Species differences in the mechanism through which the serotonergic agonists indorenate and ipsapirone produce their anxiolytic action.

The effect of three anxiolytic drugs, indorenate, ipsapirone and diazepam, on the burying behaviour of rats and mice was studied. All three drugs induced a reduction in burying behaviour interpreted as a reduction in anxiety. However, a species difference in the diazepam sensitivity was found: rats showed a clear effect after 1.0 mg/kg while already at 0.25 mg/kg an action was observed in mice. The serotonergic anxiolytics produced similar responses at similar doses (2.5-5.0 mg/kg) in both species. The serotonergic antagonists, pindolol (3.1 mg/kg), alprenolol (5.0 mg/kg) and methiotepin (0.31 mg/kg), induced a slight reduction in the time spent burying but effectively counteracted the anxiolytic action of the serotonergic agonists in mice but not in rats. By contrast, in rats, the beta blocker, practolol (0.5 mg/kg), was the only drug effective in preventing the anxiolytic actions of ipsapirone. The combined treatment of indorenate and methiotepin resulted in an impairment of motor coordination and ambulatory behaviour in both species studied, thereby suggesting that the lack of effect of such combination was mediated by altering the motor behaviour. Finally, the reduction in ambulatory behaviour in mice produced by ipsapirone was effectively prevented by the antagonists methiotepin, pindolol and alprenolol indicating the involvement of a serotonergic receptor in this effect. From these results it is concluded that a different mechanism underlies the anxiolytic actions of indorenate and ipsapirone in mice and rats.


Gepirone, a selective serotonin (5HT1A) partial agonist in the treatment of major depression.

1. The present study assessed the potential antidepressant action of gepirone hydrochloride, an azapirone serotonin (5-HT1A) partial agonist in patients with major depression. 2. Overall, gepirone demonstrated a significant antidepressant activity within the entire patient group (p less than 0.001). However, when subjects were stratified based upon the presence or absence of DSM III-R melancholic features, the melancholic depressives showed little change in weekly depression ratings compared to patients without melancholic symptoms (p less than 0.001). 3. Similarly, patients who were more severely ill at the pretreatment period had less improvement compared to those with more modest illness severity (p less than 0.001). 4. These observations compliment those of prior studies suggesting antidepressant activity for gepirone. 5. However, a consistent efficacy comparable to conventional neuronal reuptake inhibitor antidepressants remains to be established in patients with more severe depression characterized by melancholic features.


Influence of some dopaminergic agents on antinociception produced by quinine in mice.

1. The analgesic effect of quinine and the influence of some dopaminergic agents on it were studied in mice. 2. Quinine (25-130mg/kg, ip) effectively elicited antinociceptive effect in a dose related manner. 3. D-Amphetamine (2.5-4mg/kg, ip), L-dopa (25mg/kg, sc), L-dopa (25mg/kg, sc) plus benserazide (12.5mg/kg, sc), alpha-methyl-p-tyrosine (50mg/kg, ip) plus L-dopa (25mg/kg, sc) and pargyline (50mg/kg, ip) significantly attenuated the antinociceptive effect of quinine (50mg/kg, ip), while DOPS (4mg/kg, ip) did not affect quinine antinociception. 4. Pimozide (4mg/kg, ip), L-sulpiride (40mg/kg, ip), SCH 23390 (0.2mg/kg, sc) and alpha-methyl-p-tyrosine (50mg/kg, ip) effectively potentiated the antinociceptive effects of quinine (50mg/kg, ip). 5. Pimozide (4mg/kg, ip) also antagonised the antagonistic effect of d-amphetamine (4mg/kg, ip) on the antinociceptive effect of quinine (50mg/kg, ip). 6. These data indicate that quinine elicited antinociception dose dependently. Furthermore, the influence of pimozide, L-sulpiride and SCH 23390 on quinine antinociception suggests the involvement of dopaminergic mechanisms.


Actions of sex hormones on the brain.

1. The brain is a target for sex steroid hormones. As a result of sex hormone actions on the brain various behavioral changes are observed in animal and man. This paper gives a brief overview over the multiple central nervous functions that are under modulatory control of sexual hormones and describes the complex sex steroid actions on the brain by giving an example for "activating" and "organizing" effects of estrogens on noradrenergic neurons in the brain of rats. 2. Estradiol-17 beta induced sex specific alterations in the turnover of noradrenaline in the preoptic area and mediobasal hypothalamus showing "female" or "male" responses. 3. Neonatal manipulations of female rat pups by testosterone, estradiol-17 beta or 4-hydroxyestradiol-17 beta defeminized the "female" response of the noradrenaline turnover in the preoptic area. 4. Defeminization was not observed when neonatal females received the non aromatizable sex steroid dihydrotestosterone. 5. Activating and organizing effects of sex steroids on animal brain as shown here for noradrenergic neurons are discussed in relation to the regulation of behavior in man. Special regard is given to psychic disorders that might be associated with abnormalities in the production or metabolism of or the response to gonadal hormones.


Lithium reduced synaptic transmission and increased neuronal excitability without altering endogenous serotonin, norepinephrine and dopamine in rat hippocampal slices in vitro.

1. Extracellular field potentials were recorded in the CA1 pyramidal cell layer following stimulation of stratum radiatum in rat hippocampal slices during superfusion with different concentrations (1, 2, 5, 10, 20, and 30 mM) of lithium (Li+). Control slices were exposed similarly to choline (Ch+) or sodium (Na+). 2. At high concentrations (greater than or equal to 10 mM), Li+, Ch+ and Na+ reduced the amplitude of the field excitatory postsynaptic potential (EPSP). However, Li+ increased, whereas Ch+ and Na+ reduced the population spike amplitude. Thus, Li+ specifically enhanced the excitability of CA1 pyramidal cells. 3. Electrophysiologically monitored slices, plus an additional group exposed to Li+, Ch+ or Na+ without concomitant field potential recordings, were processed for measurement of endogenous levels of serotonin (5-HT), norepinephrine (NE) and dopamine (DA). The mean endogenous levels of 5-HT and NE were not significantly different in 1-30 mM Li+, Ch+ and Na+. Dopamine contents were unchanged after exposure to Li+ and Na+, but were reduced by Ch+. 4. The non-specific effects of Li+ on synaptic transmission and its specific effects on neuronal excitability appeared independent of changes in endogenous 5-HT, NE and DA levels.


Somatostatin inhibition of gastrin gene expression: involvement of pertussis toxin-sensitive and -insensitive pathways.

These studies were performed to determine the intracellular pathways involved in regulating gastrin gene expression. The inclusion of 10(-4) M forskolin or 10(-4) M dibutyryl cyclic AMP (DBcAMP) in incubation medium containing dog antral mucosa resulted in 249% and 323% increases, respectively, in gastrin mRNA levels. The stimulatory effects of forskolin and DBcAMP were both inhibited significantly by 10(-6) M somatostatin. Preincubation of antral mucosa with pertussis toxin nearly abolished the inhibitory effects of somatostatin on gastrin mRNA stimulated by forskolin, but had no effect following DBcAMP. To examine whether calcium-dependent pathways might be involved in regulating gastrin gene expression, antral mucosa was incubated with increasing concentrations of calcium or the ionophore ionomycin. Both agents produced only modest increases in gastrin mRNA, which were abolished by the addition of somatostatin to the incubation medium. These studies indicate that somatostatin appears to inhibit gastrin gene expression through mechanisms involving both pertussis toxin-sensitive and -insensitive pathways.


Neuropharmacology of cocaine and ethanol dependence.

Drug addiction includes two important characteristics, chronic compulsive or uncontrollable drug use and a withdrawal syndrome when use of the drug is stopped. Animal models for the motivational components of drug dependence have been developed allowing a systematic exploration of the neurobiological mechanisms of drug dependence. The reinforcing actions of acute cocaine as measured by intravenous cocaine self-administration appear to be mediated by the presynaptic release of dopamine in the region of the nucleus accumbens and may preferentially involve the dopamine D-1 receptor subtype. The nucleus accumbens circuitry involved in the reinforcing actions of cocaine may include the ventral pallidum and may be modulated by serotonin. Chronic cocaine produces increases in brain reward thresholds that may reflect the "dysphoria" and anhedonia associated with cocaine dependence and suggests a dysregulation of brain reward systems possibly involving dopamine. Reliable measures for the acute reinforcing effects of ethanol in nondependent animals have been established in the rat using a lever press operant and a taste habituation procedure. Important roles have been established for serotonin, GABA, dopamine, and opioids in the acute reinforcing properties of ethanol, perhaps acting on some of the same neural circuitry subsuming the reinforcing actions of other drugs of abuse. Studies of the motivational aspects of ethanol dependence have suggested a functional role for brain corticotropin-releasing factor. These results suggest that the neurobiology of drug dependence involves not only neurotransmitters that mediate the acute reinforcing properties of drugs, but also the aversive motivational and emotional aspects of drug withdrawal. Advances in our understanding of brain changes associated with the switch from acute effects to chronic actions may provide a key to our understanding of not only drug dependence, but also psychopathology such as, anxiety, and affective disorders.


Recent advances in pharmacological research on alcohol. Possible relations with cocaine.

Alcohol dependence is a major public health problem. Studies have shown that a person dependent on alcohol often coabuses other substances, such as cocaine. Cocaine is a powerful stimulant whereas ethanol is generally considered to be a depressant, with some stimulating properties. The subjective effects of these two substances in a dependent individual may often appear to be more similar than they are different. Animals also self-administer both substances. Basically, although both substances have anesthetic properties and both act to functionally increase catecholaminergic function, especially that of dopamine, there are some differences in their actions. Both alcohol and cocaine have various effects on several neurotransmitters and systems, which ultimately interact to produce the feeling of well-being avidly sought by many individuals today. This drive often eventually produces a dependence which has associated social and medical consequences. It seems likely that the neurochemical changes that ensue following abuse of these substances underlie the phenomena of dependence, tolerance, and subsequent withdrawal. The apparent similarities and differences between these two substances will be reviewed in this chapter.


Molecular mechanisms associated with cocaine effects. Possible relationships with effects of ethanol.

Cocaine has been shown to be a highly addictive and toxic drug. It produces these effects and a variety of other physiological and behavioral effects through its interactions with several distinct central nervous system receptor sites. We present the results of a series of studies that utilized multiple site analyses to elucidate which cocaine binding sites influence the reinforcing and toxic effects of cocaine and with what proportion of influence. The nature of cocaine interactions with monoamine transporters is also discussed, especially with the dopamine transporter, which has been shown to be the cocaine binding site that is primarily associated with the reinforcing effects of cocaine. We also provide evidence that vulnerability to both the toxic and addictive effects of cocaine may be significantly influenced by genetic differences in both humans and animals. In view of the fact that cocaine is commonly abused in a polydrug situation, we present the results of both behavioral and biochemical experiments which suggest that common biochemical pathways may mediate the reinforcing or addictive properties of drugs of abuse. Finally, we discuss research on the biochemical mechanisms associated with effects of ethanol, particularly those which may also influence cocaine self-administration and speculate on pharmacotherapeutic strategies for concurrent abuse of cocaine and ethanol.


