Effects of adrenoceptor agonists and antagonists on cardiovascular functional parameters in rats.

The effects of intravenous administration of adrenoceptor agonists and antagonists on electrocardiographic or blood pressure (BP) functional parameters were assessed in urethane-anesthetized rats. The responses of cardiovascular functional parameters produced by these drugs included: (1) isoproterenol decreased the duration of a whole BP cycle (Wd), duration of the diastolic wave (Dd), peak amplitude of the systolic wave (SYa), amplitude of the diastolic notch (DNa), amplitude of the diastolic wave (DWa), pulse pressure (dp) and mean arterial pressure (mp) but increased the heart rate (HR) accompanied by prolonged R-R (RR) or P-P interval (PP) (2) propranolol decreased SYa, DNa, dp, mp, HR, the amplitude of the P wave (Pa) and amplitude of the S wave (Sa) but increased the duration of the QRS wave, P-R interval, duration of the R wave (Rd) and duration of the P wave (Pd); (3) adrenaline decreased HR (accompanied by prolonged RR and PP), Rd, Pa and amplitude of the T wave (Ta) but increased Pd, Wd, Dd, DNA, the time interval between aortic valve opening and closure (Dw), dp, mp, amplitude of the Q wave and amplitude of the R wave (Ra); (4) noradrenaline decreased HR (accompanied by prolonged RR and PP) and Pa but increased Wd, Pd, SYa, DNa, Dw, dp, mp, Ra and Ta; (5) phenylephrine decreased HR (accompanied by prolonged RR and PP) and Pa but increased Wd, Dd, DNa, mp and Ra; (6) phentolamine decreased SYa, DNa, DWa, Dw, dp and mp. This study illustrates the utility of the automated electrocardiogram (ECG) and BP analysis system for investigation of adrenoceptor agonists and antagonists. The use of this methodology not only reproduced most of cardiovascular functional parameter effects produced by these drugs using the conventional methodology but also realizes some new information about the drug-induced ECG or BP waveform effects.


Treatment of generalized anxiety disorder: comparison of a new beta-blocking drug (CGP 361 A), low-dose neuroleptic (flupenthixol), and placebo.

In an attempt to evaluate an alternative drug treatment to benzodiazepines in generalized anxiety disorders, a placebo controlled trial was carried out with a new beta-adrenergic blocker (CPG 361 A). A low-dosage neuroleptic (flupenthixol) was included as a reference drug. Depending on the clinical assessment scales the placebo treatment resulted in moderate to excellent improvement in 36% to 56% of the patients after four weeks of treatment. The active drugs generally had a higher improvement range (from 31% to 80%). The global improvement scale was found to be better than the other scales in discriminating between placebo (50% improvement) and the active drugs (CGP 361 A brought about 78% improvement and flupenthixol brought about 80% improvement). However, only for flupenthixol was the difference of statistical significance.


The effects of neuroleptics on facial action in schizophrenic patients.

This paper describes the influence of neuroleptic therapy on facial action in drug-naive schizophrenics. In a comparative study of medicated and unmedicated schizophrenic patients, the coordinates of 12 small light-reflecting points, attached to subjects' faces, were computer-recorded and analyzed automatically during a semi-standardized clinical interview. In addition, facial activity in videotaped interviews was coded using the Facial Action Coding System (FACS). Each sample group comprised of eight patients with the DSM-III-R diagnostic criteria "schizophrenia" or "schizophreniform disorder". Subjects were studied on two occasions, one shortly after admission to the hospital, the other three weeks later. Group 1 was unmedicated during the first session, whereas group 2 was medicated throughout the study. Three weeks after the start of medication, at the second interview, both recording methods showed a reduction in facial activity and facial expression across all subjects in group 1. The facial action of patients in group 2, however, remained unchanged.


Use of bromocriptine to prevent puerperal lactation during neuroleptic treatment of chronic schizophrenia.

Bromocriptine, the ergotamine alkaloid 2-bromo-alpha-ergocriptine, is known as a dopamine D-2 receptor agonist with strong prolactin-lowering actions and potential mental side-effects. The case reported here involves a female chronic schizophrenic patient in childbed who was treated both with neuroleptics and with bromocriptine; the latter was given in order to prevent inappropriate puerperal lactation. The described therapeutic regimen succeeded in preventing puerperal lactation without exacerbating schizophrenic symptoms. The simultaneous use of neuroleptics and bromocriptine was accompanied by monitoring for changes in mental status and plasma prolactin level. The high prolactin plasma levels that persisted in spite of treatment with bromocriptine would seem to be a reason to carry out further research into the mechanism of action of the drug.


Uranium-series dating and the origin of modern man.

Uranium-series dating is based on measurement of the radioactivity of short-lived daughter isotopes of uranium formed in samples which initially contained only the parent uranium. Materials suitable for U-series dating are found in many prehistoric archaeological sites, and include stalagmitic layers (flowstones), and spring-deposited travertines. Some marls and calcretes are also datable using isochron methods, whereas dates on molluscan shells, bones and teeth are less reliable. Ages obtained using alpha counting to determine isotope ratios have errors greater than 5%, and can range from 1 to 350 ka. Mass spectrometric methods slightly increase the range (0.1-500 ka) but greatly decrease the error to less than 1%, making this the optimal method for high-precision dating of the origin of modern man.


Luminescence dating relevant to human origins.

Luminescence dating provided the first direct and independent evidence that anatomically modern humans had a presence in western Asia earlier than is consistent with the 'regional continuity' model. The reliability of the result concerned, 92 (+/- 5) ka for burnt flints from Qafzeh Cave, is excellent and consistent with isochron analysis of the data. Flint dating has also confirmed palaeoenvironmental indications that the Mousterian industry in Europe was present somewhat earlier than the 100 ka limit previously accepted. Burnt quartz and unburnt sediment have also been important in Palaeolithic dating and the latter has a particularly high potential.


Electron spin resonance (ESR) dating of the origin of modern man.

Many materials found in archaeological sites are able to trap electronic charges as a result of bombardment by radioactive radiation from the surrounding sediment. The presence of these trapped charges can be detected by electron spin resonance (ESR) spectroscopy: the intensity of the ESR signal is a measure of the accumulated dose and thus of the age. Tooth enamel is ubiquitous at archaeological sites and is well suited for ESR dating, with a precision of about 10-20%. This method has now been used to date many sites critical to the biological and cultural evolution of modern man. Dates for sites in Israel and Africa have demonstrated the existence of anatomically modern humans more than 100 ka ago.


Pleistocene geochronology and palaeothermometry from protein diagenesis in ostrich eggshells: implications for the evolution of modern humans.

Proteinaceous residues incorporated within the crystal structure of ostrich eggshells (OES) are retained without loss over geological time exceeding 10 million years. Degradation of the polypeptides, including hydrolysis to smaller peptide fragments and eventual release of free amino acids, decomposition, and racemization and epimerization occur at regular, predictable rates dependent on ambient temperature. The extent of isoleucine epimerization (aIle/Ile ratio) in OES follows linear first-order reversible kinetics in controlled-temperature laboratory simulations of time up to an aIle/Ile ratio in excess of 1.0. The hydrolysis of leucine also follows a predictable pattern, but deviates from first-order kinetics. A nonlinear mathematical model has been developed that adequately describes the pattern of leucine hydrolysis through a wide temperature range. Arrhenius parameters were derived from laboratory experiments combined with rate constant values found for 14C-dated OES from stratified caves in southern Africa. These parameters for isoleucine epimerization and leucine hydrolysis differ by ca. 10%, allowing the simultaneous solution of the two equations for temperature, independent of sample age. Although the uncertainty of the simultaneous temperature is relatively high (+/- 10 degrees C), it provides an effective means of identifying burned samples. If sample age is known, palaeotemperatures (the integrated thermal history experienced by an eggshell as opposed to an 'instantaneous' temperature) can be calculated with a precision of better than +/- 1 degrees C. The ages of levels at Border Cave, South Africa, from which anatomically modern human skeletal remains have been recovered, are dated by the extent of isoleucine epimerization in associated OES.(ABSTRACT TRUNCATED AT 250 WORDS)


Evolution of modern humans: evidence from nuclear DNA polymorphisms.

Previously we have described studies of the evolution of modern humans based upon data for classical genetic markers and for nuclear DNA polymorphisms. Such polymorphisms provide a different point of view regarding human evolution than do mitochondrial DNA sequences. Here we compare revised dates for major migrations of anatomically modern humans, estimated from archaeological data, with separations suggested by a genetic tree constructed from classical marker allele frequencies. Analyses of DNA polymorphisms have now been extended and compared with those of classical markers; genetic trees continue to support the hypothesis of an initial African and non-African divergence for modern humans. We have also begun testing non-human primates for a set of human DNA polymorphisms. For most polymorphisms tested so far, humans share a single allele with other primates; such shared alleles are likely to be ancestral. Populations living in humid tropical environments have significantly higher frequencies of ancestral alleles than do other populations, supporting the hypothesis that natural selection acts to maintain high frequencies of particular alleles in some environments.


New approaches to dating suggest a recent age for the human mtDNA ancestor.

The most critical and controversial feature of the African origin hypothesis of human mitochondrial DNA (mtDNA) evolution is the relatively recent age of about 200 ka inferred for the human mtDNA ancestor. If this age is wrong, and the actual age instead approaches 1 million years ago, then the controversy abates. Reliable estimates of the age of the human mtDNA ancestor and the associated standard error are therefore crucial. However, more recent estimates of the age of the human ancestor rely on comparisons between human and chimpanzee mtDNAs that may not be reliable and for which standard errors are difficult to calculate. We present here two approaches for deriving an intraspecific calibration of the rate of human mtDNA sequence evolution that allow standard errors to be readily calculated. The estimates resulting from these two approaches for the age of the human mtDNA ancestor (and approximate 95% confidence intervals) are 133 (63-356) and 137 (63-416) ka ago. These results provide the strongest evidence yet for a relatively recent origin of the human mtDNA ancestor.


Southern Africa and modern human origins.

