Pharmacokinetic studies on aztreonam in late pregnancy in sheep and humans

The transplacental passage of single intravenous doses of aztreonam (AZT), 1 g or 2 g, was examined in 7 sheep and 14 women in late pregnancy, respectively and the obtained data were analyzed by a two-compartment model. The obtained results were summarized as follows. After single 2 g intravenous doses were given to pregnant sheep, the mean peak level of AZT in maternal blood was 83.79 micrograms/ml and the half-life of the beta-phase was 1.525 hours. After single 1 g intravenous doses were administered to pregnant women, the mean peak level of AZT in blood was 102.62 micrograms/ml and the half-life of beta-phase was 2.128 hours. The peak levels in umbilical venous blood and amniotic fluid were 14.43 micrograms/ml and 11.86 micrograms/ml, respectively.     

Elevated anti-alginate serum titers in patients with acute cholangitis and gallstones imbedded withPseudomonas aeruginosa

Electron microscopy and bacteriological culture revealed viable bacteria covered with a glycocalyx (biofilm) in choledochal stones recovered from two patients with acute cholangitis. On the cut surface of the choledochal stones, the cholesterol stone component was surrounded with a layer of brown pigment stone. In each case, bacterial culture of the choledochal stone recoveredPseudomonas aeruginosa. Since alginate is the main component of the glycocalyx produced byP. aeruginosa, serum IgM, IgG and IgA anti-alginate antibodies were measured in each patient. The present study is the first to demonstrate acute and transient IgM seroconversion to alginate in cases of acute cholangitis. In one case, the elevation of anti-alginate IgM preceded the elevation of anti-alginate IgG. The authors propose that the bacterial glycocalyx may play a significant role in acute cholangitis.     

IgG Anti-GM1 antibody is associated with reversible conduction failure and axonal degeneration in guillain-barré syndrome

To investigate the pathophysiological role of anti-GM1 antibody in Gullain-Barre syndrome (GBS), we reviewed sequential nerve conduction studies of 345 nerves in 34 GBS patients. Statistically significant correlation between IgG anti-GM1 antibodies and electrodiagnoses was found. Sixteen IgG anti-GM1-positive patients were classified as having acute motor sensory axonal neuropathy (AMAN or AMSAN) (12 patients), as having acute inflammatory demyelinating polyneuropathy (AIDP) (3 patientsrpar;, or as undetermined (1 patient) by electrodiagnostic criteria. Besides axonal features, there was rapid resolution of conduction slowing and block. In 3 patients initially diagnosed as having AIDP, conduction slowing was resolved within days, and 1 of them and 3 AMAN patients showed markedly rapid increases in amplitudes of distal compound muscle action potentials that were not accompanied by prolonged duration and polyphasia. The time courses of conduction abnormalities were distinct from those in IgG anti-GM1-negative AIDP patients. Rapid resolution of conduction slowing and block, and the absence of remyelinating slow components, suggest that conduction failure may be caused by impaired physiological conduction at the nodes of Ranvier. Reversible conduction failure as well as axonal degeneration constitutes the pathopsiological mechanisms in IgG anti-GM1)positive GBS. In both cases, immune-mediated attack probably occurs on the axolemma of motor fibers.     

Morphologic analysis of rat retinocollicular neuron terminals containing monoamine oxidase

The retino-collicular neuron terminals containing type A monoamine oxidase (MAO-A) in the stratum griseum superficiale of the rat superior colliculus were analyzed to provide a morphologic basis for the physiologic role of these neurons in the visual pathway. A computer-assisted, three-dimensional re-construction of the terminal complex associated with the MAO-A-positive terminals was performed. MAO-A-positive terminals originated in the retina and terminated in the stratum griseum superficiale. This was confirmed by tract tracing and enucleation experiments. The terminals were densely grouped in clusters of irregularly shaped swellings. Electron microscopy revealed that the MAO-A-positive terminals were located in a glomerulus-like structure. In this terminal complex, a significant proportion of the axonal profiles (42.96%) synapsed with the MAO-A-positive terminals. Most of the profiles (24.16%) resembled presynaptic dendrites, which represent intermediate elements between the retinal terminals and conventional dendrites. Unlike the glomerulus in the dorsal lateral geniculate body, the MAO-A-positive terminal swellings were not located in the central part of the terminal complex. The terminals had an irregular shape and were located in the complex. The terminal complex was partially ensheathed by glial processes. Furthermore, the membrane surfaces exhibiting synaptic specializations were very small compared with the total surface of the terminal swellings. The membrane length of the synaptic specialization was 5.38% of the total perimeter of the MAO-A-positive terminals.     