[Bronchodilator effect of salmeterol and inhibition of bronchial hyperreactivity].

Salmeterol is a new long acting bronchodilator which is specific for beta-2 adrenergic receptors. Its bronchodilator effects can persist for at least 12 hours after inhalation. This drug can inhibit the bronchoconstrictor effects of methacholine up to 12 hours after inhalation and this effect is proportional to the administered dose. Salmeterol improves daily expiratory flow rates and blocks exercise-induced bronchoconstriction. A 50 micrograms dose, inhaled before an antigenic bronchoprovocation, can markedly reduce for up to 24 hours the immediate and late bronchospastic responses to antigen. Moreover, salmeterol inhibits the increase in bronchial responsiveness induced by antigenic exposure. This latter effect does not seem to be related to a persisting bronchodilatation. The responsible mechanisms for this inhibition of allergic response or if its effects are only due to a functional antagonism remain to be explored. A particularly relevant point would be to determine of salmeterol diminishes or blocks the inflammatory bronchial asthmatic reaction.


[Salmeterol and prolonged treatment of asthma: international clinical data].

Salmeterol is an original molecule with a selective-beta-2-sympathomimetic effect which is intended to a prolonged treatment of asthma. This inhaled preparation has a long duration of action which points to its use on a BID regimen. Results of the phase III development has been assessed in 2,277 subjects. Salmeterol administered at a dose of 50 micrograms morning and evening results in a marked increase in FEV1, which remains superior to 15% by comparison with baseline 12 hours after the last dose in the majority of subjects. In the specific case of more severe asthma (FEV1 less than 50% of predicted), the use of 100 micrograms morning and evening allows for an extra-improvement in FEV1. In the majority of studies, salmeterol has resulted in an almost complete remission of the clinical symptomatology: disappearance or major diminution in the use of inhaled salbutamol administered as a rescue medication on a PRN basis (during the day and at night) and of nocturnal awakenings, global improvement of clinical scores. Daily peak expiratory flow rates (morning and night values) are considerably improved (greater than or equal to 50 l/min) with a significant reduction of daily swings. Lung function tests are also very significantly improved. Salmeterol has proved to be largely superior to the comparison medications, salbutamol taken at a dose of 200 micrograms four times a day, and optimal therapy with theophylline. Clinical acceptability of salmeterol is good and is not different from salbutamol.


[Duration of bronchial protective effect of salmeterol in asthma induced by hyperventilation with dry cold air].

The duration of the blocking effect of salmeterol (50 micrograms), albuterol (200 micrograms) and placebo was compared in a double-blind study carried out in 12 adult asthmatic subjects who underwent hyperventilation tests with cold dry air on 4 study days. On the first day, the hyperventilation test was carried out at various time intervals with spontaneous functional recovery between each test. The response was assessed by interpolating the dose of cold dry air causing a 20% fall in FEV1 (PD20). On the three other days, the active or placebo medications were administered. Spirometry was assessed 15 minutes and 1 hour later. The hyperventilation test was then performed and repeated at various time intervals after administering the drug. The mean duration of the blocking effect was 0.25 hour for placebo, 3.5 hours for albuterol, and of 15.9 hours for salmeterol. Eight of the 12 subjects still showed some blocking effect eight hours after salmeterol by comparison with only one subject after albuterol. The authors conclude that salmeterol has a significantly longer effect than albuterol on bronchoconstriction induced by hyperventilation.


[Usefulness of salmeterol in nocturnal asthma: a comparative study with theophylline-ketotifen association. A French multicenter group].

Ninety-six patients with nocturnal asthma (FEV1 = 60-90% pred, reversibility greater than or equal to 15%, at least 2 awakenings in the week preceding the trial) were included in a double-blind, randomized, crossover, multicenter study which compared the efficacy and side effects of inhaled salmeterol (50 micrograms morning and evening) to the association theophylline-ketotifen (300 mg and 1 mg morning and evening, respectively). The trial included a run-in period of 14 days and 2 periods of successive treatment of 28 days each. The efficacy was expressed in terms of therapeutic success, defined by the total disappearance of nocturnal symptoms during the treatment week. A statistically significant difference (p less than 0.01) was found between salmeterol and the association for this criteria: during the first period, 46% of subjects treated by salmeterol did not present nocturnal awakenings during the last treatment week by comparison with 15% of subjects taking the association; during the second period, corresponding figures were 39% for salmeterol by comparison with 26% for the association. Differences were also significant, favoring salmeterol, for other criteria (lung function tests, extra-need for salbutamol). Side effects were 5 times more frequent for the association (p less than 0.004). Salmeterol is clearly superior to the association theophylline-ketotifen in the treatment of nocturnal asthma.


[Prolonged effect against exercise-induced bronchospasm: salmeterol versus sodium cromoglycate].

Nineteen subjects with isolated exercise-induced asthma (FEV1, FEF25-75%, PEFR, FVC greater than 95% predicted values, fall in FEV1 of at least 15% after exercise, typical recent symptoms of exercise-induced asthma, no other treatment) were entered in a multicenter trial carried out in a double blind, double placebo, cross-over manner. After a one-month baseline period, subjects underwent an exercise after inhaling 100 micrograms of salmeterol (n = 12) or 40 mg of sodium cromoglycate (n = 7). Treatments were alternated before the second exercise which took place at least 2 days after the first. Efficacy was assessed by examining changes in FEV1, FEF25-75% after exercise carried out 30 minutes and 7 hours after administering the treatment by comparison with baseline values (assessments done 1, 10 and 30 minutes after exercise, lowest of three values kept for the analysis of each parameter). FEV1 and FEF25-75% were significantly higher 30 minutes after taking salmeterol. Salmeterol was found to be superior to sodium cromoglycate for all parameters 7 hours after administering the drug. Both treatments were well tolerated. This study confirms that the longer duration of effect of salmeterol and its superiority by comparison with the standard treatments of exercise-induced asthma.


[Can the management of patients with asthma be improved at present?].

The author suggests various means to improve the management of asthma through: 1) a multidisciplinary approach; 2) prevention which should include reduction of allergenic and offending exposure; 3) a better information and education of asthmatic patients; 4) a more objective therapeutic follow-up; 5) a "physical medicine". A therapeutic improvement is also needed through a better comprehension of asthma by the patient and the physician. Salmeterol is a promising medication because of its long bronchodilator and protective effect. A better knowledge to define its strategic use of this new drug is needed.


[Salmeterol: towards new perspectives in the treatment of asthma].

Asthma is now considered as an inflammatory condition and the purpose of the treatment is directed towards the control of inflammation. Recent therapeutic guidelines have been proposed and suggested the early use of antiinflammatory preparations. Salmeterol has a prolonged bronchodilator and protective effect against physical stimuli such as exercise and exposure to cold air. Clinical studies have all shown a superiority of salmeterol by comparison with salbutamol in the treatment of asthma. Recent in vitro and in vivo studies also suggest that salmeterol may have an extra non-bronchodilator effect. Salmeterol appears to be a safe preparation if administered at a dose of 50 to 100 micrograms on a BID regimen. It has been argued that the regular use of salmeterol can mask the worsening of bronchial inflammation although clinical studies have not substantiated this potential risk. Other studies are required to answer this question. A scheme incorporating salmeterol in the guidelines for the treatment of asthma is proposed.


[Pharmacological properties of salmeterol].

Salmeterol is an original molecule characterized by its long duration of action (greater than 12 hrs in humans). Salmeterol is a highly selective beta-2 agonist that is from 2 to 15 times more potent than salbutamol on beta-2 receptors of bronchial smooth muscle and 10,000 times more potent than isoprenaline on beta-1 receptors. The duration of action of salmeterol on bronchial smooth muscle has been shown to be much superior than all other beta-2 sympathomimetics that have been studied, including formoterol. Salmeterol has two side chains that are linked by a long hydroxycarbon chain. Its long duration of action could be explained by the link to the cell membrane through an exo-site which is distinct from the beta-2 receptor. In vitro and in the animal model, salmeterol has a triple effect: inhibition of the liberation of inflammatory mediators (histamine, prostaglandins, leukotrienes), inhibition of cell influx and of protein extravasation. The relevance of this effect remains to be establish in humans.


Glucagon mediates arginine-induced somatostatin secretion from isolated rat pancreatic islets.

Glucagon has been suggested to be a mediator of intra-islet paracrine effect of insulin and somatostatin during nutritive stimulation. The aim of this study was to reveal possible intra-islet interactions between insulin, somatostatin and glucagon in a batch stimulation model with isolated pancreatic islets. Such interactions may influence stimulus-secretion experiments in this experimental model. In our hands arginine stimulated somatostatin secretion only in the presence of insulin antiserum. Furthermore, arginine-induced glucagon secretion was greatly increased following addition of insulin antiserum. The addition of glucagon antiserum inhibited these effects of insulin antiserum on somatostatin secretion. In conclusion, glucagon apparently represents the central mediator of arginine effects on somatostatin secretion in isolated rat pancreatic islets in batch stimulation experiments.


Time-related decrease in diffusion capacity in HIV-infected patients with impaired immune function.

The purpose of this study was to investigate acute and time-related changes in lung function, i.e. forced expiratory volume in 1 second (FEV1), vital capacity (VC) and transfer factor (KCO) in HIV-infected patients with CD4 cell counts less than 400 x 10(6)/l. 66 males with no history of HIV-related pulmonary symptoms participated in a prospective lung function study for 9 months with 3-month intervals between examinations. 15/66 patients (23%) developed acute pulmonary symptoms, i.e. dyspnea (n = 12), cough (n = 13), fever greater than 38 degrees C (n = 13) and interstitial infiltrates on the X-ray (n = 9). Among the 51 asymptomatic patients, a significant time-related decrease in KCO (median decrease of 7%) was found, whereas no significant change in FEV1 or VC was observed during the study. Baseline KCO, i.e. KCO at entry, was found to be significantly higher in the asymptomatic patients (102% predicted (pred.) than in those patients who developed pneumonia (88% pred.). Development of pulmonary symptoms was both followed by a significant decrease in KCO (median decrease 17%), FEV1 and VC. We therefore conclude that HIV-infected patients with impaired immune function have in the absence of pulmonary symptoms a decrease in KCO. In case of pneumonia an acute decrease in both KCO, FEV1 and VC occurs.


[Biological markers of alcoholism].