This paper argues that southern Africa was a remote part of the Old World in the late Pleistocene (125-10 ka ago). Because of this isolated position there was continuity without significant replacement in the resident population. Isolation and the relatively recent spread of agriculture to the region has allowed a section of this population to survive into the present. They are the Bushmen (San). Studies of geographic patterning in conventional genetic markers and mitochondrial DNA indicate that the Bushman clade has a long evolutionary history in southern Africa. Estimates of more than 100 ka for the continued presence of this population in the region are supported in archaeological investigations of sites with long sequences such as Klasies River main site and Border Cave. Human remains dating to the earlier part of the late Pleistocene have been recovered from these sites and the samples form a morphological series with the Klasies River remains possibly 20 ka older than those from Border Cave. There is no fossil record for the later Pleistocene, however, at a period when selection for a gracile morphology may have been pronounced. The cultural associations in the earlier late Pleistocene are with the Middle Stone Age. Expressions of cultural 'style' and the occurrence of similar artefact design types in the Middle and Later Stone Ages can be interpreted with reference to the ethnographic present. Temporal continuity can be shown in the geographical distribution of stylistic markers and this suggests participation in a shared cognitive system.(ABSTRACT TRUNCATED AT 250 WORDS)


Recent human evolution in northwestern Africa.

The first modern humans in the Maghreb are said to be associated with the Aterian industries which appeared at least 40 ka BP in the northwest. Their predecessors are mainly represented by the Jebel Irhoud (Morocco) specimens. Palaeontological evidence, as well as electron spin resonance (ESR) dating, suggests that this series is older than previously published, and should belong to oxygen isotope stage 5 or even 6. There is no evidence of any Neanderthal apomorphy in this group which can no longer be considered as 'African Nanderthals'. Clear synapomorphies with modern man combined with some plesiomorphic retentions indicate a slightly more primitive (and older?) grade than the Qafzeh-Skhul sample in southwestern Asia. The Northwestern evidence demonstrates that the mediterranean sea was a major biological barrier during the upper Middle and lower Upper Pleistocene and that the rise of anatomically modern features cannot be restricted to a sub-Saharan of eastern African area.


The role of western Asia in modern human origins.

Western Asia provides the best collection of human skeletal remains relevant to the two basic models for the emergence of modern humans, namely the 'rapid replacement' and the 'regional continuity' models. Regardless of the taxonomies of particular hominids, their chronology is of crucial importance. Thermoluminescence (TL) and electron spin resonance (ESR) dates demonstrate that the Acheulo-Yabrudian and Mousterian entities and their associated fossils (Zuttiyeh, Tabun, Skhul, Qafzeh, Kebara, Shanidar, Amud) span the late Middle and Upper Pleistocene period. These new dates initiated major chronological revisions and renewed discussion of the cultural-archaeological implications. One of the most important conclusions is that the Middle to Upper Palaeolithic transition (or Revolution) 45-40 ka ago has nothing to do with the appearance of anatomically early modern humans in western Asia, which occurred some 100 ka ago or more. The Levant, the coastal region of the eastern Mediterranean, was both a corridor for movement of humans and animals as well as a refugium during climatically harsh periods. The mixture of morphological characteristics among the available Middle Palaeolithic human fossils is interpreted as reflecting the presence of immigrant and local populations. Archaeologically observable behavioural changes are taken as hints to the pre-adaptations of the Middle to Upper Palaeolithic revolution. The archaeological record of western Asia can contribute significantly to explaining the Middle to Upper Palaeolithic revolution. This region was the core area where the 'Neolithic Revolution' took place. The shift to systematic cultivation and the domestication of animals occurred within a short time.(ABSTRACT TRUNCATED AT 250 WORDS)


African and Asian perspectives on the origins of modern humans.

The ways in which the cultural evidence - in its chronological context - can be used to imply behavioural patterning and to identify possible causes of change are discussed. Improved reliability in dating methods, suites of dates from different regional localities, and new, firmly dated fossil hominids from crucial regions such as northeast Africa, the Levant, India and China, are essential for clarification of the origin and spread of the modern genepool. Hominid ancestry in Africa is reviewed, as well as the claims for an independent origin in Asia. The cultural differences and changes within Africa, West and South Asia and the Far East in the later Middle and early Upper Pleistocene are examined and compared, and some behavioural implications are suggested, taking account of the evolutionary frameworks suggested by the 'multiregional evolution' and 'Noah's Ark' hypotheses of human evolution. A possible explanation is proposed for the cultural differences between Africa, West Asia and India on the one hand, and southeast Asia and the Far East on the other. The apparent hiatus between the appearance of the first anatomically modern humans, ca. 100 ka ago, and the appearance of the Upper Palaeolithic and other contemporaneous technological and behavioural changes around 40 ka ago, is discussed. It is suggested that the anatomical changes occurred first, and that neurological changes permitted the development of fully syntactic language some 50 ka later. The intellectual and behavioural revolution, best demonstrated by the 'Upper Palaeolithic' of Eurasia, seems to have been dependent on this linguistic development - within the modern genepool - and triggered the rapid migration of human populations throughout the Old World.


Reconstructing recent human evolution.

The two most distinct models of recent human evolution, the multiregional and the recent African origin models, have different retrodictions concerning specific archaic-recent population relationships. The former model infers multiple regional archaic-modern connections and the ancient establishment of regional characteristics, whereas the latter model implies only an African archaic-all modern relationship, with recent (late Pleistocene) development of regionality. In this paper, four late archaic groups from Europe, southwest Asia, Africa and East Asia are compared with various fossil and recent Homo sapiens crania or cranial samples. The results of Penrose shape comparisons narrowly favour a late archaic African-modern special relationship over an East Asian-modern one, with European and southwest Asian Neanderthal groups much more distant. No specific archaic-recent regional relationships are indicated in the shape analyses, nor in separate examinations of patterns of regionality, which indicate a recent origin for present day regionality. The Skhul-Qafzeh sample provides an excellent shape intermediate between the archaic and recent samples.


Archaeology and the population-dispersal hypothesis of modern human origins in Europe.

The transition from anatomically 'archaic' to 'modern' populations would seem to have occurred in most regions of Europe broadly between ca. 40 and 30 ka ago: much later than in most other areas of the world. The archaeological evidence supports the view that this transition was associated with the dispersal of new human populations into Europe, equipped with a new technology ('Aurignacian') and a range of radical behavioural and cultural innovations which collectively define the 'Middle-Upper Palaeolithic transition'. In several regions of Europe there is archaeological evidence for a chronological overlap between these populations and the final Neanderthal populations and, apparently, for various forms of contact, interaction and, apparently, 'acculturation' between these two populations. The fundamental behavioural adaptations implicit in the 'Upper Palaeolithic Revolution' (possibly including language) are thought to have been responsible for this rapid dispersal of human populations over the ecologically demanding environments of last-glacial Europe.


Recent human evolution in East Asia and Australasia.

In both East Asia and Australasia arguments for evolutionary continuity between middle-late Pleistocene hominid populations and modern Homo sapiens are of long standing. In both regions, however, problems of chronological distribution, dating and preservation of hominid skeletal materials provide an effective barrier to extending regional sequences back to 'archaic' Homo sapiens or Homo erectus. The earliest securely dated modern Homo sapiens in East Asia are currently represented by Zhoukoudian Upper Cave at a minimum of 29 ka BP. In Australia skeletal remains of modern Homo sapiens have been dated to 26 ka BP, with archaeological materials at 38 to 50 ka BP. Late Pleistocene human skeletons from sites like Coobool Creek are morphologically and metrically outside the range of recent Australian Aboriginal populations. Similarly Liujiang and the Upper Cave crania can be distinguished from recent East Asian 'Mongoloids'. Evolutionary change within the Holocene needs to be taken into consideration when the evidence for regional evolutionary continuity is considered.


Models and realities in modern human origins: the African fossil evidence.

The recent application of such chronometric techniques as electron spin resonance (ESR), thermoluminescence (TL), and uranium series dating has had a significant impact on perceptions of modern human origins. Claims for the presence of anatomically modern humans in Africa prior to 100 ka and for the transition leading to modern Africans at an even earlier date have been made, partly based on results of these techniques. However, a careful examination of the pertinent record shows that these claims are not unequivocally supported by the available fossil and chronological evidence.


Effects of adrenalectomy and deprivation condition on food intake after phenylpropanolamine or clonidine.

alpha-Adrenergic receptors within the paraventricular hypothalamus (PVN) modulate feeding such that activation of alpha 2-adrenoceptors by drugs such as clonidine (CLON) increase feeding; whereas activation of alpha 1-adrenoceptors by drugs such as phenylpropanolamine (PPA) suppress feeding. Prior studies suggest that the feeding-stimulatory effect of alpha 2-adrenergic activation is a function of drug dose as well as the deprivation condition and adrenal status of the animal. Specifically, CLON's effects on feeding are greatest at low doses in food-satiated adrenally intact rats. Whether a similar profile is produced by alpha 1-adrenoceptor agonists such as PPA has not previously been explored. Thus, the present study provides a comparison of the effects on food intake of drug dose, deprivation condition, and adrenalectomy induced by these alpha 2- and alpha 1-adrenergic drugs. Accordingly, both adrenalectomized (ADX) as well as sham-control (SHAM) adult male rats underwent a series of 1-h feeding tests following administration of PPA (5, 10, 20 mg/kg, IP) as well as CLON (0.0125, 0.025, 0.05, 0.1 mg/kg, IP) under both deprived and nondeprived testing conditions. The results suggest that the deprivation condition, but not the surgical condition (ADX vs. SHAM), exerts the greatest overall effect on food intake following administration of alpha-adrenergic drugs.


Treatment of tardive dyskinesia with ceruletide: a double-blind, placebo-controlled study.

The effectiveness of a once-weekly i.m. injection of ceruletide (0.8 microgram/kg) in suppressing the symptoms of neuroleptic-induced tardive dyskinesia (TD) was evaluated in a double-blind, placebo-controlled, matched-pairs study. Global evaluation of the severity of TD symptoms over the 8-week study period revealed a significant improvement with ceruletide as compared with placebo. Analysis of the therapeutic response to ceruletide over the course of treatment revealed a slow, but long-lasting improvement of TD symptoms. Side effects, which were mild and transient, consisted mainly of nausea and epigastric discomfort. The incidence of side effects did not differ between the ceruletide- and placebo-treated groups. Ceruletide appears to be a novel and practical treatment that can substantially alleviate the symptoms of dyskinesia.


Cerebrospinal fluid and serum levels of neuron-specific enolase in patients with schizophrenia.

Some patients with schizophrenia appear to have brain abnormalities, including enlarged third and lateral ventricles and reduced volumes of temporal lobe structures. These abnormalities could be attributed to a developmental abnormality or a neurodegenerative process. Neuron-specific enolase (NSE), a protein that is found primarily in neurons and neuroendocrine cells, has been used as an index of neuronal damage or degeneration. Levels of NSE in cerebrospinal fluid (CSF) and serum from 50 patients with acute and chronic schizophrenia were compared with those in normal and neurological control subjects. A double-antibody, solid phase iodinated radioimmunoassay was used to determine NSE levels. There was no evidence of elevated levels in patients with schizophrenia, whereas control subjects with neurological illnesses had increased levels of NSE in CSF. Because NSE is rapidly cleared from CSF, however, elevated levels could have been missed. Unmedicated patients tended to have lower levels than medicated patients.


