[Treatment center staff and the children referred by DDASS for specialized foster home care]. Many children placed in foster families chosen by the local administrative authorities need an intensive and complex treatment, which would well justify their case being handled by the Specialized Psychiatric Unit responsible for a number of selected foster families. The foster family, which is often chosen hurriedly, is generally unprepared to deal with the child's psychological problems. Moreover, the child's links with his own family have not always been maintained. Soon social workers and the foster mother will be expecting the local Child Psychiatry Outpatient Unit to provide them with massive aid, which this unit is not properly equipped to give. It happens frequently that members of this team will have to face particular counter-transfer difficulties. However certain aspects of this medical structure are helpful for the treatment of these children: the Child Psychiatry Unit offer specific facilities, like therapeutic groups, and as the members of its team have no part in the factual decisions concerning the fate of the child, they feel more neutral and can be considered so by the different actors involved, including the child him- or herself. We discuss two clinical cases, and then touch upon the fundamental issue involved, that of the organizing power of psychiatry in a given environment.


[The work of collecting materials of artistic expression from various media]. Work of collection of productions made in workshops of expression constitute a specific need for evaluation in art-therapy. The Mediatised Observation is completed by special validated (K-test) and built instruments of description for productions from each mediation (paintings, writings, music...) and for observed behaviours in situ during therapeutic work of creation. The two benefits are for nurses education, and for elaboration of a clinic of aesthetic.


[Nursing problems in intensive care for psychiatric patients]. Two cases illustrate psychotherapeutic aspects of surgical intensive cares for psychiatric patients. Comparison with their style of expression in art-therapy allows a better understanding in their relations with the technical and non human environment.


[Hippocratic concept of hysteria].

[Hippocratic concept of hysteria]. The Greek physicians of the fourth century B.C. painstakingly described a number of symptoms that they thought were caused by migrations of a restless uterus, said "wandering womb". According to this concept, we can use the term "hysteria", despite the fact that the noun itself never appears in any of the Hippocratic texts. We can determine its origin as being in ancient Egypt from the medical writings of the Egyptian papyri. In the same way, the therapy is mainly of Egyptian origin, using a combination of recipes to make the moving womb return to its proper place in the body cavity. However, we can also identify the rationality of the Greeks, in particular as regards mechanical physiopathology. Hippocratic authors are closely connected with presocratical physics, and manifest a distinct break with magic and religion. Furthermore, they claim that hysteria may result from prolonged sexual continence, an opinion which was to influence medical history for over two thousand years.


[Induction by neuroleptics of certain genes in the central nervous system]. Prolonged administration of neuroleptic drugs increases the density of dopamine D2 receptors in several brain regions. We have recently shown that such treatment also raises dopamine D2 receptor mRNA levels in the striatum. To elucidate some of the initial events which lead to this upregulation, we studied the acute effects of dopamine D2 agonists and antagonists on the expression of c-jun and c-fos. A single injection I.P. of haloperidol (2 mg/kg) produced a rapid and transient increase in c-jun and c-fos mRNA in the rat striatum. This induction was specifically blocked by a D2 agonist (1 mg/kg quinelorane). In contrast, by itself quinelorane was without effect. These results show that dopamine D2 receptors inhibit the expression of a set of immediate early genes in the striatum, and these may be involved in the up-regulation of D2 mRNA upon prolonged neuroleptic treatment.


[Physiopathology of dementia of the Alzheimer type: role of the amyloid beta-protein]. Biological research on Alzheimer's disease is expanding quickly, and the mechanisms of the disease are better understood today. Progress has been specially impressive in the knowledge of the brain lesions (senile plaques, neurofibrillary degeneration). It is likely that the beta-amyloid protein, which accumulates in the senile plaques plays a major role in the development of the brain lesions and, subsequently of the clinical symptoms. The metabolism of the precursor of this protein might be abnormal, leading to the beta-amyloid protein deposits. Some discrete genetic abnormalities (such as punctate mutations on the beta amyloid precursor gene) have been described recently in familial cases of the disease. It seems unlikely that such punctate mutations would be responsible for the majority of the cases. Therefore it is possible that Alzheimer's disease has multiple causes, the genetic factors being only one of them.


[Alcohol and the serotonin system].

[Alcohol and the serotonin system]. There is considerable evidence from animal and human studies that serotonin plays a role in the modulation of alcohol intake and/or alcohol dependence. Biochemical, behavioral and pharmacological studies both in animal and man had verified this hypothesis. Central and peripheral levels of serotonin and of its metabolite 5-hydroxyindoleacetic acid (5-HIAA) are modified by alcoholisation. Moreover, the use of pharmacological drugs modifying specifically serotonin transmission decreases ethanol intake. Our own studies suggest that a dysfunctioning of serotonin uptake system could be implicated in the individual risk of alcohol dependence. Even if other systems, e.g. amino acids, are involved in the regulation of alcohol behavior, all data are in favor of a modulation of alcohol intake by serotonin transmission.


[Evolution, capabilities and limits of psychopharmacology]. Evolution of psychopharmacology is discussed from the viewpoint of the growth of the number of psychotropic drugs, their use and the rate of scientific reports related to them. Power is discussed from the standpoint of economic perspectives, although it is not the only aim. On the other hand, the influence of the psychopharmacological "boom" on the development of the specialty is analyzed. The limits of psychopharmacology achieve their maximum extent when they are combined with the study of psychological, social and cultural factors and determinants and, hence, to other therapeutic methods.


[Nonspecific factors and variations in biological parameters studied in biological psychiatry]. Some studies found no connection at all between biological parameters and mental illness. There are many reasons for the discrepancies: populations and parameters investigated as well as the method used, widely differed. The discrepancies observed, could also be partly due to several non-specific factors such as age, sex, hormonal status, circadian or circannual variations, and washout period. The authors report here some data gathered in the course of a psychobiological research program on healthy volunteers. Their results indicate that human plateler MAO activity shows an apparent menstrual cycle related variation [3H] IMI binding in human platelets shows circadian variations in summer and some antidepressant drugs have a residual effect on serotoninergic parameters during one month. These studies oblige investigators to be cautious when interpreting biological data in psychiatry. Ideally longitudinal studies should be implemented at the various stages of mental illness.


[Importance and limits of statistical methods in psychiatry]. Clinical reasoning and statistical treatment of psychiatric data interact to reduce the risk of random diagnosis and prognostic probabilities. Errors of statistical procedures are found in an important amount of papers in the most reliable psychiatric journals. Guide-lines for reporting statistics are given advising the authors about mistaking statistic application. Unfortunately, on a more elementary level, representation of data are often criticizable for they are incomplete, or make difficulties of decoding. Harmonization of data representation is then desirable. Some remarks are expressed about paucity of negative studies in literature.


[Significance of studies of motor activity in depression]. Actometry is a technique that enables continuous monitoring of spontaneous motor activity. This technique can be applied to the study of depression either by studying qualitative motor activity patterns or by measuring quantitative motor parameters. We present here the results of a quantitative actometric analysis. 13 depressive in-patients were evaluated both clinically by depression scales and by actometry before and after trimipramine treatment. Correlation analysis was made between actometric and clinical rating scores at different moments of the treatment. Some actometric parameters appear to be specific indices of depression and psychomotor retardation. Future prospects for the use of actometric techniques in depression are discussed.


[The lithium test, test of endogenous criteria]. The lithium-test (Li-T) requests hospitalisation of the patient, administration of Li to obtain a plasma/level of at the lust 0, 8 mEq/l, since the third to the eight day. It improve depressions, acute delusions, pseudo-dementias: the field of the lithiodépendent endogenic diseases as to be enlarged. The Li-T may distinguish between this lithiodependence of the other, non-lithiodépendent, in dysthymic psychotic disorders.


[Correlations between delayed auditory evoked potentials and clinical evaluation of schizophrenic symptoms]. Late auditory evoked potentials (AEPs) were recorded by the "odd-ball" method in 20 schizophrenic patients according to DSM III R diagnosis criteria compared with 30 control subjects matched for sex and age. Patients were on antipsychotic medications; mean duration of illness was 3, 55 years. We have also proceeded to a clinical quantitative assessment of negative and positive symptoms of schizophrenia with Andreasen's rating scales. In the group of patients, we have observed a significant lengthening of the latency of N 1, N 2, P 3, N 3 and a decreased amplitude of N 1 and P 3. These results are in favour of an impairment of cerebral information processing probably localized in the subcortical level. Statistically significant correlations have been noticed between the anomalies of the last stages of information processing (P 3, N 3) and negative symptoms, more particularly affective flattening and attentional impairment. The disturbances of the first stages of information processing (P 2) and of automatic information processing (N 2) were related to positive symptoms, hallucinations and delusions especially. The anomalies of N 2 were also related to the sum of the global scores: an attentional impairment could be a main factor in the determinism of schizophrenia.


