than 0.01), the current required to evoke a near-threshold population spike was increased (P less than 0.05), and the population spike amplitude was reduced for a given field excitatory postsynaptic potential (EPSP) (P less than 0.01). Twenty-eight days after the last kindling stimulus, however, paired-pulse inhibition in the dentate was slightly less in slices from kindled rats (P less than 0.005). In other respects the CA1 and dentate regions did not differ between kindled and control groups within 24 h of the last stage V seizure. Thus the maximum amplitudes of presynaptic fiber volley, population spike, and field-excitatory postsynaptic potential (EPSP) slope, and the number of population spikes evoked by a near-maximally effective afferent stimulus, were unchanged. In the CA1 region the input-output curve of field EPSP versus population spike, and the current intensity required to evoke a near-threshold population spike were also unchanged. In addition, no spontaneous bursts were recorded from CA1 in 3.5 mM K+. We conclude that either synapses or neurons intrinsic to the hippocampus are altered by kindling stimuli applied outside this brain area. The transient increase in inhibition in the dentate gyrus suggests that it may reflect a compensatory reaction to kindled seizures. In contrast, the long-lasting (at least 28 days) increase in burst firing in CA2/3 may represent a mechanism for the initiation or propagation of kindled seizures.(ABSTRACT TRUNCATED AT 400 WORDS)

Sustained potential shifts and paroxysmal discharges in hippocampal formation.

Paroxysmal firing was provoked by electric stimulation of afferent pathways in hippocampal formation of intact, urethan-anesthetized rats, of freely moving unanesthetized rats, and in hippocampal tissue slices in vitro. The electric responses of fascia dentata and CA3 zone of the hippocampus of urethan-anesthetized rats were recorded with extracellular microelectrodes. Paroxysmal discharges were provoked by stimulating the ipsilateral angular bundle. During repetitive stimulation, intercurrent paroxysmal discharges (IPaD) took the form of compound action potentials (population spikes) of large amplitude, provoked by but not locked in time to the stimulus pulses. IPaD was often but not always followed by paroxysmal after-discharge (PaAD), usually consisting of bursts of population spikes, sometimes superimposed on a slow wave. Stimulus pulses that were not strong enough to evoke population spikes when applied singly could provoke the paroxysmal firing of large amplitude spikes when applied repetitively. The liminal frequency to provoke paroxysmal firing, with 10-s train duration and with pulses evoking 60 to 80% of maximal amplitude focal postsynaptic potential (PSP) waves, varied between 6 and 15 Hz in urethan-anesthetized rats. The outbreak of IPaD was always accompanied by a marked sustained potential (SP) shift. The polarity of the paroxysmal SP shift was the opposite of the polarity of the PSP waves. We conclude that the extracellular paroxysmal SP shifts in fascia dentata are probably generated mainly by current flowing from the dendritic trees toward the cell somata of granule cells. The amplitude of the population spikes fired during paroxysmal discharges could reach 30-40 mV, indicating the precise coincidence of the impulses fired by many neurons. These spikes often arose without a detectable preceding synaptic potential. We conclude that the synchronization of the action potentials fired by granule and pyramidal cells during paroxysmal discharge is probably due to electric interaction among the neurons. In unanesthetized freely moving rats IPaD and PaAD consisting of bursts of population spikes were provoked. These were similar to those observed in urethan-anesthetized rats. Motor seizures provoked in kindled rats were associated with intense and prolonged spike bursts followed by spikeless positive waves recorded in the granule cell layer of fascia dentata. In hippocampal tissue slices maintained in vitro, paroxysmal firing could be provoked in CA1 zone by repetitive stimulation of Schaffer collaterals. IPaD and PaAD could be provoked in some slices exposed to normal (3.5 mM) [K+] and in all slices exposed to elevated (5.5 or 7.0 mM) [K+].(ABSTRACT TRUNCATED AT 400 WORDS)

Potassium and calcium concentrations in interstitial fluid of hippocampal formation during paroxysmal responses.