Since most patients with an alcohol problem downplay their alcohol consumption, reliable tests for detection of alcohol abuse would be of value in clinical practice. Single determinations of common laboratory tests such as gamma-glutamyl transpeptidase, transaminases or mean corpuscular volume are only of limited reliability in detecting alcohol abuse. Most newer parameters, including the serum ASAT/ALAT ratio, the ratio of mitochondrial to total ASAT in serum, and serum levels of acetaldehyde-hemoglobin adducts or of antibodies against acetaldehyde adducts, still do not allow us to discriminate reliably enough between alcoholic and nonalcoholic liver diseases. beta-hexosaminidase activity and desialylated transferrin levels in serum appear to be the most promising tests for detecting alcohol abuse in the future. They require, however, additional validation and technical simplification respectively before they are suitable for daily clinical use. Thus, it remains valid that no single test can replace a careful history, clinical examination and laboratory results in detecting patients with alcohol problems.


Somatostatin receptor imaging of endocrine gastrointestinal tumors.

Somatostatin receptors are present on various tumors of neuroendocrine origin. We recently developed a technique for the in vivo visualization of somatostatin receptor positive tumors, which offers a powerful alternative to tumor imaging with labeled monoclonal antibodies. Instead of injecting radiolabeled antibodies against the somatostatin receptor, we labeled a somatostatin analogue ([Tyr3]-octreotide) which is known to bind specifically to the somatostatin receptor, and injected this labeled hormone analogue in order to visualize somatostatin receptor positive tumors. We previously reported the successful visualization of the primary tumors or metastases of various endocrine gastrointestinal tumors after injection of the iodinated somatostatin analogue [123I-Tyr3]-octreotide. The primary tumors or metastases of 12 out of 13 carcinoids, 3 out of 3 gastrinomas, 2 out of 4 insulinomas, and 1 out of 1 somatostatinoma were visualized. Using 111In-coupled octreotide, we were able to visualize 19 out of 19 carcinoids, 7 out of 7 gastrinomas, 4 out of 7 insulinomas, 1 out of 1 glucagonoma, and 3 out of 3 non-functioning endocrine pancreatic tumors, but none of 18 exocrine pancreatic tumors. In a large proportion of patients with endocrine gastrointestinal tumors, previously unrecognized metastases were demonstrated. Also, the absence or presence of in vivo visualization of these tumors after the injection of radiolabeled octreotide seems to predict the ability of octreotide therapy to control symptoms caused by hormonal secretion from these tumors. 111In-octreotide scintigraphy is a simple and sensitive technique for localizing of the primary tumor and its metastases in the majority of patients with carcinoids or endocrine pancreatic tumors.(ABSTRACT TRUNCATED AT 250 WORDS)


[Acral vasospasm in Crohn's disease].

55 patients with Crohn's disease and 55 sex- and age-matched healthy controls were studied by nailfold capillary microscopy for evidence of microcirculatory abnormalities. Digital capillary blood flow measurements in combination with a local cooling test were assessed by videocapillaroscopy using the flying-sport technique. We found a blood flow stop with cold exposure in 44 of the 55 patients with Crohn's disease (mean duration 39 seconds) but in 5 of the 55 control subjects only (mean duration 19 seconds). There was no significant difference in skin temperature between the two groups. Intravital microscopy of nailfold capillaries revealed a marked reduction in capillary density (p less than 0.001) compared to normal subjects. The association of vasoconstrictive reaction in finger microcirculation of patients with Crohn's disease suggests a vasospastic tendency in this disorder.


Recovery from experimental parkinsonism in primates with GM1 ganglioside treatment.

A parkinsonian syndrome can be produced in nonhuman primates by administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Parkinsonian-like symptoms induced acutely by MPTP were ameliorated after treatment with GM1 ganglioside, a substance shown to have neurotrophic effects on the damaged dopamine system in rodents. Treatment with GM1 ganglioside also increased striatal dopamine and metabolite levels and enhanced the dopaminergic innervation of the striatum as demonstrated by tyrosine hydroxylase immunohistochemistry. These results suggest that GM1 ganglioside may hold promise as a therapeutic agent for the treatment of Parkinson's disease.


Identification of heregulin, a specific activator of p185erbB2.

The proto-oncogene designated erbB2 or HER2 encodes a 185-kilodalton transmembrane tyrosine kinase (p185erbB2), whose overexpression has been correlated with a poor prognosis in several human malignancies. A 45-kilodalton protein heregulin-alpha (HRG-alpha) that specifically induced phosphorylation of p185erbB2 was purified from the conditioned medium of a human breast tumor cell line. Several complementary DNA clones encoding related HRGs were identified, all of which are similar to proteins in the epidermal growth factor family. Scatchard analysis of the binding of recombinant HRG to a breast tumor cell line expressing p185erbB2 showed a single high affinity binding site [dissociation constant (Kd) = 105 +/- 15 picomolar]. Heregulin transcripts were identified in several normal tissues and cancer cell lines. The HRGs may represent the natural ligands for p185erbB2.


G protein activation of a hormone-stimulated phosphatase in human tumor cells.

The growth-inhibiting peptide hormone somatostatin stimulates phosphotyrosine phosphatase activity in the human pancreatic cell line MIA PaCa-2. This hormonal activation was mediated by a pertussis toxin-sensitive guanosine 5'-triphosphate-binding protein (G protein) in the membranes of these cells. Activation of this G protein by somatostatin stimulated the dephosphorylation of exogenous epidermal growth factor receptor prepared from A-431 cells in vitro. This pathway may mediate the antineoplastic action of somatostatin in these cells and in human tumors and could represent a general mechanism of G protein coupling that is utilized by normal cells in the hormonal control of cell growth.


Heteromeric NMDA receptors: molecular and functional distinction of subtypes.

The N-methyl D-aspartate (NMDA) receptor subtype of glutamate-gated ion channels possesses high calcium permeability and unique voltage-dependent sensitivity to magnesium and is modulated by glycine. Molecular cloning identified three complementary DNA species of rat brain, encoding NMDA receptor subunits NMDAR2A (NR2A), NR2B, and NR2C, which are 55 to 70% identical in sequence. These are structurally related, with less than 20% sequence identity, to other excitatory amino acid receptor subunits, including the NMDA receptor subunit NMDAR1 (NR1). Upon expression in cultured cells, the new subunits yielded prominent, typical glutamate- and NMDA-activated currents only when they were in heteromeric configurations with NR1. NR1-NR2A and NR1-NR2C channels differed in gating behavior and magnesium sensitivity. Such heteromeric NMDA receptor subtypes may exist in neurons, since NR1 messenger RNA is synthesized throughout the mature rat brain, while NR2 messenger RNA show a differential distribution.


Biliary laser lithotripsy.

Laser lithotripsy is an excellent method of fragmenting those biliary stones that cannot be removed easily by less technically advanced methods such as basket extraction. The energy can be delivered through fine flexible fibers, around 200 to 320 microns in diameter, that can be passed through the channels of a variety of small endoscopes. Currently, the optimal laser seems to a pulsed system because of the conversion of light to acoustic energy with minimal heating of the surrounding tissues, thus avoiding the chance of tissue injury and perforation. The best wavelength seems to be 504 nm, because at this wavelength, there is maximum absorption of laser energy by pigment stones, resulting in fragmentation using low-energy pulses. With further research, optimal wavelengths and pulse durations may emerge.


Postnatal development of T-lymphocyte subpopulations in the intestinal intraepithelium and lamina propria in chickens.

Postnatal development of various T-lymphocyte subpopulations expressing CD3, CD8, CD4, and antigen-specific TCR heterodimers alpha beta (TCR2) or gamma delta (TCR1) was investigated in two different inbred chicken strains, SC and TK. The ratios of jejunum T-cells expressing TCR1 to TCR2 in the intraepithelium of SC and TK strains gradually increased after hatching and were 3.40 and 4.28 by 12 weeks in TK and SC chickens respectively. The ratios of TCR1+ to TCR2(+)-cells in intraepithelium and the lamina propria in SC chickens were 0.96 and 1.23 at 8 weeks and 4.29 and 2.15 at 12 weeks, respectively. Jejunum intraepithelial lymphocytes expressing the CD8 antigen increased gradually until 4-6 weeks of age and subsequently declined as chickens aged. CD4(+)-cells represented a minor subpopulation among the intestinal lymphocyte subpopulations. Therefore, the composition of various T-cell subpopulations in the intestine depended upon host age, the regions of the gut examined and host genetic background. These results suggest that changes in T-cell subpopulations in the intestine may reflect age-related maturation of the gut-associated lymphoid tissues.


Cutaneous innervation in chronic renal failure patients. An immunohistochemical study.

Most chronic renal failure patients suffer from generalized pruritus. An involvement of cutaneous nerve terminals in the pathogenesis of uremic pruritus has been suggested. Skin specimens from 24 uremic patients and 10 healthy subjects were processed with an indirect immunofluorescence method to investigate the presence and distribution of a number of neuronal markers and neuropeptides. No difference was found between the two groups in the distribution pattern of the positive nerve fibres. However, a reduction in the total number of skin nerve terminals in the uremic patients was detected. No correlation could be found between the immunohistochemical findings and the clinical features. Our results suggest that the skin innervation is altered in most chronic renal failure patients, possibly as a consequence of neuropathy.


Cholinergic and adrenergic sweating in atopic dermatitis.

Sweating responses to methacholine and adrenaline were compared with an evaporimeter in normal-looking back and forearm skin from patients with atopic dermatitis (AD) and from non-atopic controls (NA). With both stimulants, the sweat rates were higher in forearm than in back skin in both groups, and between the two sites the rates showed positive correlations which were statistically significant in both groups. With methacholine the responses were slightly depressed in both areas in AD. With a low suprathreshold adrenaline concentration (5 x 10(-6) mol/l) the responses were equal in both groups but a tenfold higher adrenaline concentration elicited an increase of 55% in sweating rates in the back skin of NA and a 15% depression in the back skin of AD subjects (p less than 0.05). On arm skin there was a similar trend, but less marked. Between the cholinergic and adrenergic sweating responses a positive correlation was found on arm skin in AD, suggesting that the unknown mechanism of sweat depression in AD might be the same for both drugs.


Completion pancreatectomy following pancreaticoduodenectomy: clinical experience.

While pancreaticoduodenectomy is today performed with an operative mortality of less than 5%, the incidence of significant operative morbidity remains at least 25%. Albeit rarely, completion pancreatectomy during the early postoperative period may be required to manage uncontrolled pancreatic anastomotic leaks. From 1964 to 1988, pancreaticoduodenectomy was performed on 479 patients at our institution, 178 (37%) of whom required re-operation in the early postoperative period. Of these, 11 (6%) patients underwent completion pancreatectomy at a mean interval of 18 days following Whipple resection. The indications prompting re-operation included a suspected pancreatic leak (n = 8), intraabdominal hemorrhage (n = 2), and pancreaticocutaneous fistula (n = 1). Operative findings necessitating completion pancreatectomy included pancreatic anastomotic dehiscence with severe surrounding inflammation/necrosis prohibiting reanastomosis or repair (n = 10) and necrotizing pancreatitis with uncontrolled hemorrhage (1). Seven (64%) of these 11 patients died postoperatively of sepsis and multiple organ failure. The mean hospital stay in the 4 surviving patients was 46 days (range, 26 to 53 days). These 4 patients survived for a mean period of 24 months following hospital dismissal.


