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Two benzodiazepine antagonists were tested in an animal model of anxiety, the social interaction test. Ethyl β-carboline-3-carboxylate (1 and 2 mg/kg) had a potent anxiogenic action; the imidazodiazepine RO 15-1788 (4–10 mg/kg) had a weak anxiogenic effect that with a larger dose (20 mg/kg) disappeared and RO 15-1788 (10 mg/kg) significantly counteracted the anxiogenic effect of the β-carboline (1 mg/kg). The implications of these results for the understanding of the pharmacological basis of anxiety and for the existence and nature of an endogenous ligand for the benzodiazepine binding site are discussed.

The biology, management, and results of primary repair and secondary reconstruction are reviewed. Repair of the tendon sheath and controlled mobilization appear to improve the results of both groups.

The effect of lorazepam (2.5 mg) was assessed in two tests of short-term retention (digit-span and Benton Visual Retention), and in verbal learning and picture recognition tests. Lorazepam was without effect in a test of digit-span, but it impaired performance in the Benton Visual Retention and picture recognition tests. In the verbal learning test lorazepam caused a severe anterograde amnesia. Increasing arousal during the presentation of material partially overcame this effect, but also improved the performance of controls. Lorazepam-treated subjects were able to learn a backwards-reading task at a rate no different from controls. The deficits caused by lorazepam are similar to those that have been observed in patients with the amnesic syndrome.

The behavioral effects of two highly selective alpha 2-adrenoceptor antagonists, atipamezole and idazoxan, were investigated in mice using the plusmaze test of anxiety and the holeboard test of directed exploration and locomotor activity. No anxiogenic effect, as assessed by the tendency to enter the closed as opposed to open arms of the plusmaze, was noted for either drug at any dose tested. Neither were there any significant effects on locomotor activity or directed exploration (head-dipping) in the holeboard, or total plusmaze arm entries at any dose of either drug. The co-administration of either atipamezole or idazoxan had no effect on either the anxiolytic effect of ethanol (2 g/kg) or its locomotor stimulant effect in the holeboard. Atipamezole (1.0 and 3.0 mg/kg) significantly reversed the ethanol-induced reduction in exploratory head-dipping; a similar trend was seen for idazoxan. There was also a significant potentiation of the ethanol-induced increase in the number of total arm entries made on the plusmaze caused by 1.0 mg/kg (but not 3.0 mg/kg) atipamezole and both 0.3 and 1.0 mg/kg idazoxan. The results suggest that some of the behavioral effects of ethanol can be reversed by alpha 2-adrenoceptor antagonists whilst others are unchanged.

Quantitative assessment of pulmonary metabolic function has been shown to be a novel and important approach to obtaining specific and subtle biochemical information regarding endothelial cell function in the normal and diseased lung. A primary consideration in this measurement of whole organ metabolism, whether it be enzyme, transport, or binding functions, it is to be able to separate convective from kinetic aspects of endothelial cell physiology. Significant progress has been made in both our understanding of the influence of convective factors, as well as of possible solutions relying on mixed order kinetics. Nonetheless, the pervasive influence of surface area on these metabolic measurements and the distinct likelihood that this variable is simultaneously altered with endothelial cell function in acute lung injury makes definitive statements premature at this time. Several approaches to resolve this important issue have been attempted and include simultaneous measurement of nonmetabolic endothelial cell function including DLCO or permeability to urea; simultaneous measure of microvascular space for water or antipyrine; comparison with complex uptake and binding of a lipophilic basic amine such as propranolol; and multiple metabolic markers that may be selectively affected by injury. Other advances that should prove useful include an on-line computer registration of metabolic information, as well as gamma-scintigraphy for the purpose of obtaining regional information.