The concentration of potassium ([K+]o) and of calcium ([Ca2+]o) in interstitial fluid of the hippocampal formation of rats anesthetized with urethan was recorded with double-barreled ion-selective microelectrodes. The ipsilateral angular bundle was stimulated with trains of repetitive pulses. [K+]o increased during angular bundle stimulation in both dendritic and cell body layers of the fascia dentata. When stimulation was frequent and intense enough to provoke intercurrent paroxysmal discharge (IPaD), [K+]o in the granule cell body layer rose much above the level it attained during previous, nonparoxysmal activation. No similar excess increase of [K+]o related to paroxysmal firing was observed in the dendritic layer. It is concluded that tonic paroxysmal discharge of the granule cells is associated with an outflow of K ions from the cell somata, but not the dendrites. Extracellular sustained potential (SP) shifts and responses of [K+]o associated with paroxysmal firing showed no consistent correlation in fascia dentata. It is concluded that paroxysmal SP shifts in fascia dentata (unlike in spinal cord and cerebral neocortex) are dominated by the extracellular currents generated by granule cells, not by neuroglia. In the postparoxysmal phase, however, a small residual SP shift was observed in both soma and dendrite layers, which had characteristics compatible with its being generated by glial cells. Responses of [Ca2+]o varied from rat to rat. During nonparoxysmal excitation [Ca2+]o increased, decreased, or remained unchanged. During paroxysmal firing [Ca2+]o always decreased in the granule cell body layer, but the magnitude of the response varied greatly. In the dendritic layer a similar but smaller decrease was observed in some but not all cases. Probable reasons for the unpredictability of the responses of [Ca2+]o are discussed. The responses of [Ca2+]o recorded in fascia dentata of urethan-anesthetized rats that have previously been kindled were not detectably different from those of control animals. Leão's spreading depression (LD) was associated with large increase of [K+]o, decrease of [Ca2+ )o, and intense negative SP shift in both dendritic and cell body layers of fascia dentata, as well as in CA1 zone of hippocampus. It is concluded that LD in hippocampal formation is associated with more widespread depolarization of pyramidal and granule cells than in cerebral neocortex and cerebellar cortex where changes of [K+]o are limited to the more superficial layers.

The kindling model of epilepsy: a critical review.

Kindling is an animal model of epilepsy induced by electrical stimulation of the brain. This model has attracted the interest of many neuroscientists, in part because it involves a robust, permanent modification of brain function. This report will describe the kindling phenomenon and critically review current understanding of the underlying mechanisms. The review will carefully consider whether this model accurately reflects analogous processes in humans. The review will consider some hypotheses inspired by the kindling studies which may be relevant to human epilepsy.

Lateral entorhinal cortical kindling can be established without potentiation of the entorhinal-granule cell synapse.

Kindling is an animal model of epilepsy which involves a permanently enhanced neuronal response to an electrical stimulus. It has been proposed that long-term potentiation (LTP) of excitatory synaptic transmission is the cellular basis of kindling. Therefore, LTP was examined in the monosynaptic projections from the lateral entorhinal cortex (LEC) to dentate granule cells (DG) in unrestrained, unanesthetized rats kindled via the LEC. Population excitatory postsynaptic potentials (pEPSPs) were recorded from the granule cells before, during, and after kindling of the LEC. Controls were unkindled rats recorded during the same time period as the experimental rats. No consistent changes were found in plateau pEPSP amplitudes or initial slopes although kindling via the LEC proceeded through the typical stages. There was also no significant change in the stimulus intensity needed to elicit a 50% maximal or "plateau" pEPSP. Thus, whereas kindling was indeed established by stimulation of the LEC, there was no evidence of LTP detected in the granule cell response either during the development or after completion of kindling. Either LTP does not underlie the mechanism of kindling via this pathway or it occurs in different brain regions receiving LEC input.

Total hip replacement in patients with renal transplants.

In a retrospective study of total hip replacement (THR) arthroplasty in patients with renal transplants, femoral head avascular necrosis (AVN) was found in 19 of 138 (15%) patients. Nine THRs in eight of these 19 patients (average age, 47 years) were studied. Preoperatively, all patients had hip pain due to AVN and a history of long-term treatment with systemic corticosteroids. Six of the eight patients had been treated with parenteral pulsed steroids on three occasions, and the other two patients on one occasion, for rejection episodes. All patients showed some degree of femoral head collapse roentgenographically. There were no major surgical complications. All patients had markedly improved functional capacities and relief of pain. With follow-up averaging three years, there has been no evidence of component loosening.