Impairment of some granulocyte functions in Sweet's syndrome.

Chemotaxis, phagocytic and intracellular killing activities of polymorphonuclear leukocytes (PMNL) were investigated in vitro in 7 patients suffering from the acute phase of Sweet's syndrome. A moderate but consistent impairment of neutrophilic chemotactic activity (NCA) was revealed in all patients. Intracellular killing of blastospores of Candida albicans was diminished in 5/7 patients. Phagocytosis and oxidase activities were within normal levels. These results point to an alteration of some PMNL functions in the acute phase of Sweet's syndrome.


Evaluation of thyroid function and anti-thyroid autoantibodies in systemic sclerosis.

Parameters of thyroid metabolism, and the presence of anti-thyroid antibodies were investigated in 43 patients with systemic sclerosis. Anti-thyroid antibodies were detected in 14 cases. Elevated levels of anti-thyroglobulin antibodies were determined in 4 cases, anti-thyroid peroxidase (TPO) antibodies in 11, and anti-microsomal antibodies in 5. The detection of anti-TPO antibodies gave the most remarkable information about the presence of autoimmune thyroiditis. The patients with anti-TPO and/or reduced T3 concentration tended to have secondary Sjögren's syndrome. Our results provide further evidence that anti-thyroid antibodies might be responsible for the remarkable appearance of autoimmune thyroiditis in systemic sclerosis.


Skin cancer after renal transplantation: the causal role of azathioprine.

In 167 unselected patients with renal allografts, after a lag of 3.5 years the prevalence of dysplastic keratotic lesions increased linearly by 6.8%/yr and number of lesions also increased. There was no relationship to sun exposure or skin type. Malignancies occurred in 5 patients after 9 years. Viral warts occurred in 42% but prevalence and extent were not related to time after transplantation or keratoses. Comparison with other drugs and diseases suggests malignant keratoses are initiated in two stages by the cytotoxic effect of azathioprine, the role of immunosuppression remaining unproved. Psoriasis and eczema remitted and the prevalence of zoster and fungal disease increased. P. orbiculare (but not P. ovale) infection increased, unlike in other states of immunosuppression, suggesting the organisms are distinct, not transitional, and differently influenced by the different immunodeficient states induced by drugs and disease.


Indication for the identity of palmoplantar keratoderma type Unna-Thost with type Vörner. Thost's family revisited 110 years later.

Palmoplantar keratoderma (PPK) type Unna-Thost is known to be the most common form of a hereditary disorder of keratinization of palms and soles. The disease is clinically identical with PPK type Vörner which is histologically characterized by epidermolytic hyperkeratosis. By reinvestigation of the family originally seen by Thost in 1880, the features of epidermolytic hyperkeratosis were found histologically confirming the diagnosis PPK of Vörner. This proves the identity of PPK type Thost with PPK of Vörner. Because of the histological variability of epidermolytic hyperkeratosis, detailed light and electron microscopic studies are necessary in cases of diffuse types of PPK.


Regional distribution of melanocytic naevi in relation to sun exposure, and site-specific counts predicting total number of naevi.

The role of exposure to ultraviolet light in the formation of melanocytic naevi was analysed by investigating the regional naevus distribution in 310 subjects (30-50 years) from a Swedish census file. The lateral aspect of the arms and the back had the largest concentration of naevi. The mean naevus count per unit surface area was higher in intermittently exposed than in rarely exposed skin (p less than 0.001), while the lowest mean count was found in chronically exposed skin. These results support the idea that intermittent exposure to ultraviolet light has a "naevogenic" effect while chronic exposure might be protective. Dysplastic naevi had a distribution pattern quite different from common naevi. Considering the distribution pattern solely, dysplastic naevi seem to develop independently of exposure to ultraviolet light. The numbers of naevi in different skin areas were tested for their power in predicting the total body naevus count. The strongest correlations were found between total counts and counts on the anterior surface of the thighs and the lateral aspect of the arms. Counts from any of these areas will provide a practical and satisfactory estimate of the total number of naevi.


Group G streptococcal infections on a dermatological ward.

Groups A, B, C and G streptococci were cultured from 63 consecutive in-patients recruited between November 1987 and April 1988 and monitored until the end of July 1988. Chronic leg ulcers were present in 34 patients. Group G was found in 34 patients, 25 of whom had pyoderma and 3 had sepsis. Six of the patients had no signs of clinical infection, and treatment with antibiotics was therefore withheld. Recurrent phlegmon or erysipelas developed in 2 of 28 patients with clinical Group G infections. Erysipelas developed some 1-7 months later in 3 of the 6 patients who were not initially treated. No significant difference in severity or additional medical conditions was found between the patients with either Group G or Group A streptococci. In comparison, data on all streptococcal cultures at the Department indicated that Group G was isolated 2.6 times as often as Group A streptococci for the in-patients, compared with 1.1 for all patients seen. It is concluded that Group G streptococcal skin infections must be regarded with the same clinical vigilance as Group A infections.


The unexpectedly rapid response of fungal nail infection to short duration therapy.

To test our hypothesis that, by laying down a fungicidal barrier in the growing nail, a short course of antifungal therapy should be effective against onychomycosis, we treated 8 subjects with Trichophyton rubrum nail infection with terbinafine 125 mg b.d. for 14 days. All but one patient showed marked improvement, and 80% of fingernails and 37% of toenails were clinically cured after 6 months. Although this confirmed our prediction, the onset of response measured by outward movement of affected nail and negative cultures from distal nail clippings occurred after as little as 4 weeks. This was too soon for a fungicidal barrier to have grown out and indicates that the drug must have been carried directly into the diseased distal nail, presumably from newly formed ventral nail beneath it. The findings show that 1) short duration therapy, perhaps even a single dose, is possible in fungal nail infections; 2) the ventral nail provides unexpectedly rapid access of drugs to the site of distal disease.


A double-blind study of superficial radiotherapy in psoriatic nail dystrophy.

In a double-blind controlled study, superficial radiotherapy (SRT) was given to psoriatic fingernails as three fractionated doses of 150 cGy (90 kV, 5 mA, 1.00 mm aluminium filter). The treated nails demonstrated a significant fall in scoring on a clinical rating scale 10 and 15 weeks after therapy (mean scores = 4.4 and 4.6 respectively) when compared with a mean pretreatment score of 5.5 at week 0 (p less than 0.0001 and p less than 0.05 respectively); the treated nails also showed significant clinical improvement when compared with the sham-treated nails at weeks 10 and 15 (p less than 0.05). Mean nail thickness in treated nails 15 weeks after therapy was significantly thinner (mean thickness = 0.75 mm) than that of sham-treated nails (0.88 mm, p = 0.005), but the difference was not significant at week 20. The rate of linear nail growth was unaffected. SRT appears to confer a definite albeit temporary benefit on psoriasis of the nails at this dosage.


Mucosal desquamation in psoriasis.

Urinary epithelial cell counts were determined in 102 patients with active plaque psoriasis. Cell counts were significantly higher in psoriatic patients than in the controls. A significant fall in the cell counts was observed after regression of psoriasis.


Lysozyme and IgA concentrations in serum and saliva from psoriatic patients.

Significantly lower lysozyme concentrations were found in saliva of 15 psoriatic patients compared with controls, whereas in serum, lysozyme activity, was significantly higher than in controls. The concentrations of IgA in serum of psoriatic patients were significantly higher than in controls, whereas in patients' saliva IgA concentrations were not significantly different from the controls. The findings indicate that lysozyme and IgA may be of significance in the pathophysiology of psoriasis.


The hair root pattern in psoriasis of the scalp.

Several reports suggest that a localized effluvium of scalp hair may occur in patients with psoriasis. The percentages of telogen and catagen hair have been claimed to be normal or increased in isolated cases. In the present study the anagen/telogen ratio was quantified under standardized conditions in psoriatic plaques and uninvolved areas of the scalp in 22 patients and the scalp of 22 normal controls. This assessment was carried out by light microscopic analysis of hair roots, obtained by the hair pluck-method. A consistent increase in the percentages of telogen and catagen hair was shown in psoriatic plaques, compared with the uninvolved areas. Compared with the scalp of normal controls, this percentage was significantly increased in psoriatic plaques, but not in the uninvolved areas.


Folliculitis decalvans. Long-lasting response to combined therapy with fusidic acid and zinc.

In 3 patients, the diagnosis of folliculitis decalvans was based on clinical, histopathological and laboratory criteria. All patients responded to a combination therapy consisting of oral and topical fusidic acid and oral zinc sulphate. The follow-up period exceeded more than one year.


Eosinophilic pustular folliculitis (Ofuji's disease) and non-Hodgkin lymphoma.

The authors report the third case of eosinophilic pustular folliculitis (EPF) associated with a non-Hodgkin lymphoma. The dermatosis occurred after an autologous bone marrow transplantation performed as treatment for the lymphoproliferative disorder. Although EPF was initially described as an idiopathic disease, the association of some cases with immunologic alterations or diseases, such as immunodeficiencies, suggests a possible immunopathologic event in the pathogenesis of EPF.


Acne in pubertal boys undergoing treatment with androgens.

In the present study, the development of acne lesions was studied in boys deemed to be too tall, for which they were treated with injections of androgens. In a retrospective and a prospective group of pubertal boys, an increased incidence of acne was observed as a consequence of treatment with androgens.


A double-blind comparison of acitretin and etretinate in the treatment of Darier's disease.

The objective of this double-blind study was to compare the therapeutic effects of acitretin with those of etretinate in patients with Darier's disease. Twenty-six patients (10 males and 16 females) were included in the study. Patients were treated with 30 mg daily for the first 4 weeks and with an individually adjusted dose (10-50 mg/day) for the subsequent 12 weeks. Remission or marked improvement was obtained in 10 of the 13 acitretin-treated patients and in 8 of the 11 etretinate-treated patients who completed the 16-week treatment. The usual mucocutaneous adverse reactions of retinoids were observed in all but one patient. There were no significant differences between treatment groups with regard to the incidence of these reactions.


Correlation between cutaneous sarcoidosis and systemic sarcoidosis.

Twenty patients with cutaneous sarcoidosis and 21 patients carrying isolated skin sarcoids were studied. (We use the term 'sarcoid' to emphasize that exclusively skin was altered.) Both groups were compared by clinical and histological patterns and certain data concerning the state of the mononuclear phagocyte system (MPS). It was found that skin lesions in sarcoids and sarcoidosis do not differ regarding either in clinical or histological manifestations. The changes in the functional activity of monocytes and macrophages were the same. The data obtained allow us to suggest that sarcoids should be regarded as a systemic disease connected with changes in the MPS reaction.