In choosing which flap to employ for a particular defect, the surgeon should think again about areas of skin availability. Where insufficient skin is present for a flap design that permits no skin graft, such as a rotation or a rhomboid flap, then a simple transposition flap with a graft on the secondary defect may serve admirably. In planning a local flap, the inexperienced surgeon should always think of an elegant escape should this plan not work--the experienced one always does. In raising the flap, the surgeon should remain aware that he is challenging its blood supply and thereby rendering it more vulnerable to injury; he should take care that he not inflict that injury during dissection. The skin hook and the knife are more precise and less damaging than the forceps and the scissors and should be used in preference. By rendering tissues tense with judicious hook traction, natural planes are revealed. By pursuing such planes much less trauma is inflicted than in creating planes where none exist. The design and execution of a local flap is an intellectual and elegant pursuit worthy of any surgeon. If the surgeon, in turn, is worthy, he or she will appreciate that fact and gain much satisfaction from the practice.

We have recently found that, besides an increase in aggression, isolation increases social interaction in NIH Swiss mice. In the present study the effect of isolation in other behavioral paradigms and their relation to brain monoamine concentrations were investigated. Mice, isolated for 0–20 days, were tested in the holeboard test of exploration and locomotor activity, the plus-maze test of anxiety, and Porsolt's swim test of behavioral ‘despair.’ Isolation reduced exploratory head-dipping, increased locomotor activity and increased the preference of mice for the open arms of the plus-maze. The immobility time in the swim test was shortenedin mice isolated for 2 or 5 days, suggesting an improved ability to cope with stressful situations. Monoamine assays failed to show significant changes in the noradrenaline, dopamine, HVA, 5-HT or 5-HIAA contents in the amygdala, hypothalamus, hippocampus or brain stem. The results indicate that isolation of NIH Siwss mice for less than three weeks induces several behavioral changes, but is not particularly stressful.

In the foregoing discussion we have attempted to provide an overview of much of the information available on the effects of changes in systemic oxygen transport on the neonatal and young subject. Using data synthesized from both human and animal studies, we have described the normal developmental changes and the findings of studies in which oxygen transport has been acutely altered by experimental means. This was intended to highlight the potentially delicate balance that can occur between oxygen supply and utilization during the critical period of rapid growth after birth. Finally, using the left-to-right shunt as an example, we have tried to show how a common pathologic condition can impair oxygen transport at multiple sites, and how normal development can make matters worse. It is anticipated that from an understanding of both normal and abnormal physiology, we will be able to develop rational approaches to the management of infants in whom the oxygen transport system has been stressed beyond its reserve.

The intrinsic effect of the benzodiazepine receptor inverse agonists RO 15-4513 and FG 7142 on the behavior of mice in a holeboard were investigated. Both drugs caused dose-related decreases in exploratory head-dipping. The highest dose of FG 7142 (40 mg/kg) also reduced locomotor activity. RO 15-4513 (1.5 and 3.0 mg/kg) and FG 7142 (10 and 20 mg/kg) reversed the reductions in the number of head-dips caused by ethanol (2 g/kg). The higher doses of these two drugs also partially reversed the locomotor stimulant action of ethanol. Animals that received ethanol in combination with either inverse agonist spent less time head-dipping than vehicle-treated controls. These data indicate that FG 7142 and RO 15-4513 can reverse, at least in part, some of the behavioral effects of ethanol. Neither drug significantly altered blood alcohol concentrations suggesting that the antagonism does not result from pharmacokinetic changes.

The microwave spectrum of acetaldehyde cyanohydrin shows two series of μ a R branch transitions of almost equal intensity which are accompanied by similar patterns of vibrational satellites. The most probable explanation of these two series of lines consistent with the expected conformational behaviour of acetaldehyde cyanohydrin is that they belong to the two non-equivalent rotamers in which the hydroxyl group is gauche to the cyanide group.