A two-year prospective study of treatment compliance in patients with schizophrenia.

The study is a prospective investigation of the factors associated with treatment compliance in 61 patients discharged from hospital with a ward diagnosis of schizophrenia. All cases were classified using reliable diagnostic criteria and all were followed up for two years. Compliance was assessed by inspection of records and by analysis of urine. Sociodemographic factors and illness variables were unrelated to compliance. Some aspects of a patient's insight and attitude, namely, a belief that medication had helped during the admission, a stated willingness to take treatment after discharge and a generally optimistic outlook, were associated with improved compliance. Other variables which showed such an association were the absence of the drug side-effect akinesia, good previous compliance and voluntary, as opposed to compulsory, admission to hospital.


Alpha-2 adrenergic agonists decrease distractibility in aged monkeys performing the delayed response task.

With advancing age, monkeys become impaired on a test of spatial working memory, the delayed response task, and show increased susceptibility to interference from irrelevant stimuli (Bartus and Dean 1979). Alpha-2 adrenergic agonists such as clonidine and guanfacine have been shown to improve the delayed response performance of aged monkeys under standard testing conditions (e.g. Arnsten et al. 1988). The current study examined whether these drugs could protect the delayed response performance of aged monkeys when irrelevant stimuli were presented during the delay intervals. Aged monkeys were tested on the variable delayed response task with short delays to minimize memory demands and optimize performance on control (no interference) sessions. During interference sessions, distractors were presented during the delays on 9 of the 30 trials ("distractor" trials). If the aged monkeys had been pretreated with saline, performance was significantly disrupted by the irrelevant stimuli compared to matched saline control sessions. This impairment was not only evident on the 9 distractor trials, but on the 21 remaining "nondistractor" trials as well. However, if the aged monkeys had been pretreated with clonidine or guanfacine, performance was not impaired on the interference sessions. This beneficial effect of the alpha-2 agonists was most apparent on the nondistractor trials. Guanfacine was able to decrease the harmful effects of distraction without any apparent sedative side effects. Co-administration of the alpha-2 antagonists idazoxan or SKF104078 with clonidine blocked the protective effects of the agonist on delayed response performance, consistent with actions at alpha-2 adrenergic receptors. These findings suggest that alpha-2 agonists improve delayed response performance, at least in part, by helping to protect memory from irrelevant stimulation. Clonidine is already used in the treatment of Attention Deficit Disorder, and the current data suggest that guanfacine may also be useful in this regard.


Dexmedetomidine synergism with midazolam in the elevated plus-maze test in rats.

The anxiolytic profile of dexmedetomidine, a novel, highly-selective alpha 2-adrenergic agonist, was examined in rats in the elevated plus-maze test when administered either alone or in combination with the benzodiazepine agonist midazolam. Dexmedetomidine, 0.1-10 micrograms/kg, was inactive in modifying the rats' behavioral response in this test. Midazolam, 0.1-10 mg/kg, dose-dependently produced an anxiolytic-like profile characterized by an increased time spent in the open arms of the elevated plus-maze. A combination of dexmedetomidine 0.5 micrograms/kg and midazolam 0.5 mg/kg produced a synergistic interaction. This heterergic interaction of dexmedetomidine on midazolam's anxiolytic-like profile was dose-dependently blocked by pretreatment with an alpha 2-adrenergic antagonist, atipamezole, 10-50 micrograms/kg, and a benzodiazepine antagonist flumazenil, 1.0 and 10 mg/kg, but not by the alpha 1-adrenergic antagonist, prazosin, 0.1-10 mg/kg. While the transmembrane signal transduction pathways for benzodiazepine- and alpha 2-agonist responses do not share any molecular component, there does appear to be "crosstalk" between these two systems. These may involve GABA or noradrenergic "downstream" effects of either dexmedetomidine or midazolam, respectively.


Morphine withdrawal aggression: modification with D1 and D2 receptor agonists.

Morphine withdrawal increases aggressive behaviors, induces explosive motor behaviors, and disrupts homeostatic functions in mice and rats. While many of these effects appear to result from altered dopaminergic activity during morphine withdrawal, the relative contributions of the D1 and D2 receptor subtypes remain unclear. In the present experiments, the D1 agonist SKF 38393 and the D2 agonist quinpirole were administered to male "resident" Swiss-Webster mice 5 h after the removal of a subcutaneously-implanted morphine or placebo pellet. These mice were then observed alone to determine changes in various motor activities and in confrontation with a group-housed male "intruder" to assess changes in aggressive behaviors. SKF 38393 decreased the display of aggressive behaviors by placebo and morphine-withdrawn mice without consistently altering walking or rearing. Quinpirole greatly decreased the display of aggressive behaviors by placebo mice and decreased aggressive behaviors in morphine-withdrawn mice to a lesser degree. The inhibitory effects of quinpirole were not specific to aggressive behaviors; low quinpirole doses also decreased the display of walking and rearing. In mice which received a low dose of SKF 38393 preceding quinpirole injection, pretreatment with the D1 agonist did not alter the effects of the D2 agonist quinpirole on motor activities but maintained high levels of aggression in morphine-withdrawn mice. The differential modification of aggressive and motor behaviors by selective dopaminergic agonists during morphine withdrawal further supports the suggestion that aggressive and motor behaviors are controlled independently; furthermore, D1 receptor stimulation appears to have particular relevance for the display of aggressive behaviors during morphine withdrawal.


Chronic imipramine treatment normalizes levels of tyrosine hydroxylase in the locus coeruleus of chronically stressed rats.

Previous studies have demonstrated that chronic stress increases and antidepressant treatments decrease levels of tyrosine hydroxylase (TH) in locus coeruleus (LC). In the present study, the influence of chronic antidepressant treatment on the induction of TH immunoreactivity in response to cold stress is examined. It was found that chronic imipramine pretreatment (18 days) attenuated the induction of TH in response to cold stress, resulting in levels of TH immunoreactivity not different from control. In contrast, imipramine pretreatment for 1 or 7 days was not sufficient to normalize the stress-induced elevation of TH immunoreactivity. These findings raise the possibility that the therapeutic action of antidepressants may be derived, in part, from the ability of these treatments to normalize levels of TH and thereby the function of the NE neurotransmitter system under conditions of stress.


Kappa opioid receptor activity modulates memory for peck-avoidance training in the 2-day-old chick.

To examine the role of kappa opioid receptors in memory formation, 2-day-old chicks were injected intracerebrally with either the endogenous opioid peptide dynorphin(1-13), the highly kappa selective agonist U-50,488 or the kappa selective antagonist nor-binaltorphimine (nor-BNI), given one-trial peck-avoidance training, and tested 24 h later. Dynorphin(1-13) impaired memory in a dose dependent manner at 24 h test. Injection of U-50,488 caused a biphasic dose-dependent effect on memory; low doses caused a trend toward enhanced memory and high doses caused significant impairment. Conversely, injection of low doses of nor-BNI caused a trend toward memory impairment, and higher doses caused significant memory enhancement. The results indicate that memory formation for one-trial peck-avoidance training may be modulated by kappa opioid receptor activity.


5-HT1A receptor agonists prevent in rats the yawning and penile erections induced by direct dopamine agonists.

The new compound (+) S-20499, an amino chromane derivative (8[-4[N-(5-methoxychromane-3yl)N-propyl]aminobutyl] azaspiro[4-5] décane-7,9 dione), is a high affinity full 5-HT1A agonist. We have investigated its effects on dopaminergic transmission. (+) S-20499 displayed a 10(-8) M affinity for D2 dopamine (DA) receptors, 100 fold lower than for 5-HT1A receptors. The hypothermic effect of the drug was reversed by haloperidol in mice, suggesting that it behaves as a direct dopamine agonist. However, increasing doses of (+) S-20499 induced neither yawning nor penile erections, which constitute characteristic responses of direct DA agonists administered at low doses. In addition, (+) S-20499 prevented the apomorphine (100 micrograms/kg SC) induced yawning and penile erections. This inhibition appears to result from the stimulation of 5-HT1A receptors since it is an effect shared by both buspirone (from 5 mg/kg) and 8-OH-DPAT (from 0.10 mg/kg). In addition, when rats are treated with the 5-HT1A receptor antagonist tertatolol (2-5 mg/kg; SC), increasing doses of (+) S-20499 elicit the expected yawns and penile erections. It is concluded that the 5-HT1A agonist property opposes to that of D2 dopamine receptor stimulation with regard to yawning and penile erections.


Delayed-non-match-to-sample performance in the radial arm maze: effects of dopaminergic and gabaergic agents.

Central dopaminergic transmission has been implicated in memory processes. The present experiments examined the effects of several direct acting dopaminergic agents on performance of a delayed-non-match-to-sample radial arm maze task. Preadministration of apomorphine (D1-D2 agonist; 0.25, 0.5, and 1.0 mg/kg), quinpirole (D2 agonist; 0.1 mg/kg), or SKF38393 (D1 agonist; 3 mg/kg) increased the latency of choices but did not affect any index of accuracy with a 1 h retention interval. Post-training administration of quinpirole (0.1, 0.2, 1.0, and 2.0 mg/kg), SKF38393 (0.3, 3.0, and 6.0 mg/kg), sulpiride (D2 antagonist; 3, 10, and 30 mg/kg), or SCH23390 (D1 antagonist; 0.01, 0.1, and 1.0 mg/kg) also did not affect accuracy, although quinpirole produced a dose-dependent increase in the latency of choices, assessed 10 h post-treatment. For comparison, pretraining and post-training administration of the benzodiazepine chlordiazepoxide (1, 3, 5 mg/kg) was also tested and produced dose-dependent impairments in mnemonic performance at either a 1 or 4 h retention interval. The effects of chlordiazepoxide are consistent with evidence indicating that GABAergic agents can influence memory processes. In contrast, the present findings indicate that (peripheral administration of dopaminergic agents IS) not sufficient to alter the mnemonic processes required for accurate performance of this DNMTS-RAM task.


Discriminative stimulus properties of 8-OH-DPAT: relationship to affinity for 5HT1A receptors.