Linear alopecia mucinosa along Blaschko lines.

We present a case of linear reversible non-inflammatory alopecia mucinosa in a 25-year-old Nigerian patient. The patient exhibited an arciform bald patch on the scalp and follicular mucinosis in both lesions. The possible relationships between the unusual linear arrangement of alopecia mucinosa along Blaschko's lines and lichen striatus are discussed.


Parathyroid hormone related protein is localized in the granular layer of normal skin and in the dermal infiltrates of mycosis fungoides but is absent in psoriatic lesions.

Biopsies of normal and diseased skin were immunohistochemically investigated for the presence of parathyroid hormone-related protein (PTH-rp). In normal skin and several skin disorders a monoclonal antibody against the 34-68 sequence of PTH-rp was found to be exclusively located in the granular layer. PTH-rp could not be detected in untreated psoriatic plaque lesions even when a granular layer was present. Psoriatic lesions improving after 1-2 weeks' treatment with betamethasone or vitamin D3 analogue revealed PTH-rp reactivity just above the granular layer. These findings substantiate a possible role for PTH-rp as a growth inhibitor. In the dermis the granular layer in the upper part of the hair follicles was stained for PTH-rp and the dermal infiltrates in 5 of 10 patients were stained with mycosis fungoides.


Oral acitretin in psoriasis: drug and vitamin A concentrations in plasma, skin and adipose tissue.

The purpose of the present study was to determine the concentrations of acitretin and its main metabolite, 13-cis acitretin, in epidermis, subcutis and plasma in twelve psoriatic patients treated with 30 mg acitretin orally daily for 6 months. In addition, endogenous concentrations of vitamin A were monitored. Blood samples and biopsies from normal appearing skin were obtained prior to therapy, after 1 and 6 months of treatment and finally 1 month after cessation of therapy. Using a highly sensitive liquid chromatography method concentrations of synthetic retinoids and endogenous retinoid (retinol, 3,4-didehydroretinol) were analysed in hydrolyzed tissue samples and plasma. Steady-state concentration of acitretin in epidermis (17 +/- 9 ng/g) was reached within 1 month of therapy. There was a significant correlation between the individual plasma trough value and the epidermal concentration of acitretin after 1 month of therapy. The acitretin concentrations in subcutis varied from 15 to 1437 ng/g, but the mean values at 1 and 6 months of therapy were similar (177 and 227 ng/g, respectively). After stopping therapy the acitretin level was below the detection limit in both epidermis and serum within 1 month in 9 out of 12 patients. In contrast, only 3 of the patients were negative for acitretin in subcutis biopsies obtained 1 month after stopping therapy. The occurrence of a presumed tissue contaminator with characteristics similar to 13-cis acitretin prevented quantitation of this metabolite in many subcutis samples. The epidermal, subcutis and serum composition of retinol and 3,4-didehydroretinol remained unchanged during therapy, indicating no or only minimal interaction between acitretin and endogenous vitamin A metabolism.


Suction blister fluid histamine in fixed drug eruption.

The histamine concentration was measured from suction blister fluid obtained from normal and lesional skin of 8 patients with fixed drug eruption (FDE) caused by phenazone salicylate and from that of 2 healthy control subjects. In blister fluid samples obtained before peroral challenge with phenazone salicylate, the histamine concentrations were below 5 nmol/l both in uninvolved skin and in sites of previous FDE lesion (sample 0). After challenge, samples were taken from the incipient reaction that was visible after an average of 155 min. Histamine levels were significantly elevated in the blister fluid of 2 out of 8 FDE lesions (200 and 640 nmol/l) but in none of the uninvolved skin (sample 1). Two hours later (sample 2) the histamine levels were elevated in both uninvolved (mean 51.4 nmol/l) and lesional skin (mean 168 nmol/l). After 24 h (sample 3) the corresponding mean value was 25.4 nmol/l for uninvolved skin and 108 nmol/l for lesional skin. The histamine values in the blister fluid from FDE lesions in samples 2 and 3 were significantly higher (p less than 0.05) than those in the control blisters of uninvolved skin. An elevation of histamine levels comparable to that in the uninvolved skin of FDE patients was seen in the 2 healthy control subjects studied. The present study provides direct evidence of early release of histamine from mast cells or basophils in FDE and suggests that histamine is one of the mediators of clinical symptoms of FDE.


Cross-reactivity to palladium and nickel studied in the guinea pig.

In recent years there have been several reports on concomitant patch test reactions to palladium and nickel, which belong to the same group in the periodic table. Exposure to palladium mainly takes place via dental alloys and jewelry. However, the clinical relevance of simultaneous reactivity to these metals is unknown. To elucidate the question of cross-reactivity, guinea pigs were induced with palladium or nickel and simultaneously challenged with palladium and nickel. Animals sensitized to palladium according to the guinea pig maximization test method (GPMT) or to a new method by van Hoogstraten & Scheper (H&S) reacted to palladium as well as to nickel. On the other hand, animals sensitized to nickel according to H&S reacted to nickel but not to palladium. The GPMT shows that palladium is a more potent sensitizer than nickel: could palladium be the primary sensitizer in humans?


Simple system to irradiate cultured cells with UVA light.

We developed a simple system for the irradiation of cultured cells with ultraviolet-A (UVA) light, and used it to study the colony-forming ability of fibroblasts in culture after UVA treatment. The system requires an ordinary clean bench, and the other materials and devices needed, such as dishes with a 35-mm diameter, plate glass, and 15-W UVA lamps, are easy to obtain and assemble. Neither stirring nor cooling of cells is required, because the fan of the clean bench acts as a cooler, and cells are irradiated from the bottom after they have settled in the dish. The UVA light incident on cells after its passage through both the plate glass and the bottom part of the dish contains so little of UVB wavelengths that cell killing by pyrimidine dimers was negligible.


[Statistical study of a series of cryptorchism cases].

A study was made on a series of 348 patients with uni- and bilateral cryptorchid, a right location being predominant in the former cases, and in the canaliculus the most common testicular one. The associated pathology is usually irrelevant. In view of the results revealed by optical and ultrastructural histological study, the introduction of definitive corrective medical treatment appears to be essential within 2 years. Despite existing discrepancies with regard to dosage and efficacy of hormonal therapy with HCG or LH-RH analogues we believe they should be used at doses no higher than 12000 IU of HCG in order to achieve a decrease or ease the surgical treatment. Higher doses would damage the testicle or produce early puberty with growth failure. Scrotum-bound funiculolysis is the procedure accomplishing a larger amount of therapeutic success and in our experience the results are conditioned to the testicle's anatomic location. In the event of abdominal testicles or with high canaliculus location, a section of the spermatic canals could be performed followed later by auto-transplantations using microsurgery procedures.


Thermogenesis and fructose metabolism in humans.

Resting metabolic rate was measured in 10 healthy volunteers (25 yr, 73 kg, 182 cm) for 1 h before and 4 h during intravenous (iv) fructose administration (20% at 50 mumol.kg-1.min-1) with (+P) or without (-P) propranolol (100 micrograms/kg, 1 microgram.kg-1.min-1) during the last 2 h. Some subjects were studied a further 2 h with fructose infusion and +P or -P in hyperinsulinemic (2.9 pmol.kg-1.min-1) euglycemic conditions. Glucose turnover ([3-3H]glucose, 20 muCi bolus and 0.2 muCi/min) was calculated over 30 min at 0, 2, 4, and 6 h. The thermic effect of iv fructose was approximately 7.5% and decreased to 4.9 +/- 0.4% (P less than 0.01) +P. During the euglycemic clamp the thermic effect was 6.2 +/- 0.9% (-P) and 5.3 +/- 0.9% (+P). Hepatic glucose production (HGP) was 11.7 mumol.kg-1.min-1 (0 h) and did not change after 2 h iv fructose (11.8 +/- 0.5 and 9.8 +/- 0.6 mumol.kg-1.min-1 -P and +P, respectively) but increased to 13.8 +/- 0.9 (-P) and 12.9 +/- 0.8 mumol.kg-1.min-1 (+P) (P less than 0.01) after 4 h. HGP was suppressed to varying degrees during the euglycemic clamp. It is concluded that 1) the greater thermic effect of fructose compared with glucose is probably due to continued gluconeogenesis (which is suppressed by glucose or glucose-insulin) and the energy cost of fructose metabolism to glucose in the liver. 2) There is a sympathetically mediated component to the thermic effect of fructose (approximately 30%) that is not mediated by elevated plasma insulin concentrations similar to those observed with iv glucose.


Role of transglutaminase and protein cross-linking in the repair of mucosal stress erosions.

We have recently demonstrated that polyamines are absolutely required for gastric and duodenal mucosal repair after stress. Polyamines act as substrates for transglutaminase and facilitate protein cross-linking. The current study tests whether transglutaminase and protein cross-linking are involved in the mechanism of mucosal healing. Rats were fasted 22 h, placed in restraint cages, and immersed in water to the xiphoid process for 6 h. Animals were killed immediately or 4, 12, or 24 h after stress. Gastric and duodenal mucosa were examined histologically and grossly, and transglutaminase activity was measured. Transglutaminase activity in gastric and duodenal mucosa was increased significantly from 0 to 8 h, peaking 4 h after the 6-h stress period. By 12 h, enzyme activity in duodenal mucosa had returned to control values while gastric mucosal transglutaminase did not decrease to control values until 24 h. Mucosal recovery from lesions produced by stress was evident 12 h after stress and was almost complete by 24 h. Dansylcadaverine (100 mg/kg, orally), a specific inhibitor of protein cross-linking, not only prevented the increases in transglutaminase but significantly decreased healing in both tissues. Oral administration of the polyamine spermidine (100 mg/kg) immediately after stress totally prevented inhibition of repair caused by blocking ornithine decarboxylase with difluoromethylornithine (DFMO, 500 mg/kg). Administration of dansylcadaverine, together with spermidine, significantly prevented the beneficial effect of spermidine on mucosal healing in the DFMO-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)


Granulocyte accumulation in postischemic intestine: role of leukocyte adhesion glycoprotein CD11/CD18.

Neutrophils play an important role in ischemia-reperfusion (I/R)-induced vascular injury in the small intestine. Monoclonal antibodies against the leukocyte adhesion glycoprotein CD11/CD18 afford protection against I/R-induced microvascular injury. It has been suggested that the response to I/R differs between the various layers of the bowel wall, with relatively few granulocytes accumulating in the mucosa compared with the serosa or mesentery. The objectives of this study were to determine whether I/R-induced neutrophil accumulation is 1) homogenous in the different layers of intestine (mucosa, submucosa, muscle, and mesentery) and 2) dependent on the expression and/or activation of the leukocyte adhesion glycoprotein CD11/CD18. Neutrophil infiltration was monitored by measuring myeloperoxidase activity in mucosa, submucosa, muscle, and mesentery of cat small intestine subjected to 3 h ischemia (blood flow reduced to 20% of control) and reperfusion. I/R elicited a comparable degree of polymorphonuclear (PMN) infiltration in mucosa, submucosa, and mesentery, with the muscularis exhibiting a greater response. Pretreatment with the CD18-specific monoclonal antibody (IB4) significantly attenuated the I/R-induced PMN accumulation in all layers of the bowel wall and mesentery, indicating that the granulocyte accumulation elicited by I/R is dependent on the expression and/or activation of the leukocyte adhesion molecule CD11/CD18.