[A case of delusional melancholia: "a variant of loss of psychological self-activation"?]. A 62 year-old man presented with melancholia with delusions, possibly resulting from lenticular lesion in the left and frontal damages in the right. Atypical signs of our observation led us to consider our patient not as suffering of affective disorder. We suggest that melancholia could be a consequence of a certain type of stereotyped mental activity, and we would compare this stereotyped mental activity to mental compulsive activity described in "loss of psychic self activation" of D. Laplane. In this perspective our observation would be a variant of "Loss of psychic self-activation". Heuristic value of this concept is discussed.


[Depression and functional EEG asymmetry]. A new quantified EEG index (Alpha Burst Occurrence Variability Index: alpha BVI) has been devised in order to characterize sequential variations of alpha bursts in EEG. This index makes it possible to quantify slope variations of a cumulative graph (periodogram) where the rank of alpha bursts is traced as a function of their instant of arrival. Such quantitative analysis was applied to spontaneous EEG segments which were recorded in the parieto-occipital regions (P3-Fz and P4-Fz) during a rest period, in three groups of depressed patients, one being characterized by psychomotor retardation (PRM group), another one by an emotional blunting (EB group) and a group of impulsive depressed patients (I group). The patients were compared to a group of healthy control subjects. In the three patient groups, before treatment, it was observed that the right and left alpha BVI were significantly lower than those of the control subjects. The right hemisphere was involved in all cases, but the left hemisphere was involved only in severe cases. In the EB and I groups, two strong "electro-clinical" correlations were observed, each one being specific for each hemisphere, one relating the reduction of the right alpha BVI to the depressive mood, the other relating the reduction of the left alpha BVI to the degree of speech ("ideoverbal") retardation. These results emphasize the role of the right hemisphere in the probable pathogenesis of depression.


[Panic attacks and 24-hour ambulatory EEG monitoring]. A 24 hour ambulatory EEG study performed in a population of 300 non epileptic outpatients with an anxious and depressive pathology revealed a high prevalence of abnormalities in subjects referred with panic disorder. Two groups of 150 medication-free patients each have been selected on the base of DSM-III-R = one with panic attacks (PA), the other with depressive patients without paroxystic anxiety (DS). The results showed respectively = in the PA group 63.2% abnormal, 19.7% normal and 17.1% dubious records. In the DS group = 74.5% normal, 18.3% abnormal and 7.2% dubious records. Epileptiform abnormalities were 4 times more frequent in the PA group (80%) than in the DS group (20%). Two nycthemeral peaks were found (5-8 pm and 3 hours after awakening). MRI has permitted the discovery of abnormal cerebral images in 3 patients of the PA group (cyst of the insula, temporal and parietal cryptic angiomas, sequelae of a parietal vasculo-cerebral stroke) frequency appearing to be clearly superior to the one resulting from recent epidemiologic data. The subclinical character of 2/3 of these abnormalities refers beyond epilepsy to their signification in the field of emotive and intellectual disturbances. The paradoxal efficiency of tricyclic drugs in panic disorder, sets the problem of their eventual antiepileptic action at low doses. If recent data on standard EEG in panic disorder is available, we did not find any similar study to ours in order to confront our results.


[Comprehensive epistemology aspects of human personality, as a new paradigm in psychopathology research]. To apprehend the integrality of the psycho-pathological problems of the human being, the use of a paradigm is necessary. The epistemological paradigm, based on the study of the principles which govern any dynamic system, seems very useful. Applied to the human being, it raises questions of energy, semantics, organization of functions, environments, and it can lead to a better comprehension of the psychism. In psycho-pathology, this paradigm puts in evidence the innumerable interrelations which intervene at all the levels to create disturbances in the functions, inducing troubles of communications with the consciousness resulting in diminution or non-function of the latter, type psychosis, or in its activation, type neurosis.


[Non-verbal clinical psychiatric aspects]. Mimic, involuntary movements, agitation or immobility, are parts of description, comprehension and evaluation of any human behaviour, normal or not: they were included in the classic european psychiatries. They almost disappear from the actual scales of evaluation, or from the training through scales. It seems possible to complete such scales, exclusively verbal, by scales of behaviours-suicidal attempt being a good instance of such behaviours.


[Interruption and misunderstanding. Examples of the construction of discourse in clinical interviews]. How do subjects construct shared meaning during an actual exchange? This question is treated through the study of dialogical behaviours of three psychiatric patients during a clinical interview (Two psychotics and one psychopathic). The analysis of their different ways of linking utterances shows difficulties that concern the construction of a common discursive ground. These difficulties, that can be considered either from a deficitary point of view or from a creative one, appear on the repetition of unexpected changes, of communication blocking or of inadequate indication of the way utterances mean.


[Narcolepsy and the psychiatric tableau. A specific form of narcolepsy?]. Narcolepsy is a well-known hypersomnia. Nevertheless narcolepsy in which the hallucinatory component is unusually prominent may lead to a false diagnosis of schizophrenia syndrome. This aspect is illustrated by the case of Miss B. who appears like a psychotic patient without dissociation syndrome and with a hysterical personality. Are the narcoleptics with psychiatric disorders a peculiar sub-type of narcolepsy? Fourty-five percent of our eleven narcoleptics patients have an associated psychiatric disorder. Most of them are depressive. Surprisingly fourty percent of our patients are non-DR2 at the Human Leucocyte Antigen typing. Furthermore seventy five percent of them have an associated psychiatric disorder. This would mean a peculiar sub-type of narcolepsy.


[Anthropology and delusional disorders: Antilles and Cameroon discourse]. We are sometimes compare, in our practice, with treatment of patients coming from beyond the seas (like Guadeloup, West Indies). The psychologic characters are extremely confusing because the symptoms are polymorphs in the same patient, some character of hysteric, delirious and depressive registers, and also there is a cultural color changing the deep signification of symptoms presented to the doctor. The diagnostic research are not unusual face our proper culture and with inadequation of the classic diagnostical characters. The treatment's antilly patients mind the attirance for the exotic and the unknown phobies captivate and question our proper subjectivity.


[A new approach to psychosis. Is psychosis a disorder of mental reality?]. World's knowledge is but imperfectly intelligible to thinking beings by binding Possible with Reality of the experience meaning what resists them (matter or form) as sensible organ, while time perception remains out of feeling. Although the Reason seeks coherence in its seizing of the World, only consisting in experiences, yet the various experiences are not ordered a-priori towards coherence as an aim. The Reason ascribes the experiences to be pre-classified according to three modes: Continuity-Successiveness-Reversibility, connecting a physical fact (temporarily) to a thought fact (classifying). This motion towards a coherent understanding of the World proceeds by leaps over representations in three ways: 1-induction without requirement nor warranties. 2-analogical interpretation in which the middle term offers a slight validity. 3-demonstration where experiences get authentified but needs term successiveness undoubtedly marked in time. In case of a time mark deficiency, the demonstrative way gets out of warranty. The subject loses his free choice between Possible and Reality, causing psychosis. Yet the thought, getting improper to appreciate and correct the less gap between itself and experiences becomes else: thence, filtered by matter, it responds to chemotherapeutic strategies. The various symptoms in Psychosis can be brought to a selective deficit of the experience's pre classifying such as: -lack of "reversibility" troubling the course of thoughts, causing hermetism etc... -lack of "continuity" making easier experience materiality causing hallucinations. -defect of "successiveness" supporting the Possible for loss of the Reality causing delusion conviction.(ABSTRACT TRUNCATED AT 250 WORDS)


[Are co-therapies indicated in schizophrenia?]. The "cotherapies" which are often indicated for neurotic patients, see to be more difficult to be used for psychotic patients. What are the advantages of such treatments for schizophrenic patients? Using case stories we are going to try to know the good prognosis factors for the success of these cotherapeutical treatment. Our situation is particular: one of us is a full-time, the other is psychoanalyst and a consultant-psychiatrist in the same hospital.