Potential doubling time and tumour doubling time in meningiomas and neurinomas

Summary Cell kinetic study plays an important role in treatment planning of brain tumour patients. MIB-1 antibody has recently become available, which detects Ki-67 antigen even in the formalin-fixed paraffin-embedded specimens. We performed MIB-1 immunostaining in 50 meningiomas and 50 neurinomas, and estimated the cell cycle time (tc) and potential doubling time (Tpot) from MIB-1 staining index (MIB-1 SI) and mitotic index (MI). MIB-1 SI logarithmically correlated with MI in both meningiomas and neurinomas. The tc and the Tpot were expressed as a function of the mitosis time (tm), while the tm is known to be around one hour and not exceeding two hours. When the tm was assumed to be one hour, the average tcs of meningiomas and neurinomas were 6.53±3.56 days and 7.67±3.27 days, respectively. The Tpots were447 × (MIB-1 SI)^–1.29 × tm in meningiomas, and490 × (MIB-1 SI) ^–0.98 × tm in neurinomas.The tumour doubling times (Tds) were calculated from serial imaging studies in 22 neurinomas and 15 meningiomas. The Tds were formulated as794 × (MIB-1 SI) ^–0.83 in meningiomas and1380 × (MIB-1 SI) ^–0.97 in neurinomas. Most of the Tds correlated well with the Tpots in meningiomas and neurinomas, and exceeded values of the Tpot when the tm is assumed to be one hour, although a few tumours showed unexpectedly longer Tds. The Tpot and the tc estimated from MIB-1 SI and MI are clinically useful parameters for predicting the growth potential of meningiomas and neurinomas where no other simple methods are available.     

Analysis of Responsive Cells in Tolerance by the Oral Administration of Ovalbumin

The induction of immune tolerance is the most common consequence of protein feeding, i.e., “oral tolerance”. In this study we investigated the genetic basis of oral tolerance using various kinds of recombinant and congenic mice, and the cells involved in the development of this phenomenon in mice. The footpad swelling response to ovalbumin (OVA) was inhibited in mice that were orally fed OVA 7 days before sensitization. No effect of strain of mouse was seen in this inhibition. This inhibition could be transferred by Peyer's patch cells. The CD4^-8⁺ T cells were responsible for the inhibition of footpad swelling. The number of CD4⁺ cells from OVA-fed tolerant mice decreased significantly, but CD8⁺ cells did not.

The number of CD4^-8⁺ T cells was increased in Peyer's patches of OVA-fed tolerant mice, and were involved in the development of oral tolerance.     

Expression of the glutathione S-transferase placental form in human lung carcinomas

Expression of glutathione S-transferase placental form (GST-)in human lung carcinoma tissue taken at autopsy or biopsy wasinvestigated immunohistochemically. All of 34 cases of squamouscell carcinomas, including poorly, moderatelyand well-differentiatedexamples were shown to stain positively for GST-. Poorly differentiatedadenocarcinomas were, however, negatively stained (0/5 cases),while moderately and well differentiated adenocarcinomas werefound tostain with GST- at rates of 69% (9/13 cases) and 71%(5/7 cases), respectively. Six cases of small cell carcinomasexamined were all negative. The results indicate that GST- maybe a useful marker fornon-small cell type lung cancer, especiallysquamous cell carcinoma which is in agreement with findingsfor rat lung neoplastic lesions reported previously.     