Previous studies have shown that discriminative stimulus control established with the 5HT1A receptor agonist, 8-OH-DPAT, generalizes to other 5HT1A agonists and partial agonists but also to the alpha 2-adrenoceptor antagonist, yohimbine. On the basis of these results it has been proposed that the 8-OH-DPAT cue may be produced by activity at more than one receptor. In the present study rats were trained to discriminate a dose of 8-OH-DPAT (0.05 mg/kg, SC) from saline. Substitution tests showed dose-dependent generalisation with the 5HT1A compounds, buspirone, ipsapirone, MDL 72832 and MDL 73005EF, the alpha 2-adrenoceptor antagonists, yohimbine and idazoxan, and BMY 14802, which is usually described as a sigma ligand. The buspirone metabolite 1-pyrimidinyl piperazine (1-PP) which possesses mainly alpha 2-adrenoceptor antagonist properties produced only partial generalisation which was not dose related. Receptor binding studies showed that all the compounds which substituted for 8-OH-DPAT displaced [3H]-8-OH-DPAT binding to rat hippocampal membranes. Furthermore, there were statistically significant positive correlations between drug affinity for 5HT1A sites and their ED50 values for both substitution for 8-OH-DPAT and potency to decrease response rates. These results are consistent with the view that the 8-OH-DPAT cue, like the ability of the compounds tested to decrease rates of responding, is largely mediated by activity at 5HT1A receptors.


Changes in dopa decarboxylase mRNA but not tyrosine hydroxylase mRNA levels in rat brain following antipsychotic treatment.

The effects of antipsychotic administration (1-32 days, twice per day) on the levels of mRNA coding for dopa decarboxylase (DDC) and tyrosine hydroxylase (TH) in rat brain has been assessed by a procedure utilising solution hybridisation with oligonucleotides. Saline and sulpiride (20 mg/kg/day) had no apparent effect on DDC mRNA levels. Haloperidol (3 mg/kg/day) elicited increases in DDC mRNA levels of 240% after 32 days and loxapine (4 mg/kg/day) elicited increases of 180% in DDC mRNA levels. None of the drugs affected TH mRNA levels. These results indicate that DDC may be more important than TH in the long term regulation of dopamine production.


Pseudocyesis in organic mood disorders. Six cases.

Pseudocyesis, the delusion of pregnancy, has had an uncertain nosology, primarily because of the concentration on the content of the beliefs and lack of interest in the underlying phenomenology. Six patients with a major mood disorder caused by cerebral dysfunction are presented in this article. The delusion is reviewed with respect to the entities it overlaps, and the clinical manifestations are related to the mood disorders. Although no clear neuroanatomic localization was possible with this group of patients, there may be some association with desomatization caused by parietal lobe dysfunction.


Nicotinic systems and cognitive function.

Nicotinic acetylcholine receptors have been found to be important for maintaining optimal performance on a variety of cognitive tasks. In humans, nicotine-induced improvement of rapid information processing is particularly well documented. In experimental animals nicotine has been found to improve learning and memory on a variety of tasks, while the nicotinic antagonist mecamylamine has been found to impair memory performance. Nicotine has been found to be effective in attenuating memory deficits resulting from lesions of the septohippocampal pathway or aging in experimental animals. Nicotinic receptors are decreased in the cortex of patients with Alzheimer's disease. Preliminary studies have found that some aspects of the cognitive deficit in Alzheimer's disease can be attenuated by nicotine. Nicotine may prove to be useful therapeutic treatment for this and other types of dementia.


Blood-brain barrier: a molecular approach to its structural and functional characterization.

Our approach to analyze molecular components of the blood-brain barrier led to the identification of additional transcripts which can be regarded as "BBB markers". Other candidates are presently analyzed in order to find hitherto unknown cell type-specific transcripts. We investigated the expression of these marker-genes in cell culture and found all genes still being transcribed after 10 days in primary cultures, although at a lower level. This is surprising, since other authors report the disappearance of BBB characteristics under such conditions. Moreover, the BBB marker gamma-GT is found to be not only expressed in BMEC, but also in the closely associated pericytes. The hitherto unknown physiological function of the enzyme, especially the abundance in pericytes is still under investigation. Since the method of subtractive cloning has been proven as a fruitful approach, we consider to establish further subtractive cDNA libraries, using different subtraction parameters. The PCR method is applicable for amplification of subtracted cDNA (Timblin et al., 1990) and we expect to find additional clones, mainly of lower abundance which are of functional importance for the BBB phenomenon. The described characterization of cultured BMEC now allows to proceed to study BBB-specific gene expression with special regard to regulatory elements. We will perform these experiments by use of enhancer trap vectors transfected into BMEC. The isolation of the corresponding genomic DNA fragments of the BBB markers is in progress.


Development of an in vitro cell culture system to mimic the blood-brain barrier.

Primary cultures of brain capillary endothelial cells (BCECs) cocultured together with astroglia cells were used to investigate the induction of blood-brain barrier (BBB) characteristics in vitro. By immunofluorescence, histochemical staining, two-dimensional gel electrophoresis and enzyme activity tests we are able to show that BCECs in vitro loose typical blood-brain barrier properties but not their common endothelial phenotype. Astrocytes induce the expression of the blood-brain barrier characteristic enzymes gamma-glutamyltranspeptidase and alkaline phosphatase but only in a coculture system with direct cell to cell contact between BCECs and astroglia cells. C6-glioma cells also re-establish the BBB phenotype but were less effective compared to astrocytes. The susceptibility of the BCECs to an astroglial stimulus depends on the proliferative state of the BCECs.


[The structural-functional organization of the bone marrow after lethal irradiation and the transplantation of syngeneic hematopoietic cells].

A study was made of the content and morphology of haemopoietic islands in the bone marrow of lethally irradiated CBA mice, and their change after transplantation of syngeneic haemopoietic cells. The data obtained show that the haemopoietic islands are reconstructed in the injured haemopoietic tissue due to the donor's bone-marrow nuclears. A new type of structural and functional associations, namely, stromal haemopoietic islands, has been found.


Regulation of transendothelial transport in the cerebral microvessels: the role of second messengers-generating systems.

Different elements of the intracellular signaling messenger systems have been detected in the course of our studies in the cerebral endothelial cells. It has been shown that the synthesizing enzymes of and substrate proteins for the second messenger molecules are present in the cerebral endothelial cells, and their activity and/or amount can change in pathological circumstances, i.e., during the formation of brain oedema. Pharmacological treatments interfering with the second messenger systems proved to be effective in the prevention of brain oedema formation.


Sulfasalazine inhibits lyso-PAF: acetyl-COA acetyltransferase.

Sulfasalazine produced a dose-dependent inhibition of the enzymatic synthesis of platelet-activating factor (PAF) in lysates of rat pleural neutrophils, with an IC50 of 50 microM. Major metabolites of sulfasalazine, 5-aminosalicylic acid and sulfapyridine, inhibited this enzymatic synthesis at much higher concentrations. Inhibition of arachidonate 5-lipoxygenase by sulfasalazine and its major metabolites was also observed at higher concentrations (2-3 mM). Because PAF is a potent mediator of inflammatory responses, an inhibition of PAF synthesis by sulfasalazine may contribute to its therapeutic actions in conditions such as ulcerative colitis and rheumatic illnesses.


Conventional external irradiation alone as adjuvant treatment in resectable pancreatic cancer: results of a prospective study.

Between 1/85 and 1/90, 14 consecutive patients were entered into a prospective study of conventional adjuvant post-operative external beam radiotherapy after complete resection for a pancreatic adenocarcinoma. The surgical procedure was a Whipple resection in nine patients, a distal pancreatectomy in four patients and a total pancreatectomy in one patient. There were three T1b, eight T2 and three T3 tumours (UICC 1987); nodal involvement was present in five cases. The radiotherapy was delivered using a four-field box technique with a 23 x MV photon beam. All patients received a total dose of 54 Gy to the tumour bed. The mean treated volume was 900 cm3. Acute toxicities consisted mainly of weight loss (mean: 2 kg). Two patients had a grade 2 diarrhoea and two patients a grade 2 gastritis. Late effects were minimal and only observed in two patients. The overall locoregional recurrence (LR) rate was 50%. The median disease-free survival was 12 months, and the median survival was 23 months. This post-operative conventional radiotherapy treatment gives results that are comparable to the results of the GITSG-adjuvant study using a combination of split-course radiotherapy and 5-fluorouracil (5-FU).


Phenotype of a Rhizobium leguminosarum ntrC mutant.

A Tn5 insertion mutant, strain CFN2012, of Rhizobium leguminosarum biovar phaseoli devoid of glutamine synthetase II (GSII) activity was analysed. It was shown to contain Tn5 within an 11-kb BamHI DNA fragment, which was isolated (pSM261) from the wild-type strain and, when introduced into strain CFN2012, was shown to complement the absence of GSII activity. The DNA sequence of the corresponding region from the wild-type allele revealed the presence of an ntrC regulatory gene, and restriction analysis indicated that the mutant allele carried the Tn5 insertion within it. Further analysis of strain CFN2012 indicated that this mutant has reduced levels of the PII regulatory protein and that, in contrast to ntrC mutants of other Rhizobiaceae, it grows on nitrate as the sole nitrogen source.


[Treatment of depressed patients: current trends. Combination cognitive group therapy with cognitive adjustment for depressed inpatients].

Depressed patients represent a major part of the inpatient population. The following treatment program was developed in order to respond to this problem in a symptom- and cost-effective way. Cognitive therapy was chosen for it's learning aspect and combined with pharmacotherapy. The four-week treatment program is implemented in an open-ended group setting, where daily therapy sessions are associated with various group activities. The pre- and posttreatment and six months follow-up results of the first 80 patients are presented.


[Global approach to the treatment of chronic asthma in adults].

The reduction of the bronchial inflammatory reaction, in itself a triggering event for bronchospasm, is one of the main targets for treatment in bronchial asthma. An early engagement of anti-inflammatory agents is, therefore, as necessary for long-term treatment as the reduction of irritating or antigenic environmental factors. Assessment of therapeutic efficacy necessitates a regular and long-lasting surveillance of the patient. It can be provided by peak-flow measurement, performed by the patient himself. Finally, the close cooperation by patient and physician as well as the elaboration of a training program teaching the patient pathophysiology, symptoms and therapeutic possibilities are decisive for therapeutic success, i.e. the best possible restitution of pulmonary function.


[Iatrogenic neuropathies].