[The British and French systems of classification and psychiatric disorders]. We compare the french diagnostic system with that used in Great-Britain. The criteria are very similar except in the case of the non-affective functional psychoses. The French divide these into acute and chronic. Bouffée délirante, the prototype of the acute functional psychoses, is not diagnosed in Great-Britain. The British divide these psychoses into schizophrenic and non-schizophrenic disorders, particularly using Schneiderian criteria for the diagnosis of schizophrenia. Curiously, it is precisely these criteria, referred to as "automatisme mental" (Clérambault) which are used in France in order to diagnose the "chronic hallucinatory psychoses". This is a diagnosis which is unknown in Great-Britain, and which is in France classed firmly among the non-schizophrenic psychoses, truly a paradoxical situation.


[Clinical research on violence].

[Clinical research on violence]. Violence and agitation are two different behaviors however not always differentiated. There are not only physical violence but also moral violence such as erotomania eventually more dangerous. There is no clear definition of violence. Research should be improved. Today there is an increase of different types of violence, such as self-inflicted violence as in suicidal behavior, rather frequently associated with alcoholism. Clinical experience is given from l'Infirmerie Psychiatrique, a forensic psychiatric emergency department.


[Research in schizophrenia: necessity to include patients of multiple diagnostic systems]. The discrepancies of studies on symptomatology and treatment of schizophrenia could be related to the selection of different patients diagnosed by one diagnostic system, different from a study to another. Therefore, we tested whether 14 diagnostic systems could include 51 patients differently as regard to the intensity of positive, negative or depressive symptomatology and to the phase of illness. The distribution of the patients in different sets of diagnosis has been carried out by a computer program and the symptomatology has been evaluated with PANSS and MADRS. Some diagnostic criteria like DSMIII-R, Langfeldt, Taylor, ICD 9 include negative and depressive patients preferentially. Others systems like Berner, Catego, ICD 9, New-Haven, Schneider, include more patients with acute than residual symptoms. These results show the importance of the choice of one or more diagnostic criteria depending on the aim of the study.


[Stress and depression].

[Stress and depression]. Can modern life foster more depression life? Neuroendocrine, epidemiological and even immunological approaches allow us to suppose a passage between stress and depression, far beyond the archetype of exhaustion depression (break down syndrome).


[Alterations of arousal in some psychopathologic states]. An electro-behaviour dissociation was described, at first by animals next about the man, in experiment testing and in the drug addictions. This non concordance appear as lesser if it is be considered not only the sleeping waves but also all the electrical signs of the vigil state: non-existent, fluctuating, limited in topography, behind the stimulation, incomplete or emphasized. In this view we study some pathological states: narcotic and alcoholic addictions, confusion and pre-senile illness. Sometimes it is the abnormal sleep (coma or amazement) which alter the vigil state: absent, decreased, etc. Sometimes the vigilance is "numbed", the behaviour and the recording are those of lethargy. Sometimes also, the drowsiness has insomnia characteristics, associating a deep sleep loss, a reactivity to stimulations at once emphasized and undiscriminated, and "strangeness" insurmontable for the consciousness (perplexity, delusions, nightmare and level anomalies).


[Language of the clinic].

[Language of the clinic]. In this report, the authors examine the problems of specific languages in medical, psychiatric and psychologic practice. They emphasize a specific epistemological view to be able to capture the distinction between clinical tongue, common parlance and specific languages.


[Proposition of a new concept: "sequence of communication"]. What we suggest as a concept is "The sequence of communication" which is accessible to experimenting excluding the concept of "black box". The sequence of communication point out the print of sensations their coding, and a scheme of action as well. This concept enables us to treat information in its unicity taking into account its reception, its analysis and its emission all together. It's a way to avoid the differentiation, or even the clash between "what is felt", "what is said" and "what is acted". From the semiological point of view this approach allows us to stress an analogy between symptoms, which until now have been listed in different pathologies. From the methodological point of view, some hypothesis of work concerning anguish are drawn. On the therapeutic point of view, taking into account the "affects" in a logical context, enables the patient to master his own behaviour.


[Elaboration, perlaboration, in the course of antidepressant chemotherapy]. From the results of an 8 years naturalistic and pragmatical study in a Care Unit for Patients with Dysthymic Disorders at Hôtel-Dieu-Pont-L'Abbé (France), the author points out that there is during long term antidepressive therapies a facilitating action in the psychoaffective elaboration and maturation. The author stresses the importance of agonistic molecules in the serotonin which seem to favour a psychological "working-through" probably because of the lifting of compulsive-obsessive mechanisms present in chronic an residual depressions. The authors underlines the importance of naturalistic and pragmatical studies as an alternative or as a complement to protocolar and controlled studies which are often biased. These biases are increased because of complicated psychometrics and by recent legal measures which tend to lessen the clinical credibility of these "controlled" studies.


[The ego and dysphonias].

[The ego and dysphonias]. Every psycho-affective disorder may be a factor of language constitution and communication disorders. The study of it, particularly in psychosis is a major sign for diagnosis. Linguistic troubles are correlate with mind perturbations and the psychotic language is symptomatic. The most suggestive example is schizophrenia. Rythm and sound stay, yet semantics and syntactics expressions are down.


[What is meant by clinical research in psychiatry?]. The untiring questioning on the part of the two sources, somatic and psychological, in illness make a pair with contradistinction between "clinical" research and "scientific" research. However, they are good theoretic and pragmatic arguments in favour of their complementarity and full respective lawfullness. In this purpose, one had to scrutinize the explicit and implicit definitions, too often adulterated by presuppositions and exclusive preferences.


[Automatic actions with amnesia induced by taking hypnotic drugs. Association with personal and familial history of somnambulism and epilepsy]. A family which combined sleep-walking drug-induced sleep-walking and epilepsy is reported. This co-morbidity suggest various mechanisms which could explain drug induced sleep-walking. We stated the hypothesis that these behaviors were epileptic states due to a mini-withdrawal syndrome. This mini-withdrawal including of course a rebound of anxiety and insomnia during the day, but also a pro-convulsivant effect.


Conversion of human low density lipoprotein into a very low density lipoprotein-like particle in vitro. The lipid substrate specificity of Manduca sexta lipid transfer particle (LTP) was examined in in vitro lipid transfer assays employing high density lipophorin and human low density lipoprotein (LDL) as donor/acceptor substrates. Unesterified cholesterol was found to exchange spontaneously between these substrate lipoproteins, and the extent of transfer/exchange was not affected by LTP. By contrast, transfer of labeled phosphatidylcholine and cholesteryl ester was dependent on LTP in a concentration-dependent manner. Facilitated phosphatidylcholine transfer occurred at a faster rate than facilitated cholesteryl ester transfer; this observation suggests that either LTP may have an inherent preference for polar lipids or the accessibility of specific lipids in the donor substrate particle influences their rate of transfer. The capacity of LDL to accept exogenous lipid from lipophorin was investigated by increasing the high density lipophorin:LDL ratio in transfer assays. At a 3:1 (protein) ratio in the presence of LTP, LDL became turbid (and aggregated LDL were observed by electron microscopy) indicating LDL has a finite capacity to accept exogenous lipid while maintaining an overall stable structure. When either isolated human non B very low density lipoprotein (VLDL) apoproteins or insect apolipophorin III (apoLp-III) were included in transfer experiments, the sample did not become turbid although lipid transfer proceeded to the same extent as in the absence of added apolipoprotein. The reduction in sample turbidity caused by exogenous apolipoprotein occurred in a concentration-dependent manner, suggesting that these proteins associate with the surface of LDL and stabilize the increment of lipid/water interface created by LTP-mediated net lipid transfer. The association of apolipoprotein with the surface of modified LDL was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, and scanning densitometry revealed that apoLp-III bound to the surface of LDL in a 1:14 apoB:apoLp-III molar ratio. Electron microscopy showed that apoLp-III-stabilized modified LDL particles have a larger diameter (29.2 +/- 2.6 nm) than that of control LDL (22.7 +/- 1.9 nm), consistent with the observed changes in particle density, lipid, and apolipoprotein content. Thus LTP-catalyzed vectorial lipid transfer can be used to introduce significant modifications into isolated LDL particles and provides a novel mechanism whereby VLDL-LDL interrelationships can be studied.