The ability of various benzodiazepine receptor ligands to antagonize the anticonvulsant action of ethanol was investigated using intravenous infusion of the GABA antagonist bicuculline. The partial inverse agonists FG 7142, RO 15-4513 and RO 15-3505 produced dose-related reductions in seizure threshold. These compounds also partially reversed the anticonvulsant action of ethanol. However, the magnitude of the effects in each case was only equivalent to the reduction in seizure threshold caused by each compound when administered alone. That is the proconvulsant effect of each compound merely subtracted from the anticonvulsant effect of ethanol. ZK 93426, a benzodiazepine receptor antagonist which alone failed to alter seizure threshold, did not affect the anticonvulsant action of ethanol. Both RO 15-4513 and RO 15-3505 also lowered the seizure threshold of barbiturate-treated mice, again in a subtractive fashion. The ability of RO 15-4513 and other inverse agonists to antagonize the anticonvulsant effect of ethanol appears to result from their intrinsic proconvulsant properties.

To investigate whether an elevated plus-maze consisting of two open and two closed arms could be used as a model of anxiety in the mouse, NIH Swiss mice were tested in the apparatus immediately after a holeboard test. Factor analysis of data from undrugged animals tested in the holeboard and plus-maze yielded three orthogonal factors interpreted as assessing anxiety, directed exploration and locomotion. Anxiolytic drugs (chlordiazepoxide, sodium pentobarbital and ethanol) increased the proportion of time spent on the open arms, and anxiogenic drugs (FG 7142, caffeine and picrotoxin) reduced this measure. Amphetamine and imipramine failed to alter the indices of anxiety. The anxiolytic effect of chlordiazepoxide was reduced in mice that had previously experienced the plus-maze in an undrugged state. Testing animals in the holeboard immediately before the plus-maze test significantly elevated both the percentage of time spent on the open arms and the total number of arm entries, but did not affect the behavioral response to chlordiazepoxide. The plus-maze appears to be a useful test with which to investigate both anxiolytic and anxiogenic agents.

In a holeboard test the imidazodiazepine Ro 15-4513 (1.5 and 3.0 mg/kg) reduced exploratory head-dipping. This effect was reversed both by the imidazodiazepine Ro 15-1788 (5 mg/kg) and by the β-carboline ZK 93426 (2.5 mg/kg). These results indicate that the reduction in exploration caused by Ro 15-4513 is mediated by central benzodiazepine receptors.

The effects of benzodiazepines on learning and memory are examined in the various clinical situations in which these drugs are used. Alterations in performance arising from the conditions for which benzodiazepines are prescribed are also considered. Current evidence indicates that, in anxious patients, as in normal volunteers, benzodiazepines impair the acquisition of new information (episodic memory). Although some tolerance may develop to these impairments, deficits are observed even after patients have been taking their medication chronically. Like amnesic patients, benzodiazepine-treated subjects may be unaware of their impaired ability to learn. The effects of the impairments on behavioral psychotherapies are considered.

The activity of rats in a holeboard test is reduced 30, 90, and 240 min after treatment with a single dose of lorazepam. The administration of a benzodiazepine antagonist (RO 15-1788) 20 min before the holeboard test (i.e., 10, 70, or 220 min after lorazepam administration) reverses the hypoactivity of animals tested 30 min after treatment with lorazepam, partially reverses the hypoactivity of animals tested 90 min after receiving lorazepam, but is without effect on the hypoactivity observed 240 min after treatment with the benzodiazepine. If, however, RO 15-1788 is given at the same time as lorazepam then it reverses the hypoactivity seen 4 h later. The results of these experiments demonstrate that a benzodiazepine can exert a behavioral effect at a time when it no longer appears to be acting at central benzodiazepine receptors.

The intrinsic effects of two imidazodiazepines RO 15–3505 and RO 17–1812 on the behavior of mice in a holeboard test were investigated. The interactions of these two drugs with ethanol were also studied. RO 15–3505 (0.75–6.0 mg/kg) failed to significantly alter either exploratory head-dipping or locomotor activity when administered alone but doses of 0.75 and 1.5 mg/kg reversed the reduction in the number of head-dips caused by ethanol (2 g/kg) and partially reveresed ethanol's locomotor stimulant action. In contrast, RO 17–1812 (0.75–6.0 mg/kg) increased locomotor activity when administered alone, and enhanced the reduction in exploration caused by ethanol. Neither RO 15–3505 nor RO 17–1812 altered blood alcohol concentrations suggesting a pharmacodynamic basis for these interactions. The results suggest that in the holeboard test the interactions of imidazodiazepines with ethanol are related to the nature of their interaction with benzodiazepine receptors, inverse agonists antagonising and agonists enhancing ethanol's effects on exploration.