During the last few years the list of drugs capable of inducing a iatrogenic neuropathy has been considerably lengthened. Drug toxicity to peripheral nerves may be discovered at the experimental stage, but it is usually recognized after the drug has been launched on the market, hence the importance of pharmacovigilance. The responsibility of a drug for the occurrence of neuropathy may be difficult to prove, particularly when the drug is used in the treatment of a disease which, by itself, may be responsible for a lesion of the peripheral nervous system. Iatrogenic neuropathies are usually axonal, but some drugs produce a primary disorder in the myelin-Schwann cell couple. Schwann cell diseases may be induced by drugs, such as perhexiline maleate, amiodarone or chloroquine, which inhibit lysosomal enzyme activity. In such cases inclusions representing fat-loaded lysosomes can be detected in various tissues, and particularly in Schwann cells. In certain patients, notably those treated with gold salts, an immune mechanism might be responsible for neuropathy. Most drug-induced neuropathies are due to a primary lesion of the neuron which is more often an axonopathy than a neuronopathy. It is usually a retrograde distal axonopathy the occurrence of which is attributed to a disorder of the fast retrograde axonal flow. In a few cases, the finding of a biochemical mechanism perturbing the axonal flow may help in preventing the occurrence of a iatrogenic neuropathy.


[Acute respiratory insufficiency caused by hyperinfestation with strongyloides. BALF diagnosis and favourable outcome].

Hyperinfestation with Strongyloides is a severe complication in immunodepressed patients. It may present with various clinical signs, notably acute respiratory failure. Diagnosis may be difficult, particularly when the strongyloidiasis is associated with septicaemia caused by Gram-negative organisms. We report a new case of hyperinfestation with Strongyloides in a patient treated for periarteritis nodosa. This case was remarkable on two scores: the diagnosis problem raised by the presence of intrapulmonary haemorrhages, and the favourable outcome of an acute and initially severe respiratory failure which had required assisted ventilation. The role played in the patient's cure by the doses of thiabendazole given and the duration of their administration is discussed.


Studies of autacoid responsiveness and endothelium dependency in human umbilical arteries.

The effect of serotonin, prostaglandin E2 (PGE2) and PGF2 alpha on the smooth muscle tension in perfused human umbilical arteries was investigated before and after removal of the endothelium. Denudation was performed mechanically using a nylon filament loop, and the efficiency of the procedure was checked by electron microscopy. In non-denuded vessels the autacoids elicited biphasic pressure responses, all starting with a vasodilatation and followed by a strong vasoconstriction. After denudation no dilatatory responses were evoked, whereas the constrictory responses appeared to be unchanged. Pre-treatment of the vessels with methylene blue did not affect the autacoid responses. Generally the perfusion pressure decreased after the de-endothelialization, in some preparations to levels of about 50% of the initial perfusion pressure. In about one-third of the preparations exposure to methylene blue led to a definite pressure increase. The results indicate that endothelium-derived factors are involved in the autacoid responses and also in the maintenance of basic vascular tonus in the umbilical circulation.


Clinical aspects of gastroduodenal ulcer recurrence: an overview.

Duodenal ulcer is a disease characterized by very high rates of recurrence: up to 80% at 1 year, 95% at 2 years. Maintenance therapy will reduce relapse rates. However, when therapy directed against gastric acid is stopped, the slope of the recurrence curve is identical whether therapy is stopped after 6 weeks, 8 weeks, 3 months, 6 months, 1 year, or 2 years. This suggests that therapy directed against acid does nothing to change the natural history of ulcer disease. Cytoprotective therapy is equally successful as H2-blockers at healing ulcer or reducing relapse rates, but the time to recurrence is significantly prolonged after either acute or maintenance cytoprotective therapy is stopped. This suggests that cytoprotective therapy has a beneficial effect that does improve the natural history of ulcer disease. The mechanism by which maintenance therapy reduces ulcer relapse could be masking symptoms (analgesic), accelerated healing, or true prevention of ulcer recurrence. By using frequent endoscopic assessment combined with complex statistical evaluation (calculating traditional ulcer prevalence, point prevalence, and maximal ulcer prevalence), we showed that sucralfate cytoprotection genuinely prevents ulcer recurrence. The incidence of asymptomatic ulcer recurrence after sucralfate is 10% but is up to 40% after H2-blocker therapy.


H-2 class I Ld antigen positively selects different TCR V beta gene products in CD8+ and CD4+ T cells.

Expression of CD4+ or CD8+ determinants and ten different TCR V beta genes was analysed by two-colour flow cytometry in lymph node cells (LNC) of BALB/c and dm2 (a BALB/c Ld loss mutant) mice. TCR V beta 14 expression of CD8+ T cells and TCR V beta 7 and 14 of CD4+ T Cells were significantly more frequent in BALB/c than in dm2 LNC, whereas no differences were observed in the frequency distribution of TCR V beta+ CD4-CD8- double negative LNC from BALB/c versus dm2 mice. These results represent the first published evidence for positive selection of particular TCR V beta genes by individual MHC class I molecules in non-manipulated mice.


Treatment of the neuroleptic-nonresponsive schizophrenic patient.

The treatment and management of neuroleptic-resistant schizophrenic patients, who comprise 5 to 25 percent of all patients with that diagnosis, are major problems for psychiatry. In addition, another large group of schizophrenic patients, perhaps 5 to 20 percent, are intolerant of therapeutic dosages of neuroleptic drugs because of extrapyramidal symptoms, including akathisia, parkinsonism, and tardive dyskinesia. Because about 60 percent of neuroleptic-resistant schizophrenic patients respond to clozapine and a large percentage of neuroleptic-intolerant patients are able to tolerate clozapine, it should be considered the treatment of choice for such patients until other therapies are proven to be superior. A trial of clozapine alone should usually be continued for up to 6 months before it is terminated or supplemental agents are tried. Plasma levels of clozapine may be useful to guide dosage. The major side effects of clozapine are granulocytopenia or agranulocytosis (1%-2%) and a dose-related increase in the incidence of generalized seizures. Psychosocial treatments such as education of the patient and the family about the nature of the illness, rehabilitation programs, social skills training, and assistance in housing are generally needed to obtain optimal benefit from clozapine, as with other somatic therapies. If clozapine is unavailable, unacceptable, or not tolerated, a variety of approaches may be employed to supplement typical antipsychotic drugs for patients who do not respond adequately to these agents alone. These include lithium; electroconvulsive therapy; carbamazepine or valproic acid; benzodiazepines; antidepressant drugs; reserpine; L-dopa and amphetamine; opioid drugs; calcium channel blockers; and miscellaneous other pharmacologic approaches. The evidence for the efficacy of these ancillary somatic therapies in treatment-resistant patients is relatively weak. Polypharmacy should be tried only for discrete periods and with clear goals. If these are not achieved, supplemental medications should be discontinued. Psychosurgery is not a recommended alternative at this time.


Oncogenes and oncoproteins in occupational carcinogenesis.

It seems increasingly likely that an important mechanism of action of certain workplace carcinogens in contributing to occupational carcinogenesis may be via the activation of cellular oncogenes, which then cause an expression of mutated forms or increased amounts of their oncoprotein products. Two prototypical models of this mechanism may be the ras oncogene and its p21 protein and the neu oncogene and its p185 protein. Both are known to be activated by exposure to common occupational carcinogens, and both are known to occur frequently in human tumors, including those of occupational concern such as lung cancer. Knowledge of their mechanisms of action may lead to new opportunities for preventing occupational cancer.


[Current molecular prognostic factors in breast carcinoma].

In breast cancer the tumor stage, axillary lymph node metastases and hormone receptors are well established prognostic factors. Nevertheless, additional prognostic factors are still desirable. Recently, attention has focussed on molecular markers, in particular mutated genes involved in the pathogenesis of breast carcinoma. The first such marker to be tested for its clinical relevance has been the c-erbB-2 oncogene. However, the results of the many studies published on this subject are controversial. Further progress can be expected from two different strategies. The molecular pathogenesis of breast cancer must be elucidated in more detail, since it is likely that breast cancer is the result of a progressive accumulation of many different somatic mutations in diverse genes such as oncogenes and tumor-suppressor genes. Rather than relying on retrospective analyses, the clinical relevance of new markers must be tested in prospective clinical trials.


[Main coronary artery stenosis: a continuous challenge].

The pre- and postoperative course in 118 patients (104 males, mean age 62 +/- 8.1, 14 females, 60 +/- 10.7 years) who underwent coronary artery bypass surgery for significant left main coronary artery disease was studied to analyze the current management and risk factors of this lesion. Of these patients 32% (38/118) remained in hospital care from the date of diagnosis (coronary angiography) until the operation. The mean interval between diagnosis and operation was 39 days (range 0-166). Twelve patients (10%) had urgent procedures (< or = 48 hours after angiography), 25 (21%) accelerated (< or = 2 weeks), 52 (44%) anticipated (< or = 2 months) and 30 (25%) elective procedures (> 2 months). There was a significant negative correlation (p < 0.001) between the grade of stenosis and the time interval from diagnosis to operation. The operation technique did not differ from the usual procedure except for the less frequent use of the internal mammary artery as arterial conduit. Patients with stable angina received an internal mammary artery graft in 65% (80/118) as compared to 26% (6/23) of the patients with unstable angina. This differs significantly from the overall rate of 95% of the patients undergoing coronary artery bypass surgery at our institution. The rate of perioperative myocardial infarction was 18% (21/118). There was no significant relation between infarction and angina class, severity of the stenosis and the use of internal mammary artery as bypass graft. The hospital mortality was 4.2% (5/118) and thus was not different from the overall mortality of (2.5%).(ABSTRACT TRUNCATED AT 250 WORDS)


Calcium channels coupled to glutamate release identified by omega-Aga-IVA.

Presynaptic calcium channels are crucial elements of neuronal excitation-secretion coupling. In mammalian brain, they have been difficult to characterize because most presynaptic terminals are too small to probe with electrodes, and available pharmacological tools such as dihydropyridines and omega-conotoxin are largely ineffective. Subsecond measurements of synaptosomal glutamate release have now been used to assess presynaptic calcium channel activity in order to study the action of peptide toxins from the venom of the funnel web spider Agelenopsis aperta, which is known to inhibit dihydropyridine and omega-conotoxin-resistant neuronal calcium currents. A presynaptic calcium channel important in glutamate release is shown to be omega-Aga-IVA sensitive and omega-conotoxin resistant.


Isomerase and chaperone activity of prolyl isomerase in the folding of carbonic anhydrase.

Several proteins have been discovered that either catalyze slow protein-folding reactions or assist folding in the cell. Prolyl isomerase, which has been shown to accelerate rate-limiting cis-trans peptidyl-proline isomerization steps in the folding pathway, can also participate in the protein-folding process as a chaperone. This function is exerted on an early folding intermediate of carbonic anhydrase, which is thereby prevented from aggregating, whereas the isomerase activity is performed later in the folding process.