Isozymes of cyclic-3',5'-nucleotide phosphodiesterases in renal epithelial LLC-PK1 cells. Metabolism of cAMP and cGMP by the major types (families) of cyclic-3',5'-nucleotide phosphodiesterases (PDE) was studied in confluent renal epithelial LLC-PK1 cells grown in vitro. LLC-PK1 cells mainly contain the cAMP-specific rolipram-sensitive PDE type-IV (PDE-IV), the Ca(2+)-calmodulin dependent PDE type-I and cGMP-specific PDE type-V; all these PDEs are mainly localized in cytosol. Analysis of PDE activities in soluble extract of LLC-PK1 cell homogenate by FPLC ionex chromatography on Mono-Q column also disclosed the presence of low activities of cGMP-stimulated PDE-II and PDE-III. Moreover, activity of PDE-IV was resolved into four distinct chromatographic peaks. The increase of cAMP level in response to incubation of intact LLC-PK1 cells with vasopressin (AVP) was markedly enhanced in the presence of rolipram, but not in the presence of other PDE isozyme-specific inhibitors. Incubation with AVP and atriopeptin (ANP) together resulted in increase in cGMP and a small decrease of cAMP accumulation in LLC-PK1 cells. Results of these studies first show that the LLC-PK1 cells contain all five major types of PDE isozymes where PDE-IV, PDE-I and PDE-V are quantitatively predominant. The rolipram-sensitive PDE-IV, present in several chromatographically distinct forms, appears to be the key PDE isozyme involved in control of cAMP generated in response to stimulation by AVP in LLC-PK1 cells.


Congenital rubella syndrome among the Amish--Pennsylvania, 1991-1992. From February through May 1991, an outbreak of rubella occurred among the Amish in Pennsylvania that was part of a widespread rubella outbreak reported among the Amish in at least six states during 1991 (1). The Pennsylvania Department of Health (PDH), in cooperation with CDC, conducted an investigation to document cases of rubella among pregnant Amish women in Lancaster County and a cohort study to estimate the risk for congenital rubella syndrome (CRS) among infants born to Amish mothers from November 1, 1991, through January 31, 1992. This report summarizes investigation and study findings.


Anaphylactic reaction during immunotherapy related to alcohol consumption. A case of anaphylaxis related to alcohol consumption during immunotherapy is reported. We advise to consider whether there has been noticeable alcohol consumption prior to each injection.


99mTechnetium-dimercaptosuccinic acid scan in the diagnosis of acute pyelonephritis in children: relation to clinical and radiological findings. Seventy-two children, 59 girls and 13 boys, 0.1-15.9 (median 1.1) years of age, with acute pyelonephritis (APN) were investigated with the aid of a dimercaptosuccinic acid (DMSA) scan, renal ultrasonography (US) and a desmopressin test within 5 days of admission. Sixty-two children were reinvestigated approximately 2 months later when intravenous urography (IVU) and micturition cysto-urethrography were also performed. During infection, 92% of the children showed changes in the DMSA scan with 69% by US, and the two investigations agreed in 58% of the kidneys. At follow-up, 68% showed changes in the DMSA scan, 47% by US and 48% by IVU. The DMSA scan and IVU agreed in 60% of the kidneys. Twenty-nine percent of the children had vesico-ureteric reflux (VUR). The presence of grade greater than or equal to 3 VUR was associated with greater defects on the DMSA scan during infection, and at follow-up with a higher frequency of persistent changes compared with no VUR (P less than 0.02 and 0.01, respectively). During infection the size of the defect on the DMSA scan correlated with renal volume and C-reactive protein and inversely with the glomerular filtration rate, and at follow-up it correlated inversely with the renal concentration capacity. The DMSA scan is a sensitive method for diagnosing and localizing APN in children, and findings on DMSA scan show a weak but significant correlation with routine clinical and radiological parameters. It is suggested that persistent renal damage after APN in children without VUR may be more common than previously assumed.


Plasma ionized calcium and blood lactate concentrations are inversely associated in human lactic acidosis. Plasma ionized calcium [Ca++] concentrations are decreased in patients having lactic acidosis. To further investigate this observation, we prospectively studied nine critically ill patients who had lactic acidosis and measured arterial pH, PCO2, [Ca++], lactate, and albumin concentrations. We found a strong association between decreased [Ca++] and increased plasma lactate concentrations (r2 = 0.78, p less than or equal to 0.001). This unexpected association--[Ca++] usually increases with increasing acidosis--might be clinically important and the mechanism deserves further investigation.


[Pathogenesis of peptic ulcer: role of Helicobacter pylori gastritis and its course during antibiotic and/or antisecretory treatment]. A systematic investigation of the histologic pattern of antral and corpus gastritis has been carried out in 1177 patients with various clinical conditions. An increased rate and severity of antral mucosa gastritis activity as well as surface epithelium cytotoxic lesions and Helicobacter pylori colonization, coupled with low rates and severity of the same parameters in corpus mucosa gastritis (usually of superficial nature so as to spare the integrity of acidopeptic glands) were the main features associated with active gastroduodenal peptic ulcer or antroduodenal mucosal erosions. Simultaneous antisecretory (omeprazole) and antibiotic treatment of duodenal ulcer patients led to the eradication of Helicobacter in 54 to 82% of patients when amoxycillin alone was used as antibiotic, and up to 94% of patients, when metronidazole was added to amoxycillin, as against none of patients treated with omeprazole alone, despite effective healing of their ulcer lesion. Very low (usually less than 5% per year) recurrency rates are reported in the literature for patients undergoing bacterial eradication, as against 50 to 80% in non-eradicated patients whose ulcer was healed by short term antisecretory drug treatment.


Anemia in the adolescent athlete.

Anemia in the adolescent athlete. Anemia is a common disorder among adolescents regardless of level of physical activity. The major cause of anemia in adolescents is nutritional iron deficiency. Iron metabolism may be altered in some athletes training and competing in endurance sports. The dilutional "sports anemia" that can occur in the more elite adolescent athlete may be an adaptation to aerobic conditioning. Screening for anemia in adolescent athletes is warranted because anemia may contribute to morbidity and diminished exercise performance. Current concepts and controversies regarding anemia in adolescent athletes are addressed, and application of this information to preparticipation physical examinations is examined.


The effects of calcium site occupancy and reagent length on reactivity of calmodulin lysyl residues with heterobifunctional aryl azides. Mapping interaction domains with specific calmodulin photoprobe derivatives. The relationship of structural and functional moieties on calmodulin is important in all venues of cell activity. In this study, we investigate the effect of lysine modification on calmodulin function. Azidosalicylate reagents containing different "linker arm" lengths, between the photoactive terminus and an amine-reactive N-hydroxysuccinimidyl ester moiety were used to modify calmodulin lysines at three different positions in a calcium-dependent manner. The short cross-linker, (ASNE-2 (where ASNE represents azidosalicylate N-hydroxysuccinimidyl ester), modifies Lys-75, whereas the longer reagent, ASNE-6, modifies lysines 21, 75, and 94. The modification of these different lysines is shown to be calcium-dependent. At 1-100 microM levels of calcium, only Lys-94 is modified, suggesting that modification of this residue is directed by both the binding of calcium to calcium-binding loops III and IV and the hydrophobic pocket exposed between these two loops as a result of calcium binding. At higher calcium concentrations (> 200 microM), where sites I and II become filled, modification of Lys-21 or Lys-75 also was observed. All the modified calmodulins were able to stimulate 3',5'-cyclic-nucleotide phosphodiesterase fully although the Kact for the Lys-75 and Lys-21 derivatives increased 10- and 50-fold, respectively. None of the modifications affected the activation of erythrocyte plasma membrane Ca(2+)-ATPase. Only the ASNE-6 Lys-75 derivative showed efficient (40%) photocross-linking to the Ca(2+)-ATPase. The ASNE-2 Lys-75 derivative as well as the ASNE-6 Lys-21 and Lys-94 derivatives did not show efficient calcium-dependent photocross-linking to this enzyme.


Malignant seeding of the needle track during stereotaxic core needle breast biopsy. Early reports demonstrated the diagnostic advantage of large-core (14-gauge) biopsy over fine-needle aspiration biopsy of nonpalpable lesions of the breast without apparent significant increase in morbidity. A case of malignant seeding of the needle track after a large-core biopsy of a mucinous carcinoma of the breast is documented. The potential for increased risk of tract seeding of malignancy must be considered.