In 18 normal volunteers, lorazepam (2.5 mg) compared with placebo significantly impaired performance in a verbal learning task, in the digit-symbol substitution test, and in symbol copying and number cancellation tasks. These impairments were found equally in subjects with high and low state anxiety and in subjects with high and low trait anxiety. Caffeine citrate (125 to 500 mg) significantly improved performance on the digit-symbol substitution test when given alone and reduced the lorazepam impairment. In the symbol copying test caffeine counteracted the lorazepam impairment. Lorazepam produced a significant loss of appetite and made the subjects feel significantly more dizzy, physically and mentally tired, withdrawn and tranquil, and significantly less anxious. Caffeine citrate (500 mg) counteracted the lorazepam effect of reducing anxiety and making the subjects feel more relaxed.

The attributes that make the thumb unique are position, stability, strength, length, motion, sensibility, and appearance. Of these qualities, the first four must be present to an acceptable extent for function to approach normality, while the latter three are very desirable but not essential. Reconstructive alternatives following amputation can be considered in four broad groups: where the length is acceptable but the covering is poor; subtotal amputation, where length is equivocal; total amputation with the basal joint preserved; and total amputation with the basal joint destroyed. In the first group, soft-tissue cover can be improved by local flaps with or without a neurovascular pedicle or by microvascular free pulp transfer. In the second group, metacarpal lengthening by distraction, with or without phalangization, may give adequate length. In total amputations, one may choose osteoplastic reconstruction, pollicization, or toe-to-hand transfer. Which solution is selected depends on the level of the amputation, the presence and nature of injuries to other digits, occupational and social factors, and the availability of tissues.

In a social behavior test in mice ethanol (2 g/kg) significantly reduces the time spent in social interaction and increases locomotor activity. The relatively selective alpha 2-adrenoceptor antagonists atipamezole and idazoxan alone have no significant effect on either social interaction or locomotor activity in this test. However, when coadministered with 2 g/kg ethanol, atipamezole (0.3-3.0 mg/kg) significantly attenuated the ethanol-induced reduction in the time spent in social interaction without any effect on ethanol's locomotor stimulant action. Idazoxan (0.3-1.0 mg/kg) also showed a trend towards reversing the reduction in the time spent in social interaction although this was accompanied by a significant attenuation of the locomotor stimulant effect of ethanol. The results indicate that alpha 2-adrenoceptors may modulate ethanol's effects on social interaction in mice.

Rats and mice were treated with lorazepam (1.0 mg/kg) or its vehicle. Six h later seizure threshold to i.v. pentylenetetrazole was determined following treatment with the benzodiazepine-receptor inverse agonist FG 7142, the antagonist Ro 15-1788 or a second dose of lorazepam. Although lorazepam alone was anticonvulsant 6 h after its administration, animals pretreated with lorazepam were more sensitive to the proconvulsant action of FG 7142 and less sensitive to the effects of a second treatment with lorazepam.

The microwave spectrum of N,N-dimethylaniline shows the presence of low vibrational states associated with the inversion of the NMe2 group and its torsion about the N-aryl bond. The μa R-branch lines of the ground and First inversion states show small deviations from rigid-rotor behaviour which are consistent with an energy difference of a few cm−1 between these states. The quantities Δ = Ia - Ib + Ic and Δc = Ia+Ib-Ic indicate values for the CH3NCH3 angle, α, of 114° and for the angle between the ring plane and that containing the two N-CH3 bonds, φ, of 27°. The barrier to inversion is in the range 1–3 kJ mol−1

Evidence now exists that synovial fluid is a significant nutrient for tendon healing and that reconstruction of the sheath improves results following tendon grafts. Sheath closure is recommended after both primary repair and secondary reconstruction. Techniques have been developed to best effect this closure, either with available tissue or with sheath grafts transferred from elsewhere.