Negative selection of precursor thymocytes before their differentiation into CD4+CD8+ cells.

Thymic selection of the developing T cell repertoire is thought to occur at the CD4+CD8+ stage of differentiation and to be determined by the specificity of the T cell receptors (TCRs) that CD4+CD8+ thymocytes express. However, TCR signals can inhibit the differentiation of precursor thymocytes into CD4+CD8+ cells, which suggests that selection might occur earlier than thought. Indeed, in a negatively selecting male thymus, CD4-CD8lo precursor thymocytes that express a transgenic TCR to male antigen are developmentally arrested as a consequence of antigen encounter and fail to become CD4+CD8+. Thus, negative selection can occur before the CD4+CD8+ stage of differentiation.


[An autopsy case of malignant rheumatoid arthritis (MRA) which was difficult to distinguish from polyarteritis nodosa (PN)].

We encountered a patient who was diagnosed as rheumatoid arthritis (RA) at 15 years old and developed malignant RA (MRA) within one year. He suffered from mononeuritis multiplex and cutaneous infarction. Despite of treatment including steroid pulse therapy, neuritis progressed. Lung infiltration, pancreatitis and intestinal bleeding were accompanied. He died of disseminated intravascular coagulation on 153 days after admission. Autopsy revealed systemic rheumatoid vasculitis in coronary artery, pancreas, liver, small and large intestine, kidney and lung. These severe vasculitis occurred in young RA patient are rare case and it is important to consider the therapy and prognosis.


Multiple endocrine adenopathy.

The syndromes of multiple endocrine adenopathy (MEA) have associated endocrine abnormalities that are similar to the clinical syndromes based in the same hyperfunctions of parathyroid, pancreatic islets, thyroid C-cell and chromaffin tissue seen in sporadic cases. The natural history, histopathology and management of these problems when they occur in the hereditary MEA syndromes differ in significant and instructive ways over the isolated disorders. These differences and similarities of MEA adenopathies were discussed at an international conference, with the suggestion that the MEA syndromes afford opportunity to investigate regulation and control of pathogenesis in surgical endocrinological syndromes.


Dopamine supersensitivity and D1/D2 synergism are unrelated to changes in striatal receptor density.

Experiments were conducted to elucidate the relationships among striatal dopamine receptor density, behavioral manifestations of D1/D2 synergism (i.e., the requirement of concomitant stimulation of D1 and D2 receptors for the expression of stereotyped sniffing, licking and gnawing), and behavioral supersensitivity to dopamine agonists. The state of D1/D2 synergism was found to be independent of striatal D1 or D2 receptor density in rats as: (1) increasing striatal D1 and/or D2 receptor density (as confirmed by quantitative receptor autoradiography) by chronic treatment with SCH 23390 (0.5 mg/kg/day for 21 days) and/or haloperidol (0.5 mg/kg/day for 21 days) did not alter the normal pattern of D1/D2 synergism as determined by behavioral responsiveness to agonist stimulation of D1 or D2 receptors, and (2) 5 days of reserpine treatment (1 mg/kg/day), although not significantly changing striatal D1 or D2 receptor density, induced a breakdown in D1/D2 synergism (i.e., behavior was elicited by independent stimulation of D1 or D2 receptors). In addition, the density of striatal D2 binding sites was not indicative of behavioral sensitivity to D2 agonists. Chronic haloperidol treatment increased behavioral sensitivity to the D2 agonist quinpirole by a factor of 2. When tested 96 h after bilateral 6-hydroxy-dopamine injections or after 5 daily reserpine injections, supersensitivity to quinpirole was at least double that following chronic haloperidol, without accompanying increases in striatal D2 density. This enhanced sensitivity to quinpirole was no greater than that observed in neurologically intact rats treated concomitantly with a maximally stimulating dose of SKF 38393. Furthermore, rats with unilateral 6-hydroxydopamine lesions that were treated chronically with eticlopride continued to rotate contralateral to the lesion in response to quinpirole despite having hemispheric symmetry of striatal D2 receptor binding. By contrast, when rats with unilateral 6-hydroxydopamine lesions were given 5 daily reserpine injections, rotation was abolished, having been replaced by intense stereotyped sniffing, indicative of bilateral supersensitivity. The results support the hypothesis that two distinct types of dopamine supersensitivity exist: a modest one associated with increased D2 density, and a more profound one associated with a breakdown in D1/D2 synergism and independent of D2 density.


Regional distribution of neuropeptide somatostatin gene expression in the human brain.

The regional distribution of mRNA coding for the neuropeptide somatostatin has been studied in the human brain by in situ hybridization histochemistry using 32P-labeled oligonucleotides. We show that somatostatin mRNA-containing neurons are widely distributed in a number of nuclei and grey areas of the human brain, including neocortex, putamen, nucleus caudatus, nucleus accumbens, amygdala, midbrain, medulla oblongata, hippocampal formation, reticular nucleus of the thalamus, and posterior nucleus of the hypothalamus. No significant hybridization signal was observed in the substantia nigra, claustrum, globus pallidus, thalamus, and cerebellum. The topographic localization of neurons containing SOM mRNA in the human brain is in agreement with previous studies using immunocytochemical or radioimmunoassay techniques. These results show that in situ hybridization histochemistry with oligonucleotide probes can be used to map the distribution of neurons expressing SOM mRNA in human postmortem materials.


Somatostatin binding reduced by ammonium acetate in the rat hippocampus can be reversed by treatment with N-carbamyl-L-glutamate plus L-arginine.

The effects of short-term (90 min), mid-term (5 days), and long-term (15 days) administration of ammonium acetate (5 mmol/Kg day i.p.) on the somatostatinergic neurotransmitter system of the rat hippocampus have been studied. Scatchard analysis of the binding of 125I-Tyr11-somatostatin to hippocampal dissociated cells indicated that administration of ammonium acetate at the times studied were associated with a decrease in the number of somatostatin receptors in this brain area, whereas the affinity of the same receptors remained unchanged. Administration of ammonium acetate did not affect the levels of somatostatin-like immunoreactivity in the hippocampus. Treatment with N-carbamyl-L-glutamate (1 mmol/Kg, i.p.) plus L-arginine (1 mmol/kg), which lead to the conversion of ammonia into urea, prevented the ammonium acetate-induced changes in somatostatin binding in this brain area. N-carbamyl-L-glutamate plus L-arginine alone had no observable effect on the somatostatinergic system. The decrease in the number of somatostatin receptors induced by ammonium acetate might reflect a decreased sensitivity of the target cells to somatostatin, a phenomenon that could contribute to the depressed neuronal excitability induced by ammonia in the rat hippocampus.


Alteration of 5-HT1A receptor binding sites following chronic treatment with ipsapirone measured by quantitative autoradiography.

Ipsapirone, a high-affinity ligand for the 5-hydroxytryptamine1A (5-HT1A) receptor subtype, has been shown to be a full agonist at presynaptic serotonergic sites and a partial agonist at postsynaptic sites. Several recent studies have examined the effects of chronic treatment with ipsapirone or other structurally related pyrimidinylpiperazine compounds, including buspirone and gepirone, on 5-HT1A binding sites with mixed results. Since the neural mechanism responsible for the anxiolytic and antidepressant properties of these compounds is currently uncertain, further investigation of this issue appeared warranted. [3H]8-hydroxy-2-(di-n-propylamino)-tetralin ([3H]8-OH-DPAT), a ligand specific for the 5-HT1A site, has been used successfully to label these sites using both membrane binding assays and autoradiography. Experiments were performed to determine whether chronic treatment with ipsapirone would differentially affect binding to 5-HT1A receptors at different brain sites. Rats were treated twice daily with ipsapirone (10 mg/kg i.p.) for 1 day or for 1, 2, or 3 weeks. Quantitative analyses were done of autoradiograms of in vitro [3H]8-OH-DPAT binding to selected brain regions. Binding in vehicle-treated rats was highest in the hippocampus, septal nucleus, interpeduncular nucleus, entorhinal cortex, and dorsal raphe nucleus. Following 3 weeks of treatment with ipsapirone, a large decline in binding was measured in the dorsal raphe nucleus. This decline was not seen with ipsapirone treatments for shorter periods. With the 3-week treatment, there were less robust declines in [3H]8-OH-DPAT binding in the entorhinal cortex and interpeduncular nucleus. Binding in the other brain regions analyzed was unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)


Induction of tissue transglutaminase and apoptosis by retinoic acid in the limb bud.

Mesenchymal cells in the limb buds of midgestation mouse embryos suffer prominent cell death upon exposure to retinoic acid (RA), an event likely associated with the micromelic and phocomelic anomalies of the resultant fetuses. It has been suggested, but not yet shown, that cells die by an active process termed apoptosis rather than by necrotic cytolysis. In certain cell types, investigators have previously observed a specific and early effect of RA on transcriptional activation of the gene for tissue transglutaminase (tTG), an enzyme suspected to play a role in apoptosis. We report here a distinct but transient increase in tTG activity which accompanied the initiation of cell death in the mesenchymal cells located in the central core of RA-treated limb buds. We also ascertained microscopically that the cytological appearance of the affected cells was consistent with a characterization of the process of cell death as apoptosis.


Glutathione metabolic enzyme activities in diabetic platelets as a function of glycemic control.

Type 1 diabetic subjects categorized on the basis of the glycated haemoglobin content of their blood (low less than 7%; medium, greater than 7% and less than 11%; high, greater than 11%) were analyzed for total intraplatelet GSH as well as for the steady-state kinetic parameters (apparent KM and apparent Vmax) of some glutathione metabolic enzymes including glutathione reductase, glutathione peroxidase, gamma-glutamyltrans-peptidase and glutathione-S-transferase. This study indicates that intraplatelet GSH content of subjects with low glycated-haemoglobin is approximately 2-fold higher than those with medium glycated-haemoglobin. There was no further decrease in intraplatelet-GSH in subjects with high glycated-haemoglobin. The kinetic parameters of the platelet-enzymes studied (glutathione reductase, gamma-glutamyltranspeptidase and glutathione-S-transferase) were essentially independent of the glycation state of the subject. However, the apparent KM of glutathione peroxidase was approximately 4-fold higher in the subjects with high glycated-haemoglobin, in comparison to low subjects. This decrease in affinity could possibly result from the susceptibility of this enzyme to non-enzymatic glucosylation as purified samples of glutathione peroxidase incubated in vitro with glucose showed similar increases in apparent KM. These results are discussed in terms of the potential contribution of glutathione peroxidase impairment, to the hyperaggregability of the diabetic platelet.


[Affective disorders. Drug treatment and electroconvulsive therapy].