Outcome of carotid artery resection for neoplastic disease: a meta-analysis. To determine the neurologic morbidity and oncologic effectiveness of carotid resection in patients with advanced squamous cell carcinoma of the head and neck. A retrospective review of all published cases of squamous cell carcinoma of the head and neck treated by carotid resection was performed. A major neurologic complication occurred in 17% of patients. Neurologic morbidity was not associated with the method of carotid artery reconstruction. Two-year disease-free survival was 22%. The majority of recurrences were local or regional. Comparison of survival of this group to a similarly staged control group demonstrated no significant difference in survival. This review of the literature suggests that elective carotid resection achieves significant local/regional control of disease and that carotid artery involvement is not a poor prognostic factor in patients with advanced head and neck cancer.


Imaging of the knee.

Imaging of the knee. Acute and chronic knee dysfunction is a common clinical problem faced by physicians treating patients with musculoskeletal disorders. While standard roentgenograms provide most of the information needed to assess these disorders, the role of magnetic resonance imaging (MRI) is rapidly increasing in the diagnostic evaluation of soft-tissue, ligament, tendon, and osseous abnormalities. This article focuses on the role of MRI in the evaluation of disorders of the knee.


Accessory nipples: any relationship to urinary tract malformation? One hundred two infants and children age 3 days to 16.5 years, found to have accessory nipples (AN), were enrolled in this study. They were categorized by ethnic origin, sex, positive family history of AN, and number, site, and shape of AN, to determine factors for increased risk of anomalies of the urinary tract. Physical and ultrasound examinations of the abdomen did not reveal evidence of urinary tract malformation in any of the children. The results of this survey support the contentions that AN are not associated with urinary tract malformations, and that no further investigation is required in children with solitary AN.


[National study of lipids in coronary patients]. Although coronary atherosclerosis is considered to have several etiologic factors there is little doubt that elevated plasmatic cholesterol level is the main one. The present study was carried out because of the lack of information concerning cholesterol, lipoproteins and triglycerides levels in the coronary population in Argentina. Patients were selected on the basis of a demonstrated coronary atherosclerosis, detected either by an abnormal coronary arteriogram or a documented myocardial infarction. Total seric cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were determined in a core laboratory. Blood samples were obtained after a 12 hour fasting period. LDL-C was also calculated by the Friedewald formula. Patients were stratified according to sex, age, having or not myocardial infarction, type (Q or non Q wave) and localization of myocardial infarction. A total of 653 patients were included. The mean values obtained were: TC 227 +/- 1.8 mg/dL; LDL-C 153 +/- 1.8 mg/dL; HDL-C 48 +/- 0.4 mg/dL and TG 180 +/- 3.6 mg/dL (expressed as mean +/- SE). Mean values in the male and female subsets are given in Table 1. In women, TC, LDL-C and HDL-C are significantly higher than in men. Cholesterol values according to age are displayed in Table 3. Young people have higher TC and LDL-C mean values than older ones. Different cholesterol levels were not observed when the coronary population in our study was stratified according to the presence or not of previous myocardial infarction (Table 4).(ABSTRACT TRUNCATED AT 250 WORDS)


Development of a teaching model for coronal access to the canine dentition. A dolichocephalic canine skull was utilized to develop a teaching and study model for coronal access cavity preparation of the dentition. The teeth from the right side of the skull were extracted. Each tooth was radiographed in two planes to localize the "ideal" endodontic access point. Barium markers were placed over these points and each tooth was radiographed again to confirm the appropriate location of the marker. Access was created by drilling through the barium marker. Then, K-files were inserted through the access preparation into the root canal system. The teeth were radiographed with the K-files in place to verify straight pathways to the apices. Straight line access to the apex was obtained in all teeth. Creation of this model provides an opportunity for the veterinary dental student to develop and refine skills used in performing endodontic therapy. The model can be utilized by the veterinary dental practitioner in clinical practice.


Veterinary dental demonstration models.

Veterinary dental demonstration models. This article is about dental models and their construction. It is meant to be informative, entertaining and, hopefully, a little lighthearted. The use of dental models in the veterinary practice has become commonplace. The models are useful for demonstrating to clients and colleagues various dental pathologies and procedures.


Intracanal calcium hydroxide therapy--the Webber technique. Calcium hydroxide powder has been used as a treatment medication for different pathologies of the teeth. This article describes the physiological effects and general principles involved in using calcium hydroxide. The indications for its use and the contraindications are described. Filling and refilling the root canal with calcium hydroxide using the Webber technique induces a calcified tissue barrier and stimulates osteogenic healing. A case report using the Webber technique is included.


Replantation of a maxillary canine tooth after traumatic avulsion in a dog. An infrequent traumatic injury in dogs is avulsion of a tooth from its alveolus. The management of the avulsed tooth is complex. This report describes the treatment of a traumatically avulsed maxillary canine tooth in a dog. Replantation and splinting of the tooth was performed. Despite a protracted extraoral time, follow up clinical and radiographic assessment of the tooth indicated successful replantation.


The role of taurine and its derivatives on cellular hypoxia: a physiological view. Taurine (2-aminoethanosulfonic acid) appears to have an important role in cell protection against hypoxia. The mechanistic basis by which this amino acid and its derivatives are involved on these events, in brain or in other tissues, are discussed considering the antioxidant role of hypotaurine and some of its derivatives.


The inhibitory action of chlorogenic acid on the intestinal iron absorption in rats. The polyphenols are part of the composition of many foods, it is known the inhibitory effect of tea and coffee through the tannins on iron intestinal absorption; the "yerba mate" (Ilex Paraguarensis) is a beverage widely used in South America, that has a high content of a polyphenol named chlorogenic acid. The present work shows the effect of this substance in nonhem iron absorption. An intestinal loop, was made in rats, to form a closed cavity in a small section of intestine tieing it from the pilorous to a distance of six cm. In this closed cavity a solution of 59Fe was injected with different doses of chlorogenic acid; it was living 20, 40 and 120 minutes into the loop, and after this different times, the blood, spleen, liver, femur and intestine were removed to measure the 59Fe uptake to be compared with the control group. The results gave an intense inhibitory effect on the intestinal iron absorption with doses of 0.58 and 1.7 mM per rat of chlorogenic acid at the different times studied.


Caffeine effects on heart muscle energetics: species differences. The effects of caffeine (1mM) on energy expenditure and mechanical parameters in rat and toad perfused heart ventricles were examined at various stimulation frequencies. While in rat muscles caffeine significantly depressed developed tension and maximal rates of contraction and relaxation at all frequencies tested, in toad ventricle a slight positive inotropic effect was observed. Even though caffeine did not alter total contraction time in both preparations, in the rat ventricle the last part of relaxation was prolonged. In rat ventricle in the presence of caffeine, the ratios between active heat production per beat and either developed tension or tension time integral increased at all frequencies tested (+303 +/- 47 microJ.mN-1 x g-1 and +1.21 +/- 0.13 mJ.mN-1 x s-1 x g-1 respectively) indicating a decrease in contractile economy. In toad ventricle no changes on these ratios were observed. The fact that only in rat ventricle caffeine decreased muscle economy suggests that caffeine affects a system that is active in rat ventricle but it is not operative in toad ventricle. This gives support to the hypothesis that if in rat ventricle SR-Ca pump (1 ATP hydrolyzed/2 Ca transported) is inhibited by caffeine cytosolic Ca would have to be removed by alternative mechanisms such as Na-Ca exchanger or sarcolemmal Ca pump both with a higher rate of ATP hydrolysis (1 ATP hydrolyzed/Ca transported) with the consequent decrease in muscle economy. Resting heat production was increased by caffeine in both preparations and the magnitude of the increment (+3.0 +/- 0.6 mW.g-1 and +0.75 +/- 0.21 mW.g-1 for rat and toad ventricle respectively) also correlates with the different degree of SR activity in both species.