The effects of RO 15-4513, RO 15-3505 and FG 7142 on the anxiolytic properties of ethanol in mice were investigated using the plus-maze test of anxiety. Before being tested on the plus-maze, the mice were tested in a holeboard apparatus. All three inverse agonists attenuated the reduction in exploration caused by ethanol in the holeboard test. In the plus-maze, only RO 15-4513 and FG 7142, which possess anxiogenic properties when administered alone, attenuated ethanol's anxiolytic effect. RO 15-3505, which alone had no effect on anxiety, failed to significantly reduce ethanol's anxiolytic effect. Neither RO 15-4513 nor FG 7142 reduced the increase in the total number of arm entries caused by ethanol. These data indicate that the interaction between ethanol and benzodiazepine receptor ligands depends both on the intrinsic properties of the ligands and the behavior under investigation.

Microsurgical transfers are discussed for pterygium syndrome, congenital pseudarthrosis, aplasia cutis congenita, and transverse absence of the digits. Also reviewed are general considerations for the performance of microsurgical procedures in infants.

The effects of ethanol in Porsolt's swim test on mice preexposed to fight- or swim-stressors were investigated. The control mice did not change their behavior in the swim test after an acute injection of 0.4 or 0.8 g/kg ethanol; 1.2 g/kg ethanol increased their immobility in one but not in another experiment. The mice exposed to continuous fight-attacks in their home cage by one dominant mouse shortened immobility after 0.8 g/kg ethanol as well as tended to shorten it after 0.4 g/kg ethanol. The mice that were forced to swim in the water twice before the actual swim test responded to 0.4 g/kg ethanol by shortening immobility; 0.8 g/kg tended to have the same effect; 1.2 g/kg ethanol just failed to lengthen immobility of the fight-stressed mice and had no effect on the swim-stressed mice. Because antidepressant drugs decrease and stressors increase immobility in the swim test, the test may serve as a putative animal model of depression. The present findings showed that low doses of ethanol reverse lengthened immobility of mice preexposed to a stressor. This suggests that ethanol either has antidepressant-like properties, or it improves animal's ability to cope with a stressful situation, or both.

The examination of multiple bones from a child who died of complications of septicemia and osteomyelitis elucidated the pathologic processes of infantile osteomyelitis. From a metaphyseal focus, there is spread in several directions. Most important, the infection can spread across the growth plate, along transphyseal vessels, to penetrate the epiphysis. Areas of direct destruction of growth plate were frequent findings, and allowed another route into the epiphysis.

Methods for determining Ro 15-1788 in brain tissue were developed using gas chromatography with nitrogen-phosphorus detection, and using reverse-phase high performance liquid chromatography. Application of the methods to pharmacokinetic studies in the rat found the elimination half-life of Ro 15-1788 from rat brain to be 16 min. Ro 15-1788 was undetectable in rat plasma at the time points studied. Concentrations of Ro 15-1788 in the brain were reduced if chlordiazepoxide was coadministered.

The interaction between lorazepam (1.0 mg) and low doses of alcohol (1/6 or 1/2 gill of vodka, equal to 6.5 or 19.6 g, respectively) was investigated in a variety of performance tests using a double-blind crossover design. The effects on mood ratings and bodily symptoms were also studied. The subjects were normal student volunteers. Lorazepam significantly impaired performance in a digit symbol substitution test and in number and verbal learning tasks. In the latter, long term recall was also impaired. Alcohol increased subjects' simple reaction time. Self-ratings of sedation were significantly increased by both lorazepam and alcohol alone, and these sedative effects were additive when the drugs were combined. Both lorazepam and alcohol had anxiolytic effects when taken alone, but when combined they made subjects more anxious than they were on placebo. This anxiogenic action of the drug combination was found on two occasions under test conditions where significantly different levels of state-anxiety were observed. These results suggest that benzodiazepine treatment should not be combined with even small quantities of alcohol because of the risk of both psychomotor impairment and possible anxiogenic effects.