Optimal treatment of mood disorders and prevention of suicide requires biological and psychosocial methods, therapeutic alliance and psycho-education. In moderate unipolar depression an antidepressant may be sufficient, if necessary potentiated by another antidepressant or triiodothyronine. In moderate bipolar depression lithium or carbamazepine are preferred. In severe unipolar and bipolar depression the combination of an antidepressant and lithium (or carbamazepine) or electroconvulsive therapy (ECT) is indicated, in psychotic depression neuroleptics, too. Non-selective monoamine oxidase inhibitors (MAOIs) are the most potent antidepressants. Moderate acute mania and mixed state may respond to lithium, carbamazepine or valproate only. In severe cases a neuroleptic and lithium are combined, or these drugs may be combined with carbamazepine or valproate. Electroconvulsive therapy is preferable in acute mixed states with marked confusion or depression. In chronic mixed state and rapid cycling, withdrawal of antidepressants and neuroleptics should be tried. Most patients will need a combination of lithium and carbamazepine or valproate. Added to these drugs, antidepressants are less risky. Adding thyroxin may stabilize rapid cycling. The combination of lithium and an antidepressant is the most potent prophylaxis in unipolar disorder and bipolar disorder dominated by depression.


Cell physiology and pharmacology of gastric acid secretion.

Our stomach produces daily a large amount of hydrochloric acid at a pH close to 1. This secretion represents a more than one million-fold in H+ ion concentration as compared to blood and intracellular medium of a pH of 7.4. It is due to a specialized cell, the parietal cell, which contains a unique transport enzyme, the (H+, K+)-ATPase. The parietal cell is itself under the control of several endocrine and paracrine stimuli operating through appropriate receptors. The recent progresses achieved in the knowledge of these key elements of the acid secretion mechanism had led to the development of specific and potent inhibitors of crucial interest in the treatment of ulcer disease and reflux oesophagitis such as histamine H2 and (H+, K+)-ATPase antagonists.


[Sudden cardiac death. Significance of beta blockaders].

Sudden death accounts for about 15-20% of all natural fatalities in the industrially developed world. Most of the victims have a substrate of extensive myocardial injury caused by coronary heart disease, cardiomyopathy and hypertensive heart disease. In most cases, the immediate cause of death is triggered by ventricular tachycardia which degenerates into ventricular fibrillation. Changes in myocardial electrical properties may be critically modified by ischemia, imbalance in the autonomic nervous system, electrolytic disorders, and haemodynamic factors. We review the causes of sudden cardiac death, giving special attention to the effect of beta-adrenoceptor blockade as a preventive measure.


HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation.

In most PCR-based tissue typing techniques the PCR amplification is followed by a post-amplification specificity step. In typing by PCR amplification with sequence-specific primers (PCR-SSP), typing specificity is part of the amplification step, which makes the technique almost as fast as serological tissue typing. In the present study primers were designed for DR "low-resolution" typing by PCR-SSP, i.e. identifying polymorphism corresponding to the serologically defined series DR1-DRw18. This resolution was achieved by performing 19 PCR reactions per individual, 17 for assigning DR1-DRw18 and 2 for the DRw52 and DRw53 superspecificities. Thirty cell lines and 121 individuals were typed by the DR "low-resolution" PCR-SSP technique, TaqI DRB-DQA-DQB RFLP analysis and serology. The concordance between PCR-SSP typing and RFLP analysis was 100%. The reproducibility was 100% in 40 samples typed on two separate occasions. No false-positive or false-negative typing results were obtained. All homozygous and heterozygous combinations of DR1-DRw18 could be distinguished. Amplification patterns segregated according to dominant Mendelian inheritance. DNA preparation, PCR amplification and post-amplification processing, including gel detection, documentation and interpretation, were performed in 2 hours. In conclusion, PCR-SSP is an accurate typing technique with high sensitivity, specificity and reproducibility. The method is rapid and inexpensive. DR "low-resolution" typing by the PCR-SSP technique is ideally suited for analyzing small numbers of samples simultaneously and is an alternative to serological DR typing in routine clinical practice including donor-recipient matching in cadaveric transplantations.


[Mode of action of sulfasalazine in chronic inflammatory enterocolonic diseases].

We have investigated the mode of action of the sulphasalazine in ulcerative colitis and Crohn's ileitis. We point out: a) the activity of sulphasalazine and its derivative, 5-aminosalicylic acid in prostaglandin's metabolites pathway, by inhibition of lipoxygenase; b) a moderate activity on the cell-mediated immunity by weak inhibition of natural killer activity; c) the 5-amino salicylic acid is effective strongly like a radical scavenger.


Progression of HIV-related disease is associated with HLA DQ and DR alleles defined by restriction fragment length polymorphisms.

A cohort of 139 hemophiliacs was typed for HLA D region genes by means of restriction fragment length polymorphisms (RFLPs) detected by HLA DQ and DR gene probes. Disease progression was studied in the 65 HIV antibody-positive patients, who were infected by contaminated clotting factor before 1985. Strong associations were found between disease progression in HIV-infected patients and allelic DNA fragments revealed by a DQ alpha cDNA probe. A 5.5 kb fragment was reduced in frequency and a 4.6 kb fragment increased in frequency (p less than 0.005) in the faster progressing group, as measured both by development of CDC Category IV clinical symptoms and CD4 number less than 200 x 10(6)/l. These results correlate with DR types deduced from the RFLP patterns revealed by DR beta and DQ alpha gene probes. A decrease in DR4 and an increase in both DR5 and the DR3 subtype found in the A1 B8 DR3 haplotype were associated with disease progression (p less than 0.05).


Improvement in HLA-DQB typing by PCR-RFLP: introduction of a constant restriction site in one of the primers for digestion control.

The PCR-RFLP method previously reported by Inoko is a powerful technique for HLA class II typing. The reliability of RFLP interpretation depends on complete digestion by restriction endonucleases using a modified primer with restriction sites as an internal digestion control. The use of restriction enzymes which recognize specific HLA DQB allelic variations makes HLA DQB genotyping possible.


HLA class II alleles associated with celiac disease susceptibility in a southern European population.

Susceptibility to celiac disease in Northern Europe is associated with the human leukocyte antigens (HLA) B8, DR3 and DQ2, which exist together on an extended haplotype. The strong predominance of this haplotype within the Northern European celiac populations, together with the linkage disequilibrium which occurs between these loci, does not allow identification of the gene(s) primarily associated with disease susceptibility. Studies from Southern Europe using both serology and examination of restriction fragment length polymorphisms (RFLP) have demonstrated associations with DR3, DR7 and DQ2, suggesting that the DQ locus is primarily involved. We investigated 43 celiac patients and 41 healthy controls from Rome, Italy, using sequence-specific oligonucleotide (SSO) probes, in conjunction with gene amplification by the polymerase chain reaction (PCR), to determine alleles at the DRB, DQA1, DQB1 and DPB1 loci: 19% of celiac patients possessed the alleles DRB1*0301 DRB3*0101, 33% DRB1*0301 DRB3*0201 and 33% of celiac patients were heterozygous for DRB1*1101-1201/DRB1*0701. The strongest association with celiac disease susceptibility was the combination of alleles DQA1*0501 DQB1*0201 (91% celiac patients vs. 12% controls; p = 0.000002). There was no additional susceptibility associated with alleles at the DPB locus. This study confirms the hypothesis that susceptibility is associated with a particular combination of DQ alleles and the ethnic variation in DR frequencies is secondary to linkage disequilibrium with these DQ alleles.


Renal hemodynamics in canine DOCA-salt hypertension: effect of calcium channel blockade.

Systemic arterial blood pressure (BP), renal blood flow (RBF), and renal vascular resistance (RVR) were followed for 3-4 wks during the progression of DOCA-salt hypertension in the conscious dog. Accompanying the gradual increase in BP was an increase in RBF; however, RVR was unchanged. The hypertension was totally reversed 5-7 days after cessation of DOCA-salt treatment, but the increase in RBF persisted, presumably as a result of renal hypertrophy. Renal adrenoceptor blockade with prazosin (6 dogs) and prazosin plus idazoxan (4 dogs) caused a comparable decrease in BP in the normotensive and DOCA-salt hypertensive dog; however, RVR was decreased only in the normotensive. Similar results were obtained during ganglionic blockade with hexamethonium. The i.v. infusion of diltiazem for 1 wk restored BP of the hypertensive dog to a normotensive level, and hexamethonium given i.v. had little further effect on either BP or RVR. These results suggest a non-neurogenically mediated mechanism of canine DOCA-salt hypertension that is susceptible to calcium channel blockade.


Enzyme induction and receptor-binding affinity of steroidal 20-carboxamides in rat hepatoma tissue culture cells.

The steroidal 20-carboxamides [(20R)- and (20S)-21-(N-substituted amino)-11 beta,17,20-trihydroxy-3,21-dioxo-1,4-pregnadiene] recently have been shown to possess anti-inflammatory activity in animal models of inflammation. These N-substituted methyl, ethyl, n-propyl, and benzyl derivatives also exhibited suppressive effects on plasma corticosterone and thymus function. Generally, the (20R)-hydroxy-20-carboxamides were more potent than the corresponding (20S)-epimers. In continuing investigations on the glucocorticoid effects of these compounds, we have studied their ability to induce tyrosine aminotransferase (TAT), inhibit uptake of [3H]thymidine into DNA, and complete with [3H] dexamethasone for binding to the hepatoma tissue culture glucocorticoid receptor. Results indicated that the N-substituted methyl, ethyl, and n-propyl derivatives were full glucocorticoid agonists in the three measurements. Receptor binding affinities of the N-substituted carboxamides correlated well with their ability to induce TAT activity and to inhibit thymocyte proliferation. Structure-activity relationships indicated that the larger the N-substituent, the weaker the agonist activity in this system, and 20R isomers exhibited higher glucocorticoid agonist activity than the corresponding 20S isomers. This investigation is part of our effort to elucidate structure-activity relationships of steroidal carboxamides synthesized on the basis of the antedrug concept.


Protective effect of synaptic inhibition during cerebral ischemia in rats and rabbits.