Norepinephrine--stimulated activity of hypothalamic adenylate cyclase varies throughout the estrous cycle of the female rat. The activity of hypothalamic adenylate cyclase was studied throughout the estrous cycle of the female rat. The activity of the enzyme was determined in particulate fractions obtained from hypothalami of rats killed at 10.00 h and 16.00 h of the 4-day estrous cycle. The activity was assayed in the presence of norepinephrine (10(-8) to 10(-3) M) by the capacity to produce adenosine 3',5' cyclic monophosphate. The basal activity of adenylate cyclase was higher in the morning of estrus than at any other time during the cycle. Norepinephrine-stimulated adenylate cyclase activity, as assessed by the apparent affinity (Kd) and apparent maximum effect, varied during the cycle, showing highest affinity, lowest Kd, in the afternoon of proestrus. The highest level of apparent maximum effect was also found in the afternoon of proestrus declining on diestrous day 2, diestrous day 1 and estrus. The norepinephrine stimulated activity was significantly inhibited by phenoxybenzamine, an alpha-blocker, in the morning of diestrus day 1, whereas on the day of diestrus day 2 and proestrus it was inhibited by the beta-adrenoblocker, propranolol. A similar degree of inhibition by alpha- and beta-blockers was observed in the morning of estrus. These results indicate that the hypothalamic adenylate cyclase coupled to adrenergic receptors shows dynamic changes throughout the estrous cycle.


Fluoride and phosphatidylserine induced inhibition of cytosolic insulin-degrading activity. Cytosol (C) (100,000 x g/60 min, supernatant) from liver, brain and testis (Wistar male rats) are shown to contain insulin degrading activity (C-IDA). The regulation of C-IDA in these fractions by ligands that activate G protein and PKC were examined C-IDA from liver, brain and testis was inhibited 76%; 64% and 50% by 50 mM F- respectively. Chromatography of C fraction from liver on Sephadex G-50 in presence of 1 M (NH4)2SO4 and 20% (v/v) glycerol (experimental condition to remove guanine nucleotides from G proteins) decreased in about 3-fold aluminum fluoride effect on C-IDA. Mg++ (from 5mM to 10 mM) enhanced fluoride effects by inhibiting fully C-IDA. Phosphatidylserine in presence of ATP completely inhibited C-IDA; this inhibition was 31.3% mediated by a phosphorylation reaction. It is concluded that cytosol from different tissues contain proteins capable to associate ligands as aluminum fluoride and PS to regulate C-IDA. It is proposed a mechanism of protein-protein interaction to modulate C-IDA.


Regulation of potassium conductance in the cellular membrane at early embryogenesis. At the early stages of development of the fresh water fish loach (Misgurnus fossilis) the resting membrane potential (Er) of cleaving cells oscillates periodically with an amplitude of 8-12 mV. Er oscillation correlates with the cell cycle and is accompanied by changes of K+ conductivity. Two types of K(+)-selective ionic channels with conductance of approximately 70 and 25 pS in symmetrical (150 mM KCl) solution were observed in the membrane of cleaving loach embryos. 'High' conductance and 'low' conductance channels were recorded in approximately 90% and 10% of patches investigated (n = 275), respectively? The activity of 'high' conductance channels was regulated by the application of pressure to the membrane, ie these channels were stretch-activated (SA). The activity of SA channels changes dramatically during the cell-cleavage cycle. At the beginning of interphase the probability of SA channels being in the open state (P0) was minimal, while at prometaphase the probability was increased 10-100-fold. Application of ATP to the cytoplasmic inside-out patches induced a reversible elevation of stretch sensitivity of the SA channels in 50% of the patches, while the non-hydrolyzable analogue of ATP was not effective. Combined application of ATP, cAMP and cAMP-dependent protein kinase (PK) induced a reversible elevation in the SA channel activity while inhibitors of PK prevented its activating effects. Phosphatase inhibitors prolonged the activating effect of PK on SA channels. We propose that oscillations of the resting potential during the cell-cleavage cycle arise due to modulation of SA channel sensitivity to stretch through cAMP-dependent phosphorylation.


Charge movement and Ca2+ release in normal and dysgenic foetal myotubes. Intramembrane charge movement and Ca2+ release from sarcoplasmic reticulum was studied in foetal skeletal muscle cells from normal and mutant mice with 'muscular dysgenesis' (mdg/mdg). It was shown that: 1) unlike normal myotubes, in dysgenic myotubes membrane depolarization did not evoke calcium release from the sarcoplasmic reticulum; 2) when all ionic currents are pharmacologically suppressed, membrane depolarization produced an asymmetric intramembrane charge movement in both normal and dysgenic myotubes. The relationship between the membrane potential and the amount of charge movement in these muscles could be expressed by a two-state Boltzmann equation; 3) the maximum amount of charge movement associated with depolarization (Qon max) in normal and in dysgenic myotubes was 6.3 +/- 1.4 nC/microF (n = 6) and 1.7 +/- 0.3 nC/microF (n = 6) respectively; 4) nifedipine (1-20 microM) applied to the bath reduced Qon max by about 40% in normal muscle cells. In contrast, the drug had no significant effect on the charge movement of dysgenic myotubes; and 5) the amount of nifedipine-resistant charge movement in normal and in dysgenic myotubes was 3.5 nC/microF (n = 3) and 1.7 nC/microF 1 maximum (n = 3), respectively.


Spiral waves and intracellular calcium signalling. Confocal imaging of intracellular Ca2+ brings a new level of resolution to the study of hormonal control of intracellular Ca2+ release. This approach has demonstrated the existence of pulsatile circular and spiral waves of Ca+ release induced by receptor activation. The data obtained by confocal imaging support a new framework for understanding intracellular Ca2+ signalling. The goal of this chapter is to review our data on the complexity of intracellular Ca2+ release in Xenopus oocytes, introduce the concept of Ca2+ excitability as a model for Ca2+ release and discuss the implications for encoding intracellular signal information.


The role of calcium in prolonged modification of a GABAergic synapse. Caudal hair cell impulses cause postsynaptic inhibition of ipsilateral type B photoreceptors in the snail Hermissenda. This inhibition is shown to be GABAergic according to a number of criteria. HPLC, mass spectrophotometric, and immunocytochemical techniques demonstrated the presence of GABA in the hair cells and their axons. GABA agonists and antagonists mimic and block the synaptic effect in a manner consistent with endogenous GABAergic transmission. Other properties, including I-V relations, conductance changes and reversal potentials, are comparable for exogenous GABA responses and endogenous effects of the hair cell impulses. This inhibitory synapse has been found to undergo a long-lasting transformation into an excitatory synapse if GABA release is paired with post-synaptic depolarization. GABA, via GABAA and GABAB receptors in the B cell, causes the opening of calcium sensitive chloride and potassium channels that leads to the post-synaptic hyperpolarization. GABA also induces a long-lasting intracellular calcium elevation at the terminal branches of the B cell that greatly outlasts the voltage responses. Synaptic transformation induced by pairings is caused by a decrease in both GABA induced chloride and potassium conductances in the post-synaptic B cell, as well as a significant prolongation of the intracellular calcium accumulation in the B cell's terminal axonal branches.


The role of cytoplasmic calcium in photoreceptor light adaptation. The process of light adaptation in vertebrate rod and cone photoreceptors is believed to involve a diffusible cytoplasmic messenger. Two lines of evidence indicate that photoreceptor light adaptation is mediated by a light-induced fall in cytoplasmic calcium concentration (Ca2+i). First, if changes in calcium concentration are slowed by the incorporation of calcium chelators into the photoreceptor cytoplasm then light adaptation is slowed also. Second, if the normal control of Ca2+i is prevented by simultaneously minimising calcium influx and efflux across the outer segment membrane by means of external solution changes, then all of the manifestations of light adaptation are abolished. Furthermore, recent results show that changes in Ca2+i imposed in the absence of light are sufficient to cause at least some of the manifestations of light adaptation. Together these results indicate that calcium acts as the messenger of light adaptation in the photoreceptors of both lower and higher vertebrates.


Intracellular Ca2+ stores in neurons. Identification and functional aspects. Various aspects of the rapidly exchanging intracellular Ca2+ stores of neurons and nerve cells are reviewed: their multiplicity, with separate sensitivity to either the second messenger, inositol 1,4,5-trisphosphate, or ryanodine-caffeine (the latter stores are probably activated via Ca(2+)-induced Ca2+ release); their control of the plasma membrane Ca2+ permeability, via the activation of a peculiar type of cation channels; their ability to sustain localized heterogeneities of the [Ca2+]i that could be of physiological key-importance. Finally, the molecular composition of these stores is discussed. They are shown (by high resolution immunocytochemistry and subcellular fractionation) to express: i) a Ca2+ ATPase responsible for the accumulation of the cation; ii) Ca2+ binding protein(s) of low affinity and high capacity to keep Ca2+ stored; and iii) a Ca2+ channel, activated by either one of the mechanisms mentioned above, to release Ca2+ to the cytosol. Results obtained in Purkinje neurons document the heterogeneity of the stores and the strategical distribution of the corresponding organelles (calciosomes; specialized portions of the ER) within the cell body, dendrites and dendritic spines.