A qualitative description of the acute effects of ethanol intoxication on learning and memory is presented. Mechanisms underlying the acquisition impairments observed in intoxicated subjects are discussed. Recent studies on retroactive facilitation are also considered. The importance of considering changes in attention, arousal, and mood in any account of the effects of ethanol on higher mental functions is emphasized. In the future, studies are needed in which the effects of ethanol are compared and contrasted with those of other agents. Such studies will not only improve our knowledge about ethanol's effects but will also enhance our understanding of cognition.

Effects of selective alpha 2-adrenoceptor antagonists, atipamezole and idazoxan, on ethanol-induced hypothermia were investigated in mice. Ethanol significantly reduced (P less than 0.001) core temperature whilst both alpha 2-adrenoceptor antagonists were without effect when administered alone. However, both the 1 and 3 mg/kg doses of atipamezole significantly (P less than 0.05) attenuated the ethanol-induced reduction in body temperature 20 and 40 min after administration. The 3 mg/kg dose of idazoxan (but not the 1 mg/kg dose) also significantly (P less than 0.05) attenuated ethanol's hypothermic effect 20 min after administration but this effect was not statistically significant at 40 min. In a subsequent experiment using lower doses of atipamezole (0.03-1.0 mg/kg) the attenuation of ethanol-induced hypothermia caused by atipamezole was found to be dose-related. The effect of the benzodiazepine inverse agonist Ro 15-4513 on ethanol-induced hypothermia was also investigated. This compound possessed an intrinsic hypothermic action but neither attenuated nor enhanced the hypothermic effect of ethanol. These results suggest that alpha 2-adrenoceptor can, at least partially, modulate the hypothermic effects of ethanol.

Successful manufacture of modern thermosetting Class F epoxy Mica Mat high voltage stator winding ground insulation for hydrogenerators requires rigorous attention to material input, manufacturing process detail and quality assurance. The CGE manufacturing process is described while the quality assurance program is highlighted.

The effects of caffeine and its interaction with ethanol were examined in a test of social behavior and a holeboard test of exploration and locomotion. Male mice were injected i.p. with 15, 30 or 60 mg/kg caffeine alone or in combination with 2 g/kg ethanol. The animals were then put in pairs into a familiar arena, or examined individually in the holeboard. Only the highest dose of caffeine (60 mg/kg) had a significant effect on the time spent in social interaction and motor activity in the social behavior test: both measures were reduced. The duration and frequency of avoidance-irritability behavior was dose-dependently increased by caffeine. In the holeboard, caffeine caused a dose-dependent increase in locomotor activity. 30 mg/kg caffeine reversed the ethanol-induced reduction of time spent in social interaction, and 60 mg/kg caffeine antagonized the ethanol-induced increase in locomotor activity in both the social behavior and holeboard tests. Caffeine's effects on ethanol-induced behavioral changes are compared with those of other drugs.

The social behavior of pairs of male NIH Swiss mice was assessed under a variety of experimental conditions. Increasing periods of isolation increased both the total time spent in social interaction and also increased the incidence of aggressive behavior. Familiarity with the testing arena tended to increase social behavior, but the magnitude of this effect was considerably less than that previously observed in rats. High light levels reduced social interaction. Ethanol (0.8-2.4 g/kg) caused a dose-related decrease in the total time spent in social interaction, a biphasic effect on aggressive behavior and a dose-related increase in locomotor activity. While the social interaction test in this form may not be a suitable model of anxiety in NIH Swiss mice, it should provide a useful method of assessing drug effects and investigating genetic influences on social and aggressive behavior.