Effects of histamine on guinea pig nasal mucosal secretion.

A guinea pig model of nasal secretory responses was developed to assess the contributions of vascular permeability and glandular secretion in the production of nasal secretions. The secretory responses to saline, histamine, chlorpheniramine (H1-antagonist), cimetidine (H2 antagonist), and atropine (muscarinic antagonist) on ipsilateral and contralateral (reflex) secretory responses were analyzed by measurement of total protein (Lowry method), 125I-labeled bovine serum albumin (125I-BSA; administered intravenously) and guinea pig albumin (measured by enzyme-linked immunoabsorbent assay) in nasal secretions. Significant, dose-dependent secretion of total protein, 125I-BSA, and albumin occurred after histamine provocation on the ipsilateral challenged nostril and at several doses on the contralateral (unchallenged) nostril. Histamine-induced total protein and albumin secretion were blocked by chlorpheniramine but not cimetidine. Atropine pretreatment partially reduced total protein secretion. Guinea pig albumin immunoreactive material was detected by immunohistochemistry in superficial vessels, interstitial areas, the epithelium, between glandular cells of submucosal glands, and in gland lumens. Approximately 10% of submucosal gland cells contained albumin immunoreactive material in their cytoplasm. Autoradiography demonstrated that intravenously injected 125I-BSA moved quickly into extracellular areas and then to the epithelium and glands. These observations suggest that histamine stimulates vascular permeability, glandular secretion, and sensory nerve stimulation and that the ipsilateral and contralateral glandular secretion was at least partly due to an atropine-inhibitable cholinergic reflex.


Exogenous glutathione protects endothelial cells from menadione toxicity.

Administration of menadione (vitamin K3; 2-methyl-1,4-naphthoquinone) to cultured bovine pulmonary artery endothelial cells caused a dose- and time-dependent depletion of cellular ATP and depletion of intracellular glutathione (GSH). The toxicity of menadione was correlated with an increase of menadione-glutathione conjugate in the medium and with an increase in H2O2 generation. Recent studies have suggested that GSH may be useful as a pharmacological agent to prevent oxidant injury. In the present study, treatment with exogenous GSH prevented the loss of cellular GSH and ATP caused by menadione. Protection by extracellular GSH involved two mechanisms. In one mechanism, extracellular GSH was degraded by gamma-glutamyl transpeptidase, producing substrates for subsequent intracellular de novo GSH synthesis. We found that the protective effect of extracellular GSH was decreased by inhibiting gamma-glutamyl transpeptidase. In the other mechanism, GSH reacted in the medium with menadione to form a conjugate. Although formation of the menadione-glutathione conjugate within cells may contribute to menadione toxicity, addition of menadione-glutathione conjugate to the medium was found to be nontoxic to endothelial cells. Thus exogenous GSH protected endothelial cells by two mechanisms: maintenance of intracellular GSH and prevention of menadione entrance into cells.


Burn-induced alterations in cardiac beta-adrenergic receptors.

Previous studies in our laboratory have demonstrated that burn injury (45% total body surface area, 3rd-degree scald burn) diminishes contractile and relaxation function in the isolated perfused guinea pig heart. The mechanisms responsible for the burn-mediated dysfunction are not well understood. Therefore the purpose of this study was to examine the inotropic response to isoproterenol, a beta-adrenergic agonist, and burn-induced alterations in beta-adrenergic receptors (beta-AR) in adult guinea pig hearts. Isoproterenol dose-response curves were generated in isolated perfused hearts from sham-burned and burned guinea pigs. In addition, binding studies were performed using [125I]iodocyanopindolol on hearts from sham-burned and burned guinea pigs. Both the functional response and sensitivity to isoproterenol were significantly diminished 24 h after burn injury. beta-AR density (binding capacity, Bmax) and affinity were determined by Scatchard analysis. Agonist competition curves were performed in the presence or absence of 0.1 mM 5'-guanylyl imidodiphosphate. There was no difference in Bmax in membranes from sham-burned and burned hearts; however, the affinity of beta-AR was significantly decreased after burn injury compared with sham burn [dissociation constant = 32.5 +/- 1.9 (mean +/- SE), n = 10, vs. 26.7 +/- 1.7 pM, n = 10, P = 0.039]. Furthermore, the fraction of receptors in a high-affinity state (those functionally coupled to Gs protein) was significantly decreased after burn injury compared with sham burn (41.2 +/- 4.7%, n = 9, vs. 54 +/- 2%, n = 9, P = 0.023).(ABSTRACT TRUNCATED AT 250 WORDS)


Neurogenic vasodilator control of rabbit ear blood flow.

Ear blood flow subserves thermoregulation in the rabbit. The purpose of this study was to determine if the increase in rabbit ear blood flow, in response to increases in internal temperature (Ti) of approximately 2 degrees C (38.0-40.0 degrees C), is due to an active vasodilation or a withdrawal of adrenergic vasoconstrictor activity. New Zealand White rabbits were chronically instrumented with a pulse Doppler flow probe on the central ear artery of the left and right ear for the measurement of ear blood flow velocity (EBF, kHz). Catheters were also positioned in one occipital artery for selective administration of an alpha 1-adrenergic antagonist to one ear, while the contralateral ear served as a control. During hyperthermia (H) (increase in rectal temperature) alpha 1-adrenergic blockade had no effect on the maximum EBF (5.95 +/- 0.87 before vs. 6.11 +/- 1.04 kHz after). However, alpha 1-adrenergic blockade increased resting EBF during normothermia from 0.18 +/- 0.04 to 1.23 +/- 0.27 kHz (P less than 0.05), suggesting that a decrease in alpha 1-adrenergic tone may account for approximately 20% of the increase in EBF during heating. The second protocol was designed to determine if blockade of the auricular nerve would alter EBF response to H. During maximum EBF during H, saline or procainamide was injected in the tissue surrounding the auricular nerve. Injection of procainamide decreased EBF from 5.99 +/- 0.87 to 0.48 +/- 0.19 kHz, while injection of saline had no effect on EBF of the contralateral ear (4.33 +/- 1.16 before vs. 3.97 +/- 1.04 kHz after).(ABSTRACT TRUNCATED AT 250 WORDS)


G proteins: implications for psychiatry.

There is mounting evidence that a family of guanosine triphosphate binding proteins (G proteins) play an obligatory role in the transduction of a vast array of extracellular, receptor-detected signals across cell membranes to intracellular effectors. The author reviews the literature dealing with G protein coupling to second messenger generation, the role of G proteins in regulating both the convergence and divergence of neurotransmitter action in the CNS, and the involvement of G proteins in a variety of clinical conditions, with an emphasis on psychiatric conditions and their treatments. G proteins from the basis of signal integration in the CNS, endowing the neuron with a large degree of functional diversity. Abnormalities in the function and/or expression of G proteins have been implicated in a variety of pathophysiologic states, and a number of currently available psychotropic drugs affect G proteins. The understanding of the mechanisms by which G proteins modulate neuronal activity may be one of the keys to understanding the functioning and the complexities of the nervous system. Given their widespread, critical roles in the regulation of neuronal function, it seems likely that G proteins are involved in the pathophysiology of various major psychiatric illnesses. The development of novel, site-specific drugs with primary G protein targets remains an exciting prospect for the future.


Treatment of tardive dyskinesia with vitamin E.

Vitamin E (alpha-tocopherol), a free-radical scavenger, has been reported to improve symptoms of tardive dyskinesia. The authors attempted to replicate this finding under more controlled conditions in a larger study group. Fifteen inpatients and six outpatients with tardive dyskinesia received up to 1600 IU/day of vitamin E for 6 weeks in a double-blind, placebo-controlled crossover study. Abnormal Involuntary Movement Scale (AIMS) examinations of these patients were videotaped and rated independently by two trained raters. Levels of neuroleptic medication and vitamin E were measured during both treatment periods. Eighteen patients who demonstrated high blood levels of vitamin E were included in the data analysis. Vitamin E levels were significantly higher while the patients were receiving vitamin E than while they were receiving placebo. For all 18 patients, there were no significant differences between AIMS scores after receiving vitamin E and AIMS scores after receiving placebo. In agreement with previous studies, however, the nine patients who had had tardive dyskinesia for 5 years or less had significantly lower AIMS scores after receiving vitamin E than after receiving placebo. There were no changes in neuroleptic levels during vitamin E treatment. Vitamin E had a minor beneficial effect on tardive dyskinesia ratings in a selected group of patients who had had tardive dyskinesia for 5 years or less. This effect was not due to an increase in blood levels of neuroleptic medications.


Dual-enzyme fiber-optic biosensor for glutamate based on reduced nicotinamide adenine dinucleotide luminescence.

Response characteristics are presented for a dual-enzyme fiber-optic biosensor for glutamate. An enzyme layer composed of glutamate dehydrogenase (GDH) and glutamate-pyruvate transaminase (GPT) is used to produce reduced nicotinamide adenine dinucleotide (NADH) at the tip of a fiber-optic probe. NADH luminescence is monitored through this probe and the measured fluorescence intensity is related to the concentration of glutamate. GDH catalyzes the formation of NADH, and GPT drives the GDH reaction by removing a reaction product and regenerating glutamate. Optimal response is obtained in a pH 7.4 Tris-HCl buffer maintained at 25 degrees C in the presence of 4 mM NAD+ and 10 mM L-alanine. The temperature profile reveals a strong negative temperature effect which is attributed to the temperature dependency of NADH luminescence. Under optimal conditions, the sensor sensitivity is 0.127 nA/microM over the 1-10 microM concentration range, the detection limit is 0.13 microM, and response times range from 4 to 8 min. The sensor response is stable for 12 days when stored at 4 degrees C. Selectivity for glutamate is excellent over most of the common amino acids as well as ascorbic acid, uric acid, taurine, and GABA. Only slight responses were observed for glutamine and lysine. The effect of ammonia on the glutamate response was found to be minimal at total ammonia nitrogen concentrations as high as 200 microM.


[Development of continuous monitoring of spontaneous respiration in the postoperative phase. 2. Cutaneous oxygen and carbon dioxide partial pressures following i.v. bolus application of fentanyl, buprenorphine, naloxone and amiphenazole in healthy adult subjects].