Presynaptic receptors for FMRFamide, histamine and buccalin regulate acetylcholine release at a neuro-neuronal synapse of Aplysia by modulating N-type Ca2+ channels. At an identified neuro-neuronal synapse of the buccal ganglion of Aplysia, quantal release of acetylcholine (ACh) is increased by FMRFamide and decreased by histamine or buccalin. Activation of presynaptic receptors for these neuromodulators modifies a presynaptic Ca2+ current which is nifedipine-resistant and omega-conotoxin-sensitive. The voltage-sensitivity of these N-type Ca2+ channels is increased by FMRFamide and decreased by histamine through the intermediate of G proteins. Buccalin does not implicate G proteins and reduces the Ca2+ current without affecting the voltage-sensitivity of N-type Ca2+ channels. The possibility of relating the shifts in voltage-dependence of the Ca2+ current induced by FMRFamide and histamine to the phosphorylation state of the N-type Ca2+ channels is discussed. A scheme for the complex regulation of ACh release by presynaptic auto- and heteroreceptors is proposed.


Divalent cation changes in cerebellar Purkinje cells after climbing fiber deafferentation. A secondary ion mass spectrometry (SIMS) microscope was used to detect intracellular stores of calcium, magnesium, sodium and potassium. Measurements were made in semithin sections of fixed tissues of normal and climbing fiber deafferented cerebellar cortex. Quantitative data were collected from 150 microns diameter image fields in the molecular and granule layers. The results indicate smaller quantities of both calcium and magnesium in the deafferented cerebellar cortex compared to the normals, the molecular as well as the granule layer being affected. The results are discussed in terms of the usefulness and limitations of the SIMS microscope for histological preparations.


The metabotropic glutamate receptor (MGR): pharmacology and subcellular location. A pharmacological characterization of the metabotropic glutamate receptor (MGR) was performed in striatal neurons. Among the excitatory amino acid receptor antagonists tested, only D, L-2-amino-3-phosphonopropionate (D, L-AP3) inhibited QA-induced inositol phosphate (InsP) formation in a competitive manner (mean pKi = 4.45 +/- 0.43, n = 4). However, this drug was a partial agonist of MGR since it stimulated the inositol-phosphate formation. We found that D, L-AP3 also inhibited NMDA-induced calcium increase, in a competitive manner (mean pIC50 = 4.34 +/- 0.22, n = 8, and mean pKi = 3.7 +/- 0.11 n = 5). 1 mM of the ionotropic agonists alpha-amino-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate (KA) or domoate (DO) (100 microM or higher) induced a significant InsP formation in striatal neurons. The InsP responses induced by all these agonists were totally blocked by the phorbol ester phorbol-12,13-dibutyrate (PdBu), but not by atropine or prazosin. Agonist-induced increases of intracellular calcium concentrations ([Ca2+]i) were insensitive to PdBu, suggesting that all these substances were able to stimulate the MGR in striatal neurons. Trans-1-amino-cyclopentyl-1,3-dicarboxylate (trans-ACPD) evoked dose-dependent inositol phosphate formations with an EC50 of 29 microM but had no significant effect on NMDA or AMPA receptors, as measured by the patch clamp technique. In the presence of 30 microM of AMPA, trans-ACPD induced a significant release of arachidonic acid (AA) in striatal neurons. No important AA release was observed by any of these agonists alone. 56 mM K+ did not mimic AMPA in this associative ionotropic/metabotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)


Ca2+ signalling in postsynaptic dendrites and spines of mammalian neurons in brain slice. Postsynaptic Ca2+ changes are involved in control of cellular excitability and induction of synaptic long-term changes. We monitored Ca2+ changes in dendrites and spines during synaptic and direct stimulation using high resolution microfluorometry of fura-2 injected into CA3 pyramidal neurons in guinea pig hippocampal slice. When driven by current injection from an intracellular electrode or with synaptic stimulation, postsynaptic Ca2+ accumulations were highest in the proximal dendrites with a pronounced fall-off towards the soma and some fall-off towards more distal dendrites. Muscarinic activation by low concentrations of carbachol strongly increased intradendritic Ca2+ accumulation during directly-evoked repetitive firing. This enhancement occurred in large part because muscarinic activation suppressed the normal Ca(2+)-dependent activation of K-channels that mediates adaptation of firing. Repetitive firing of cholinergic fibers in the slice reproduced the effects of carbachol. Inhibition of acetylcholine-esterase activity by eserine enhanced the effects of repetitive stimulation of chlolinergic fibers. All effects were reversible and were blocked by the muscarinic antagonist atropine. Ca2+ accumulations in postsynaptic spines might be the basis of specificity of synaptic plasticity. With selective stimulation of few associative/comissural fibers, Ca2+ accumulated in single postsynaptic spines but not in the parent dendrite. With strong stimulation, dendrite levels also increased but spine levels were considerably higher. The NMDA-receptor antagonist AP-5 blocked Ca(2+)-peaks in spines, but left Ca2+ changes in dendrite shafts largely unaffected. Sustained steep Ca2+ gradients between single spines and the parent dendrite, often lasting several minutes, developed with repeated stimulation. Our results demonstrate a spine entity that can act independent from the dendrite with respect to Ca(2+)-dependent processes. Muscarinic augmentation of dendritic Ca2+ levels might reduce diffusional loss of Ca2+ from hot spines into the parent dendrite, thus supporting cooperativity and associativity of synaptic plasticity.


Carbachol-stimulated calcium entry in SH-SY5Y human neuroblastoma cells: which route? M3 muscarinic receptors expressed on SH-SY5Y human neuroblastoma cells are linked to phosphoinositide turnover and rises in [Ca2+]i. The rise in [Ca2+]i is biphasic with the peak phase being due to release from an intracellular Ins(1,4,5)P3-sensitive site and the plateau phase being due to Ca2+ entry across the plasma membrane. Ca2+ entry does not appear to involve voltage sensitive Ca2+ channels, a pertussis toxin sensitive G-protein-operated Ca2+ channel or Ins(1,4,5)P3/Ins(1,3,4,5)P4-operated Ca2+ channel. We suggest that carbachol-stimulated Ca2+ entry in SH-SY5Y human neuroblastoma cells occurs via receptor operated Ca2+ channels and through capacitive refilling.


Calmodulin and cell cycle control.

Calmodulin and cell cycle control. Previous studies have indicated a role for the calcium receptor calmodulin in the control of eukaryotic cell proliferation. Using a molecular genetic approach in the filamentous fungus Aspergillus nidulans we have shown that CaM is required for cell cycle progression at multiple points in the cell cycle. Construction of an A nidulans strain conditional for calmodulin expression reveals that this protein is required during G1/S and for the initiation of mitosis. A lack of calmodulin results in cell cycle arrest, and a failure in polar growth that accompanies germination of A nidulans spores. In addition, increased expression of calmodulin in this organism permits growth at suboptimal calcium concentrations, indicating that cell growth is coordinately regulated by calcium and calmodulin. Together these results indicate that calmodulin-dependent processes may be conserved between A nidulans and vertebrate cells, and suggest that this approach may allow us to elucidate the molecular mechanism underlying calmodulin-regulated control of cell proliferation.


Calcium regulation of immediate early gene transcription. Cellular immediate early genes (IEGs) are a class of genes whose transcription is transiently activated within minutes of exposure of cells to a wide range of extracellular stimuli. In mature neurons IEG expression can be triggered by a variety of neutrotransmitters and neurotrophic factors. The IEGs, many of which encode transcription factors, are believed to control the physiological response of the cells to the initial stimulation event by activating secondary programs of gene expression. The mechanism by which membrane depolarization/Ca2+ influx trigger the activation of one IEG, c-fos, has been characterized in PC12 cells. In these cells, the cAMP response element-binding protein (CREB) functions as a Ca2+ regulated transcription factor. In addition, CREB is an in vitro substrate for several Ca2+ calmodulin-dependent protein kinases (CaM kinases). These results suggest a model whereby activation of voltage sensitive Ca2+ channels stimulates CaM kinase activation leading to CREB phosphorylation and c-fos transcriptional activation.