Excitatory neurotransmitters appear to cause cell death during ischemia by inducing depolarization, influx of ions, and metabolic failure in the postsynaptic neuron. If this hypothesis is correct, then postsynaptic membrane hyperpolarization and inhibition of metabolism may be protective. Antagonists of the excitotoxic amino acid glutamate protect neurons in culture and in animal models of stroke but appear to cause unacceptable side effects in humans. We propose an alternative strategy of protection using agonists of the inhibitory neurotransmitter gamma-aminobutyric acid. We caused multifocal cerebral ischemia in rats and rabbits by injecting microspheres into the carotid circulation. We administered saline, muscimol, or MK-801 within 5 minutes of stroke onset. We used a bioassay to measure outcome. In rats, we also used learning to assess cortical function, and we performed detailed quantitative brain morphometry 3 months after infarction. Using the bioassay, we found that muscimol exerted a protective effect in rats (p less than 0.01). There was a dose-response effect seen in muscimol-treated rabbits. Rats treated with muscimol or MK-801 exhibited significantly better visual-spatial learning compared with saline-treated subjects (p less than 0.001). Hemisphere volume after ischemia was comparable in all groups. Agonists of gamma-aminobutyric acid and antagonists of glutamate appear to protect brain during ischemia. Since agonists of gamma-aminobutyric acid are known to have fewer side effects in humans, they may prove more useful in the clinical setting as neuroprotective agents.


Endothelium-derived relaxing factor in brain blood vessels is not nitric oxide.

The endothelium-derived relaxing factor that mediates the actions of acetylcholine is now most frequently identified as nitric oxide. Nitric oxide is believed to have numerous important regulating actions in neurons, blood vessels, and several other biological systems. The literature concerning tissue other than cerebral blood vessels supports the conclusion that the endothelium-derived relaxing factor for acetylcholine is either nitric oxide or a compound formed from and containing nitric oxide (for example, a nitrosothiol). However, papers can be found indicating that this endothelium-derived mediator is not nitric oxide. In brain blood vessels the evidence is strongly against the conclusion that nitric oxide is the endothelium-derived mediator for acetylcholine. If this mediator is formed from nitric oxide, either in brain vessels or in other vessels, no data are available delineating how this synthesis is regulated or whether and where nitric oxide leaves the nitroso compound to initiate dilation. Indeed, cerebrovascular data now cast doubt on the commonly held belief that nitrosovasodilators regulate vascular tone by giving off nitric oxide to vascular smooth muscle. In brain blood vessels the chemical identity of the endothelium-derived relaxing factor mediating the action of acetylcholine is unknown, but this relaxing factor does not appear to be nitric oxide. If the mediator contains nitric oxide, as is probably the case, the means by which it activates vascular guanylate cyclase and/or produces dilation is unknown. Since this relaxing factor inhibits platelet adhesion/aggregation in cerebral vessels as well as relaxing these vessels, the chemical identification of this relaxing factor and the elucidation of its mode of action are extremely important to our understanding and control of cerebrovascular phenomena in health and disease.


Engraftment with peripheral blood stem cells collected by large-volume leukapheresis for patients with lymphoma.

Seven patients with refractory lymphomas underwent marrow reconstitution with peripheral blood stem cells (PBSCs) harvested by large-volume leukapheresis (LVL). PBSCs were collected from all patients more than 1 month after the last cycle of chemotherapy, and no patient received growth factors. The median number of LVL procedures performed per patient was 4.5, with a mean volume of 24.5 L of blood processed per procedure to obtain 7 x 10(8) mononuclear cells per kg. Autologous PBSCs and platelets were frozen at a controlled rate in plasma and 10-percent dimethyl sulfoxide and stored in the vapor phase of liquid nitrogen. This group of patients was compared to a control group (n = 18) who received medullary marrow (MM) transplants for the same diagnoses under the same protocols during the same period. Posttransplant days to white cell engraftment (PBSC = 17, MM = 15.5) were no different. Days to platelet independence were significantly longer in the LVL PBSC group (PBSC = 33, MM = 16; p < 0.05). This pattern of engraftment is typical of patients treated in this manner. Although Day 0 platelet counts (PBSC = 75.5 x 10(9)/L, MM = 85 x 10(9)/L) and total single-donor unit platelet use (PBSC = 8, MM = 9) were no different, Day 1 platelet counts (PBSC = 128 x 10(9)/L, MM = 61.5 x 10(9)/L; p < 0.05) and Day 14 platelet use (PBSC = 5, MM = 8; p < 0.05) were significantly different, because of the transfusion of cryopreserved autologous platelets with PBSCs on Day 0.


Psychiatric treatments in multiple chemical sensitivity.

Despite the controversy and uncertainty surrounding the causes of the MCS syndrome, psychiatric treatments may provide some relief to MCS patients. These approaches may help patient and physician focus on the most important goals: relief of symptoms and improvement of function. Success requires that physician and patient establish a collaborative relationship and negotiate a treatment plan. Behavioral treatments are most effective at reducing disability and promoting a return to active life. When directed at appropriate target symptoms, psychopharmacologic treatments may reduce some of the most distressing symptoms of chemical sensitivity.


Large-volume leukapheresis for peripheral blood stem cell collection in patients with hematologic malignancies.

Large-volume leukapheresis (LVL, 15-35 L) was performed in two groups of patients (n = 10) with hematologic malignancies to obtain peripheral blood stem cells for bone marrow rescue following high-dose chemotherapy. The target cell count was 7 x 10(8) mononuclear cells (MNCs = lymphocytes and monocytes) per kg of body weight. Group A patients (n = 4) were studied on Day 1 of LVL, and components were collected from them as four sequential samples. Total MNCs collected averaged 1.29 x 10(10), total colony-forming-units granulocyte-macrophage (CFU-GM) averaged 12.1 x 10(6), and a 1.8-fold mobilization of CFU-GM was observed (p < 0.05, Sample 1 vs. Sample 4). Group B patients (n = 6) were studied throughout the three consecutive planned days of 5-hour LVL. An average of three LVL procedures per patient was performed (range, 1.25-4), and an average of 27 L (range, 24-33) of blood per LVL was processed. The blood:ACD-A ratio was 24:1 with 3000 units of heparin per 500 mL of ACD-A; heparin was also added to the collection bags. The component had an average hematocrit (Hct) of 0.02 and MNC content of 93 percent. The patients' pre-LVL and post-LVL average Hct varied significantly (before Day 1, 0.36 +/- 0.08; after Day 3, 0.28 +/- 0.06; p < 0.05). Platelet counts also decreased, with post-Day 3 counts averaging 19 percent of the average pre-Day 1 counts (p < 0.05). A decrease in the average MNC count after LVL was significant on Day 1 only (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


The homeobox in perspective.

The discovery of the homeobox marks the beginning of a new era in developmental biology in which a class of master control genes, which determine the body plan, have been identified. Their mechanism of action can now be studied at the molecular level and their occurrence seems to be much more universal than originally anticipated.


The emergence of the chaperone machines.

To ensure proper polypeptide folding, oligomerization and transport, elaborate molecular 'chaperone machines' have evolved. These machines are usually composed of a major chaperone protein that binds promiscuously to nascent, unfolded, misfolded or aggregated polypeptides and a set of chaperone 'cohorts', whose function is to enhance efficiency and ensure recycling. These chaperone machines can function by themselves or synergistically to carry out their various tasks.


Biochemical mechanism of light adaptation in vertebrate photoreceptors.

Vertebrate photoreceptors can adjust their sensitivity to a wide range of light intensities spanning several orders of magnitude, the phenomenon of which is called light adaptation. Electrophysiological and biochemical studies have revealed that calcium can serve as an intracellular transmitter of light adaptation under the control of cGMP metabolism. After illumination, the cytoplasmic calcium concentration of a photoreceptor decreases, which in turn strongly activates photoreceptor guanylate cyclase. This calcium-dependent effect is mediated by a novel calcium-binding protein (recoverin) and leads to the restoration of the depleted cGMP pool after illumination.


Rapid induction of intercellular adhesion molecule-1 on monocytes and myelomonocytic cell lines after interferon gamma treatment.

The ICAM-1 molecule is an important adhesion factor that facilitates lymphocyte activation as well as the movement of lymphocytes into solid tissues. It is poorly expressed on circulating monocytes but higher levels have been described following the use of some activation factors. While previous work has emphasized the role of interferon gamma in inducing increased ICAM-1 expression on nonleukocytic cells, we have demonstrated time- and dose-dependent increases on human monocytes and two myelomonocytic cell lines (Rc2A & U937). The increased level of ICAM-1 expression on the Rc2A cells was associated with higher accessory cell activity as determined by an increased mitogen and allogeneic response but specific antibody inhibition studies indicated only a partial dependence (up to 50%) on this molecule. Class II MHC expression and IL-1 production were not elevated by IFNg treatment of these cells, indicating that other factors account for the remainder of the incremental activity observed following this treatment.


Inhibition of alloreactivity in vitro by monoclonal antibodies directed against restricted isoforms of the leukocyte-common antigen (CD45).

The leukocyte common antigen (LCA) is a protein tyrosine phosphatase and is identified by the CD45 cluster of monoclonal antibodies. CD45 is expressed in high-density on cells of hematopoietic lineage and generally is immunoprecipitated as 4 bands (220, 205, 190, and 180 KDa). Genetic studies have shown that a single gene produces additional forms of the molecule by alternate splicing including CD45RA (220, 205), CD45RO (180), and CD45RB (220, 205, 190). We have prepared a CD45RB Mab termed "MT3" that binds to a sialic acid dependent epitope. Since the LCA is one of the major targets of antilymphocyte globulin, we assessed a panel of CD45 and CD45R Mab for their ability to inhibit alloreactivity in vitro. MT3 (CD45RB) inhibits the allogeneic MLR and inhibits CD4+ T cells from expressing interleukin 2 receptors, and prevents CD4+ CD45RA- T cells from entering the proliferative phase of the cell cycle. Mem 93 (CD45RA) inhibits the generation of cytotoxic T cells. These data suggest that the CD45RB and CD45RA isoforms of the LCA may be appropriate targets for in vivo immunotherapy.


[Surgical interventions in ulcer diseases in Denmark. A questionnaire study].

Surgical practice in the treatment of peptic ulceration in Denmark is illustrated by means of a questionnaire. The percentage of replies was 96. The investigation reveals that the predominant method of elective surgery for duodenal ulceration is still proximal gastric vagotomy rather than vagotomy+antrectomy. In elective surgery for prepyloric ulcer, vagotomy+antrectomy is employed most frequently and for elective operation for gastric ulcer partial gastric resection. In operative interventions for complications of ulceration such as haemorrhage and perforation, the operative strategy appears to be determined by the difficult current possibilities for training in ulcer surgery to a not inconsiderable extent, rather than to be based on a rational scientific basis as the definitive intervention here is replaced to a great extent by minor interventions such as simple undersewing of a bleeding gastric ulcer followed by H2-blocker treatment and simple closure of a perforated duodenal ulcer.