In an attempt to develop a noninvasive monitoring technique for patients in the early postoperative period, cutaneous O2 and CO2 pressures (pctO2, pctCO2) were monitored in ten healthy adult volunteers of both sexes (5 male, 5 female, age 29 +/- 5 years, weight 68 +/- 11 kg) who received, in several sessions after a 60-min equilibration period, i.v. bolus doses of fentanyl (3 micrograms/kg and, 60 min later, another 1.5 micrograms/kg), buprenorphine (3 and 1.5 micrograms/kg), naloxone (1.8 and 0.9 micrograms/kg), and the respiratory analeptic amiphenazole (2 and 1 mg/kg) as well as combinations of fentanyl/amiphenazole or buprenorphine/naloxone in the aforementioned dosages. Data were collected and stored by a personal computer using the TCM3 system with a combination electrode for simultaneous measuring of pctO2 and pctCO2 (TINA, Radiometer) at 30-s intervals. The overall observation period was 240 min. Means, standard deviations, and ranges were calculated for individual data and data pooled for 15-min intervals. Groups were compared by means of Student's t-test and analysis of variance. Following i.v. fentanyl 3 micrograms/kg, pctO2 decreased and pctCO2 increased rapidly and statistically significantly. The changes were of similar intensity after the first and second doses (1.5 micrograms/kg) and normalized about 60 min after each injection. In contrast, following i.v. buprenorphine (3 and 1.5 micrograms/kg) the cutaneous partial pressures changed continuously and progressively during the observation period and did not reach the control values after 240 min. Naloxone and amiphenazole injections had no obvious influence on the time course of the blood gas tensions. If opiates and antagonists were combined, neither the fentanyl/amiphenazole group nor the buprenorphine/naloxone group differed significantly from the respective opiate groups. As was discussed in detail in a previous communication, monitoring of opiate-induced respiratory depression must be nonstimulant and, preferably, noninvasive. Whereas the precision and/or limitations of monitoring partial oxygen saturations by pulse oximetry is well documented in the literature, knowledge of the value of cutaneous partial pressure monitoring is still limited and controversial for the adult patient population. The present study was performed to define the usefulness of cutaneous blood gas analysis in healthy volunteers receiving opiate dosages well known in recovery room patients. It is concluded that continuous monitoring of pctO2 and pctCO2 can indeed detect opiate-induced respiratory depression in adults. The well-known difference in respiratory pattern for fentanyl and buprenorphine could easily be determined. It was confirmed that naloxone and amiphenazole in the dosage range studied do not influence spontaneous respiration in healthy adults. Thus, the authors are convinced that continuous monitoring of cutaneous partial pressures of oxygen and carbon dioxide is sensitive enough to be used, in combination with pulse oximetry, in a monitoring concept for patients recovering from surgery and anaesthesia. Results in patients undergoing conventional pain management or patient-controlled analgesia with relatively high opiate dosages will be presented in following papers. Concerning the controversy about clinically relevant interactions between fentanyl and amiphenazole or buprenorphine and naloxone, the present study did not confirm any useful antagonism. Whether this is due to limitations of cutaneous monitoring, the difference between volunteers and patients, or pharmacological reasons must be evaluated in further investigations.


Nucleotide regulation of heat-stable enterotoxin receptor binding and of guanylate cyclase activation.

Certain nucleotides were found to regulate the binding of the Escherichia coli heat-stable enterotoxin (STa) to its receptor in pig intestinal brush border membranes. ATP and adenine nucleotide analogues inhibited 125I-STa binding, while guanine nucleotide analogues stimulated binding, with maximal effects at 0.5-1.0 mM. The strongest inhibitors were adenosine 5'-[beta gamma-imido]triphosphate (App[NH]p) (36%) and adenosine 5'-[beta-thio]diphosphate (ADP[S]) (41%). Inhibition did not require Mg2+, and was blocked by p-chloromercuribenzenesulphonate (PCMBS). Stimulation of binding required Mg2+, was not prevented by PCMBS and was maximal with GDP[S] (41%). While App[NH]p and MgGDP[S] appeared to be acting at different sites, they also interfered with each other. These nucleotides exerted only inhibitory effects on STa-stimulated guanylate cyclase activity, in contrast with the stimulatory effects of adenine nucleotides on atrial natriuretic peptide (ANP)-stimulated guanylate cyclase. Inhibition by low concentrations of MgApp[NH]p and MgATP was weaker above 0.1 mM, while MgGDP[S] and magnesium guanosine 5'-[gamma-thio]triphosphate (MgGTP[S]) inhibited in a single phase. Inhibition by MgApp[NH]p, at all concentrations, was competitive with the substrate (MgGTP), as was that by MgGDP[S] and MgGTP[S]. Whereas membrane guanylate cyclases usually show positively co-operative kinetics with respect to the substrate, STa-stimulated activity exhibited Michaelis-Menten kinetics with respect to MgGTP. This changed to positive co-operativity when Lubrol PX was the activator, or when the substrate was MnGTP. These results suggest the presence of both a regulatory and a catalytic nucleotide-binding site, which do not interact co-operatively with STa activation.


Transglutaminase catalyses the modification of glutamine side chains in the C-terminal region of bovine beta-lactoglobulin.

The transglutaminase-catalysed incorporation of primary amines (putrescine and monodansylcadaverine) into bovine beta-lactoglobulin has been studied. In the presence of 1 mM-dithiothreitol between 1 and 2 mol of amine can be incorporated per mol of beta-lactoglobulin subunit. There is very little incorporation of amines in the absence of reducing agent. By isolating and sequencing the modified peptides, the sites of modification have been identified as Gln-159 (preferred) and Gln-155. C.d. has been used to study the structure of beta-lactoglobulin over a range of pH values and in the presence or absence of dithiothreitol. The results are discussed in terms of the X-ray-crystallographically determined structure of beta-lactoglobulin.


Expression of Ca2+ receptors in Xenopus oocytes injected with poly(A)+ mRNA from a rat calcitonin-secreting cell line.

Poly(A)+ mRNA extracted from rat calcitonin-secreting cells (rMTC 44-2) was injected into Xenopus oocytes. In mRNA-injected oocytes the intracellular Ca2+ concentration ([Ca2+]i), measured with the Ca2+ indicator dye, fura2, increased in response to an elevation of the extracellular Ca2+ ions ([Ca2+]o). In some oocytes [Ca2+]i transiently increased in high [Ca2+]o but it did not respond to the subsequent alterations of [Ca2+]o. The addition of 10 microM carbonyl cyanide m-chlorphenylhydrazone (CCCP) to the extracellular medium restored the dependence of [Ca2+]i on [Ca2+]o in such cells. It was concluded that rMTC 44-2 cells possessed a receptor which recognizes changes in [Ca2+]o and that these receptors can be functionally expressed by microinjection of messenger RNA from rMTC 44-2 cells into Xenopus oocytes.


Familial adenomatous polyposis: identification of a new frameshift mutation of the APC gene in an Italian family.

Familial Adenomatous Polyposis (FAP) is a premalignant disease of the gastrointestinal tract inherited as an autosomal dominant trait assigned to chromosome 5q21. The 15 exons of the APC gene responsible for the defect were amplified from the DNA of one FAP patient. SSCP analysis of the amplified DNA revealed a variant conformer of exon 10. The sequencing of the cloned PCR product showed a 1 base insertion at position 1370, creating a stop codon four nucleotides downstream. SSCP analysis of 20 family members and nucleotide sequencing of exon 10 in three affected members confirmed the Mendelian inheritance of the mutant allele.


Guidelines for meeting the communication needs of persons with severe disabilities. National Joint Committee for the Communicative Needs of Persons with Severe Disabilities.

In summary, the current best practices in the facilitation and enhancement of communication among persons with severe disabilities reflect six major tenets: (a) communication is social behavior; (b) effective communicative acts can be produced in a variety of modes; (c) appropriate communicative functions are those that are useful in enabling individuals with disabilities to participate productively in interactions with other people; (d) effective intervention must also include efforts to modify the physical and social elements of environments in ways that ensure that these environments will invite, accept, and respond to the communicative acts of persons with severe disabilities; (e) effective intervention must fully utilize the naturally occurring interactive contexts (e.g., educational, living, leisure, and work) that are experienced by persons with severe disabilities; and (f) service delivery must involve family members or guardians and professional and paraprofessional personnel. These six tenets have resulted in assessment, intervention, and service delivery models that offer maximum responsiveness to the need to establish communicative repertoires that will allow persons with severe disabilities to function effectively in least restrictive environments--in productive interactions with others.


Sedation and topical anesthetics in audiology and speech-language pathology. Ad Hoc Committee on Advances in Clinical Practice. American Speech-Language-Hearing Association.

Audiologists and speech-language pathologists who participate in or perform procedures on patients who have been medicated for sedation or topical anesthesia should appreciate the complex factors which may expose their patients to risk or harm. Administration of medications to achieve a desired patient state is a medical procedure requiring physician or dentist prescription, physician or dentist approval on the conditions of administration and monitoring, and physician or dentist availability for provision of emergency care that may be required. For these reasons, audiologists and speech-language pathologists should address issues of scope of practice as defined by state licensing boards and institutional regulatory committees, professional liability, and patient and practitioner safety before engaging in procedures on individuals medicated for sedation or topical anesthesia. These issues should be defined in specific, written protocols that the audiologist and speech-language pathologist develop in collaboration with physicians, dentists, and other medical professionals who are responsible for patient care. The protocols should specify responsibility for each aspect of care and limit procedures to professional settings with immediate access to emergency medical care. In all instances, both in development of written protocols and in actual professional practice, the comfort and safety of the patient must be paramount.


Analgesia induced by electroacupuncture of different frequencies is mediated by different types of opioid receptors: another cross-tolerance study.

The cross-tolerance technique was used to analyze the receptor mechanisms of analgesia induced by electroacupuncture (EA) of 2 Hz, 100 Hz, or 2-15 Hz. (1) Rats were given EA stimulation of 2 Hz, 100 Hz and 2-15 Hz for 30 min with 30 min intervals successively. The percentage increase in tail-flick latency (TFL) was taken to indicate the intensity of EA analgesia. Rats made tolerant to repeated intrathecal injection of the mu-opioid agonist ohmefentanyl (OMF, 15 pmol, Q2h x 5) or the delta-opioid agonist DPDPE (10 nmol, Q2h x 5) showed a cross tolerance to both 2 Hz- and 2-15 Hz-, but not to 100 Hz-EA analgesia; and rats made tolerant to kappa-opioid agonist dynorphin-(1-13) (5 nmol, Q2h x 5) showed a cross-tolerance to 100 Hz- and 2-15 Hz-, but not to 2 Hz-EA analgesia; (2) Rats made tolerant to 2-15 Hz EA showed cross-tolerance to either 2 Hz- or 100 Hz-EA analgesia; (3) Rats made tolerant to either 2 Hz- or 100 Hz-EA were still reactive to 2-15 Hz-EA. The results indicate that 2 Hz-EA analgesia is mediated by mu- and delta-receptors, 100 Hz-EA analgesia by kappa-receptor, and 2-15 Hz-EA analgesia by combined action of mu-, delta- and kappa-receptors in the spinal cord of the rats.