Perspectives on the Mechanism of Action of Electroconvulsive Therapy: Anticonvulsant, Peptidergic, c-fos Proto-oncogene Effects

Although the mechanism of action of electroconvulsive therapy (ECT) in affective illness has remained elusive, it is hoped that the consideration of mechanisms underlying the anticonvulsant efficacy of ECT will provide new insights into its biochemical and neuroanatomical substrates. In the amygdala-kindling model, electroconvulsive seizures (ECS) inhibit both the development and completed phases of kindled seizure evolution, and therefore, ECS is a more potent anticonvulsant modality than carbamazepine, which inhibits only completed kindled seizures. Carbamazepine is increasingly recognized for its acute and prophylactic efficacy in bipolar affective illness. Thus, comparing and contrasting effects of ECS and carbamazepine may provide insights into overlapping mechanisms of anticonvulsant and psychotropic action. Anticonvulsant effects of ECS have been most closely linked to endogenous opiate substances, perhaps acting on delta-opiate receptors, but a wide variety of other neurotransmitter and peptidergic effects are also potential candidates. Electroconvulsive seizures in mice activate the proto-oncogene c-fos in many discrete areas of brain, including a variety of limbic sites, the ventromedial nucleus of the hypothalamus, and the cerebellum. As such, c-fos induction may provide both an anatomical map of areas potentially activated by ECS and a potential mechanism for initiating a sequence of events that may be important to the mechanism of action of ECT. Although the anticonvulsant effects of ECT may ultimately prove to be separable from those mediating its therapeutic effects in affective illness, seizures and anticonvulsant effects provide easily measurable endpoints for preclinical and clinical studies. Given this clarity of effect, potential anticonvulsant mechanisms can rapidly be identified, enabling direct testing of whether or not these same mechanisms are also critical to the therapeutic effects of ECT in affective illness.     

Immunochemical characterization of cytochrome P-450 isozymes responsible for benzene oxidation in the rat liver

The contribution of cytochrome P-450 isozymes to benzene metabolismin liver microsomes from fed, fasted, pyrazole-, pbenobarbital(PB)- and ethanol-treated rats and in respective isocaloriccontrols was investigated using monoclonal antibodies (mAbs).Clone 1-7-1 mAb did not inhibit benzene metabolism, whereasclone 2-66-3 inhibited only in PB-induced microsomes at a highconcentration of benzene (6.26 mM), and clone 1-91-3 mAb inhibitedbenzene metabolism in all cases. The degree of inhibition wasas follows: fed isocaloric control PB < fasted < pyrazole ethanol. The pattern of inhibition was similar with clone 1-91-3for low (0.23 mM) and high concentrations of benzene, exceptin PB-induced mkrosomes. Western blot analysis showed that clone1-7-1 mAb did not bind any liver mkrosomal protein in the regionof cytochrome P-450s, whereas with clone 2-66-3 a clear-cutband was seen only in liver microsomes from PB-treated rats,with clone 1-98-1, a band was detected in mkrosomes from alltreated groups, in the following order: PB = isocaloric control< fed < fasted < pyrazole < ethanol. These resultsindicate that (i) cytochromes P-450b,e and P-450J contributeto benzene metabolism in rat liver; (ii) the former has a lowaffinity to benzene and is induced by PB; and (iii) P-450J hasa high affinity to benzene and is induced by 1-day fasting,pyrazole and ethanol, but decreased by PB treatment.     

Effects of D2 dopamine receptor blockade with raclopride on intracranial self-stimulation and food-reinforced operant behaviour

To examine the involvement of D2 dopamine receptors in the neural mechanism of reinforcement, raclopride tartrate, a D2 specific dopamine antagonist with a relatively fast central action, was injected into 32 rats. The D2 antagonist reduced bar-pressing responses reinforced with electrical stimulation of the ventral tegmental area (ED₅₀=0.079 mol/kg) and those reinforced with food (ED₅₀=0.58 mol/kg) in 18–30 min after IP injection. The reduction in response rates could not be attributed to an interference with motor functions. An increase in the frequency of brain-stimulation pulses and a change in the schedule of food reinforcement, which respectively increased the baseline rate of responding, did not alter the effectiveness of raclopride. SCH 23390, a D1-specific dopamine antagonist, was sensitive to similar manipulation of reinforcement. These results seem to suggest that D1 and D2 antagonists may be acting at different locations in the neural mechanism underlying the reinforcement of operant behaviour.