Effect of p-chlorophenylalanine on thermoregulation in unrestrained rats.

p-Chlorophenylalanine (PCPA), a serotonin depletor, was used to investigate thermoregulation of unrestrained unanesthetized rats exposed to warm (approximately 32 degrees C) and cold (approximately 3 degrees C) environments. PCPA (300 mg/kg, ip) was administered approximately 48-96 h prior to the experimental trials. After 60 min of warm exposure, PCPA-treated rats had a significantly smaller increase in mean tail temperature (3.05 degrees C) and a greater increase in mean core temperature (1.47 degrees C) than did the control rats (6.13 and 1.20 degrees C, respectively) as measured via chronically implanted thermistors. A noninvasive method, infrared photography, was also used to monitor skin temperatures following heat exposure. Changes were qualitatively similar to those seen with thermistors, although differences between control and PCPA-treated groups were not statistically significant. During cold exposure, thermistor measurements indicated that the decrease in mean core temperature of the PCPA-treated rats (0.62 degrees C) did significantly differ from that of the controls (1.11 degrees C), whereas tail temperatures did not. These data confirm other studies implicating serotonin in the thermoregulation of rats. In particular, these results show that in a warm environment, PCPA may alter, albeit subtly, peripheral vasodilation in unrestrained rats.

An integrated university emergency medicine - trauma program.

UNLABELLED: Systems for prehospital care, emergency medical care, and trauma care clearly overlap educationally, medically, financially, and politically. Most systems have not accomplished separation of this interdisciplinary tangle. To solve this dilemma we have customized an Emergency Medicine and Trauma Service (EM & TS) at a regional trauma medical center. The program (annually): 1)treats 32,000 patients (11,330 are trauma); 2) educates 140 paramedics, residents, students. Physician personnel: Members are fully trained in Internal Medicine, Surgery, or Pediatrics; are members of other academic departments. Each is approved by three chairman: Emergency Department, The physician's specialty, and Surgery, Structure: Board-qualified trauma surgeon always present; other faculty supplement surgical manpower; physicians are salaried; each is responsible to Director of EM & TS; trainees are not included as patient-care manpower. Organization: Academically, EM & TS is a Section of the Department of Surgery; the Section Chief is Director of EM & TS, and is responsible for Emergency Department, prehospital care, and trauma admissions. THE SOLUTION: A vertical responsibility structure to this multidisciplinary system has provided a successful solution and may be tailored to other systems.

The fate of unruptured intrahepatic hematomas.

In 4 year's experience, we admitted 283 patients suffering from severe blunt torso trauma. Sixty-five had serious hepatic injury. Of these, 49 (75.4%) had explosive hemorrhagic hepatic injuries and underwent surgery immediately. The remaining 16 (24.6%) had intrahepatic hematomas (IHHs); three were receiving anticoagulants. Fourteen IHHs were diagnosed by liver-spleen scan within 1 to 3 days after injury, one was diagnosed at autopsy and one during surgery. Nine (56.3%) were successfully treated nonoperatively. Six (37.5%) were initially treated nonoperatively, but required emergency surgery later because of life-threatening complications. The onset of complications occurred from 1 to 28 days after injury. Indications for delayed operative intervention were hepatic abscess with sepsis (four patients) and expanding hematoma and blood loss (two patients). We conclude from this experience that: (1) Patients admitted with blunt torso trauma should undergo liver-spleen scan examinations; (2) IHHs should be treated initially nonoperatively; (3) the observation period for nonoperative management should be at least 28 days; (4) serious sequela of IHHS occur approximately 1 to 28 days after injury; (5) the combination of anticoagulation and IHH is highly lethal and must be treated aggressively; and (6) patient with progressive findings--worsening sepsis, increasing peritoneal findings, evidence of progressive blood loss, or expansion of IHHs--should be treated by urgent surgical intervention.

Surgery, nutritional support, and survival in patients with end-stage renal disease.

In 216 patients with end-stage renal disease (ESRD) undergoing 406 major operations, surgery was elective in 143 cases (mortality, 1.4%) and nonelective in 263 (mortality, 11.1%). Of 82 patients who received 105 pretransplant operations to prevent posttransplant complications, eg, gastrointestinal hemorrhage, urinary tract sepsis, and azathioprine intolerance, surgical mortality was 1.9%, with 80 patients becoming active candidates for transplantation. Sepsis requiring surgical care occurred in 54 patients, in 36 of these in the posttransplant period. Parenteral and enteral hyperalimentation was used as a therapeutic adjunct in 40 of these patients. Overall mortality in those with septic complications was 35.2%, 22.5% in the nutritional support group and 71.4% in the group not receiving hyperalimentation. Improved survival rates can be achieved for surgical emergencies in ESRD, particularly in the posttransplant immunosuppressed patient, if both definitive surgical intervention and nutritional support are actively applied.