Effects of intraventricular infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist AP5 on spatial memory of rats in a radial arm maze.

Rats were trained to asymptotic performance in an 8-arm radial maze. They then received chronic intraventricular infusion of either artificial CSF or the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5- phosphonopentanoic acid (AP5), at a concentration (30 mM) that has been shown previously to prevent the induction of long-term potentiation in the dentate gyrus of the hippocampus in vivo. Subsequently the rats received another 9 trials in the maze in a quasi-random order, 3 uninterrupted trials, and another 6 trials each with mid-trial delays of 5, 20 or 60 min during which the animals were placed in their home cage. The mean number of errors for the AP5 rats did not differ significantly from that of the controls in the uninterrupted trials throughout the experiment, nor did it differ from that of the controls in any of the 3 delayed trials when these were first introduced. However, the control animals performed better at the longer delays when these were introduced for the second time, whilst there was no such improvement (but rather a deterioration) for the AP5 animals. The impairment of performance in the AP5 rats during the second block of delayed trials was significant, and independent of the length of the delay. These results show that NMDA receptor blockade does not impair working memory in the radial maze per se, but that it does prevent an improvement of working memory persistence with further training.


N-methyl-D-aspartate antagonist D-APV selectively disrupts taste-potentiated odor aversion learning.

Two experiments examined the effects of the competitive N-methyl-D-aspartate (NMDA) antagonist D-APV (D-2-amino-5-phosphonovalerate) on rats' ability to acquire potentiated aversions to the odor element of a taste-odor compound. In Experiment 1, pretreatment with D-APV (2.5 micrograms/side icv) caused stereospecific deficits in potentiated odor aversion learning but left simple taste and odor aversion learning intact. In Experiment 2, pretreatment with D-APV had no effect on rats' acquisition of an illness-based odor discrimination task. These results parallel those previously obtained using a noncompetitive NMDA antagonist (Robinson, Crooks, Shinkman, & Gallagher, 1989) and show that interference with NMDA receptors can selectively impair potentiated odor aversion learning. These results suggest that NMDA receptors play a critical role in some, but not all, forms of learning and memory.


Altered expression of NGF and P75 NGF-receptor by fibroblasts of injured teeth precedes sensory nerve sprouting.

Profuse sprouting of sensory nerve fibers occurs in tooth pulp by 1-4 days following dentin injury. A possible role for nerve growth factor (NGF) in that neural response is suggested here by the demonstration that NGF mRNA and protein are increased 6 hr after injury to adult rat molars. The enhanced expression of NGF mRNA was localized to fibroblasts underlying the injury. A concomitant depletion of mRNA encoding the 75 Kd NGF receptor (NGFR) was observed in those fibroblasts. The increase in NGF mRNA was transitory and mRNA levels fell below normal levels by 2 days after injury. Both NGF and NGFR mRNA remained low thereafter in injured pulp. The inverse shifts in fibroblastic mRNA encoding NGF and NGFR were not affected by prior denervation of the tissue, or by pretreatment with dexamethasone. The regulatory mechanisms therefore must involve endogenous, non-neuronal, non-inflammatory factors that are released in response to injury.


Tamoxifen up-regulates c-erbB-2 expression in oestrogen-responsive breast cancer cells in vitro.

Expression of the c-erbB-2 proto-oncogene is inhibited by oestrogens in oestrogen-responsive human breast cancer cells, at both mRNA and protein level. Here we report that, where the regulation of c-erbB-2 is concerned, tamoxifen displays a full anti-oestrogenic activity, enhancing the expression of c-erbB-2 in oestrogen receptor-positive cells cultured with untreated fetal calf serum or reversing the inhibitory effect of added oestrogens. Meanwhile, tamoxifen strongly inhibited cell growth. Tamoxifen was inactive on both c-erbB-2 expression and growth of oestrogen receptor-negative cells. These results may have important implications to explain occasional failure of tamoxifen therapy in oestrogen receptor-positive breast cancers.


Detection of the HER-2/neu proto-oncogene protein p185erbB2 by a novel monoclonal antibody (MAB-145ww) in breast cancer membranes from oestrogen and progesterone receptor assays.

Amplification of the proto-oncogene HER-2/neu and/or overexpression of the transmembrane protein p185erbB2 that it encodes occur in approximately 30% of human breast and gynaecological cancers seen clinically and are strongly associated with an unfavourable outcome. We report on the use of a new monoclonal antibody (Mab-145ww) together with immunoblotting for detection of p185erbB2 in membranes that remain after routine processing of breast cancer tissue for steroid receptor assays. Human breast cancer cell lines SKBR3 and MCF-7 were used as high and low controls, respectively, for p185erbB2 expression. Mab-145ww was detected p185erbB2 in more than half of the breast cancer specimens; the expression was intense in SKBR3 cells, but only faint in MCF-7 cells. These results demonstrate that routine processing of cancer tissue for steroid receptor status can include providing a preparation with which to assess p185erbB2 expression and, thus, can provide information potentially useful for the clinical management of individual cancer patients.


Calcitonin and PDN-21 as tumour markers in MEN-2 family screening for medullary thyroid carcinoma.

Calcitonin is expressed in medullary thyroid carcinomas (MTC). It is processed from a large molecular weight precursor and is flanked at its C-terminal end by a 21 aminoacid peptide (PDN-21) formed in equimolar concentrations to calcitonin by enzymatic cleavage of the prohormone. This investigation compared basal measurements of calcitonin and PDN-21 and the response of the two peptides following pentagastrin stimulation in normal controls and in family members with C-cell hyperplasia or early neoplasia. The results showed that calcitonin and PDN-21 may both be used in family screening for the MEN-2 syndrome, but the unstimulated circulating concentrations of calcitonin were higher and more influenced by C-cell hypersecretion than PDN-21 (P less than 0.01), and the increase in stimulated concentrations of calcitonin were significantly higher than for PDN-21 (P less than 0.01). These findings may be explained by differences with respect to secretion and metabolic clearance rate for the two peptides.


Overexpression of the c-erbB-2 oncoprotein: why does this occur more frequently in ductal carcinoma in situ than in invasive mammary carcinoma and is this of prognostic significance?

Overexpression of c-erbB-2 occurs in 60% of in situ and 25% of infiltrating ductal carcinomas. We have previously found very strong associations between immunohistochemical staining for c-erbB-2 and histological pattern and nuclear size in ductal carcinoma in situ (DCIS) and less strong correlation with proliferative activity. In a further study of infiltrating ductal carcinomas we have found that, in addition to tumours arising from c-erbB-2 positive, large celled, rapidly proliferating, comedo carcinomas and c-erbB-2 negative small celled cribriform/micropapillary carcinomas with a low proliferative rate, there is a third group of c-erbB-2 negative tumours with large nuclei and variable proliferative activity. These latter tumours are not seen in pure DCIS suggesting that they have a very transient in situ stage. Therefore, although in pure DCIS c-erbB-2 positively appears to be associated with tumours with a greater invasive potential, and c-erbB-2 negativity with tumours having a more favourable prognosis, the latter is not necessarily true in infiltrating disease.


Prevalence of amplification of the oncogenes c-myc, HER2/neu, and int-2 in one thousand human breast tumours: correlation with steroid receptors.

The frequency of oncogene amplification described in the literature shows a large fluctuation, which could be attributed to the study of relatively small series of tumours, to selection of subgroups of patients, or, especially in retrospective studies, to selection of tumour material from the tumour-bank. To address this question, we have studied amplification of c-myc, HER2/neu and int-2/bcl-1 genes in a series of 1052 collected human breast tumours. The retrospective and prospective subgroups in this collected series of tumours were of equal size. c-myc was amplified in 17.1%, HER2/neu in 18.7% and int-2/bcl-1 in 14.1%, of all breast cancer specimens studied. In the retrospective subgroup the prevalence of amplification was 18.1% for c-myc; 22.6% for HER2/neu and 11.6% for int-2/bcl-1, whereas in the prospective subgroup an incidence of amplification of 16.1%, 15.1% and 16.3% for c-myc, HER2/neu and int-2/bcl-1, respectively was observed. HER2/neu amplification was negatively correlated with oestrogen receptor (ER) and progesterone receptor (PR) status (P less than 0.0001; for both), c-myc amplification was more prevalent in the PR-negative subpopulation (P less than 0.05) and int-2/bcl-1 amplification was positively correlated with ER status (P less than 0.001).


A developmental perspective on the pathology and neurochemistry of the temporal lobe in schizophrenia.

Neuropathological, neuroimaging, clinical and epidemiological evidence suggests that many cases of schizophrenia are developmental in origin. Dysplastic changes in the medial temporal lobes appear to be of particular importance. However, research implicating a neurodevelopmental origin for schizophrenia has proceeded largely in isolation from knowledge concerning the neurochemistry of the disorder. This paper attempts to integrate these disparate lines of research, and examines the role of trophic mechanisms in the formation of the hippocampus. Those neurotransmitters which have been most consistently found to be abnormal in the temporal lobes of schizophrenics (excitatory amino acids and CCK), are involved in the control of hippocampal development. We suggest that these neurotransmitter findings are the residue of abnormalities in their role as trophic factors in foetal or neonatal life, and that the latter contribute to the developmental aberrations considered fundamental to schizophrenia.


Expression of c-erbB2, TGF-beta 1 and pS2 genes in primary human breast cancers.

The presence of c-erbB2, TGF-beta 1 and pS2 mRNAs was examined in primary breast tumours. The c-erbB2 mRNA was overexpressed in 34% of the tumours. There was a positive, statistically significant correlation between c-erbB2 gene overexpression and nodal status. TGF-beta 1 mRNA was detected in 84% of the tumours, regardless of their clinical status. When possible, the c-erbB2 and TGF-beta 1 proteins were identified immunohistochemically on frozen sections from the same tumours. For TGF-beta 1, the mRNA and immunohistochemical results were divergent in 6 cases, 5 of which did contain clearly detectable mRNA but did not stain with the antibody. The pS2 mRNA was detected in 22% of the tumours and in the BT474 cell line. There was a significant correlation between the presence of pS2 mRNA and of oestrogen receptors. No statistically significant correlation was observed between pS2 and TGF-beta 1 genes expression and the clinical parameters of the tumours.


Elevated IgG anti-histone antibodies in a subgroup of medicated schizophrenic patients.

A total of 57 schizophrenic patients (of which 17 were first-episode, neuroleptic naive) and 76 healthy controls were screened for anti-histone IgG antibodies using an enzyme immunoassay (ELISA). All patients had significantly higher anti-histone antibody titers than controls (t = 3.1, p less than 0.003). Previously medicated patients had significantly higher titers than neuroleptic-naive first episode patients (t = 2.87, p less than 0.006). This study suggests that neuroleptic medications are associated with anti-histone antibodies.