Altered mechanical responses of malignant hyperthermic skeletal muscle during repetitive stimulation. This investigation examined the mechanical responses of malignant hyperthermic (MH) and normal porcine skeletal muscle to repetitive stimulation. Twitch and maximal tetanic tensions were not significantly different between muscle types. Tensions produced during stimulation at 20-80 Hz were significantly less in MH muscle than in normal muscle. In addition, MH muscle showed significantly greater force decline (tetanic fade) at the end of contractions evoked by 20-80 Hz stimulation. When stimulated to fatigue, both normal and MH muscle exhibited similar rates of tension decline during the initial minutes. Further stimulation caused additional decline in normal muscle, but a tension plateau in MH muscle. In all cases, normal muscle had greater magnitudes of fatigue than did MH muscle. Results show that there are marked differences between MH and normal muscle in the mechanical responses to repetitive stimulation. Due to its inability to properly regulate intracellular Ca2+ exchange, it is possible that MH muscle might be a useful tool for identifying the mechanisms of muscle fatigue in normal muscle.


Atrial natriuretic peptide during water deprivation or hemorrhage in rats. Relationship with arginine vasopressin and osmolarity. The concentrations of atrial natriuretic peptide (ANP) in atria, hypothalami and plasma were investigated in relation to the variations of the plasma endogenous immunoreactive arginine vasopressin (Ir-AVP) during water deprivation or hemorrhage in normal conscious Wistar rats. Furthermore, the in vitro and in vivo effect of extracellular hyperosmolarity on ANP release from right atrium and hypothalamus was examined. Water deprivation elevated circulating immunoreactive ANP (Ir-ANP: pg/ml) to 153 +/- 7 (24 h); 174 +/- 1 (48 h) from the control level (109.6 +/- 7.8). This increase in Ir-ANP concentration which correlated with atrial (r = -0.93) or hypothalamic (r = -0.87) Ir-ANP content decrease, was associated with significantly enhanced levels of plasma Ir-AVP, plasma sodium, osmolarity and hematocrit. An acute volume depletion by hemorrhage significantly reduced plasma Ir-ANP (67 +/- 8.4 pg/ml) from the sham operated level (140 +/- 18 pg/ml). Plasma Ir-AVP was elevated dramatically (207.4 +/- 53.4 pg/ml) compared with the sham operated level (8.8 +/- 2.6 pg/ml). These results, indicating the lack of correlation between plasma Ir-ANP and Ir-AVP in vivo, suggest that the ANP secretion, which is regulated mainly by plasma volume, may be modulated by a change in plasma osmolarity. Extracellular hyperosmolarity stimulated the ANP release from superfused sliced normal rat atria and hypothalami.


Characterization of cultured rat aortic endothelial cells. We describe a new method to obtain rat aortic endothelial cells without contamination by vascular smooth muscle cells. The endothelial cells were characterized up to the 20th passage by low density lipoprotein incorporation, the absence of alpha-smooth muscle actin, the production of endothelium derived relaxing factor, and an elevation in intracellular free calcium concentration in response to bradykinin and ATP but not to AMP and angiotensin II.


Agonist-induced production of inositol phosphates in human airway smooth muscle cells in culture. Smooth muscle cells (SMC) from human bronchi were isolated by elastase treatment, subcultured, and characterized by their positive reaction with a monoclonal antibody against alpha-smooth muscle actin (alpha SMA). In each cell line tested, at least 95% of the cells were positively stained. The functional properties of these cells were examined by measuring the metabolism of inositol phosphates (IPs). For that purpose, cells were incubated for 3 days before reaching confluency in the presence of myo-[3H]inositol in order to label the phosphoinositide pool, and the various [3H]IPs were separated by HPLC on a SAX column with a phosphate gradient. IP1 isomers were separated in three peaks; IP2, IP3, IP4, IP5 and IP6 (phytic acid) were each eluted as single peaks. The identity of the [3H]peaks was verified with corresponding [3H]IP standards. The accumulation of [3H]IPs was measured by incubating cells up to 30 min in the presence of 10 mM LiCl, with or without a bronchoconstrictor agent (carbachol, histamine, PGF2 alpha). Histamine, 10(-4) M, elicited a four times larger IP accumulation than carbachol, 10(-4) M, and than PGF2 alpha, 5 10(-5) M. Dose-response curves were established for histamine and carbachol in the range 10(-7)-10(-4) M. At 10(-7) M, carbachol was more effective than histamine in stimulating the IP metabolism. Atropine blocked the response to carbachol, and diphenhydramine inhibited the effect of histamine, indicating the specificity of the response to the agonists. These results indicate that cultured human bronchial SMC are a suitable preparation for studying physiological aspects of membrane transduction in the airways.


Rat liver response elicited by long-term cold exposure. We measured mitochondrial protein mass as well as State 4 and 3 respiratory rates using different substrates in isolated liver mitochondria from 30-day cold-exposed rats. In addition, we measured the respiration under different conditions of stimulation in isolated hepatocytes from long-term cold-exposed rats. The results show that long-term cold exposure elicits a significant increase in hepatic mass and mitochondrial protein mass. No variation was found in oxygen consumption of isolated mitochondria and hepatocytes. On the whole, the results indicate that long-term exposure elicits an increase in hepatic mitochondrial protein mass but not in hepatic oxygen consumption.


Does episiotomy prevent perineal trauma and pelvic floor relaxation? To compare the outcomes of the current practice of liberally or routinely employing episiotomy to prevent perineal tears and pelvic floor relaxation (control group) to a policy of restricting episiotomy use to specific fetal and maternal indications (experimental group). A randomized controlled trial (RCT). Three university hospitals in Montreal. Seven hundred three low-risk women enrolled at 30 to 34 weeks of gestation were randomized late in labor to the designated trial arm, by parity, and followed up to 3 months postpartum. Antepartum and postpartum information on perineal trauma and pain, pelvic floor symptoms (urinary incontinence), and sexual activity was collected through the use of standard questionnaires; pelvic floor function was measured by electromyographic (EMG) perineometry. Restricting episiotomy use in primiparous women was associated with similar sutured perineal trauma to the liberal or routine approach. Multiparous women in the restricted episiotomy group more often gave birth with an intact perineum (31% compared with 19%, odds ratio (OR) = 1.85, 95% confidence interval (CI) = 1.09 to 3.16). All but one 3rd/4th-degree perineal tear was associated with median episiotomy (46 of 47 in primiparous women and 6 of 6 among multiparous women). No difference between trial groups was found in postpartum perineal pain, antepartum and 3-month postpartum EMG perineometry, and urinary and pelvic floor symptoms. We found no evidence that liberal or routine use of episiotomy prevents perineal trauma or pelvic floor relaxation. Virtually all severe perineal trauma was associated with median episiotomy. Restriction of episiotomy use among multiparous women resulted in significantly more intact perineums and less perineal suturing.


Will publication bias vanish in the age of online journals? A major advantage of online journals, in contrast to printed journals, is that lack of space is not an obstacle. One obvious benefit of this is the ability to include material that might help clarify or emphasize important points, but that might not be considered essential in the context of the limited space available in a printed journal. A more important benefit of removing space constraints is the potential to eliminate publication bias. This bias occurs when a study is not published because it fails to find any statistically significant differences or associations. While authors play a major role in generating this bias, their belief that publication depends on statistical significance has some foundation in the existing printed literature. Nevertheless, realizing the potential to eliminate publication bias depends largely on the willingness of authors to submit their work. The Online Journal of Current Clinical Trials will judge papers on the quality of the work and the importance of the findings, not on the level of statistical significance achieved in any comparisons made. Valuable papers need no longer be turned away simply because of lack of space.


A clinical trials database as a research tool in health care. The rapid, efficient, and accurate communication of clinical research findings to both clinicians and researchers is essential to the process of improving medical care. This information should be conveyed in a form that facilitates the interpretation of the complete body of research on a specific condition. Unfortunately, the prevailing system for dissemination of clinical research fails to meet these criteria. This paper proposes a system for cataloging clinical trials and communicating their results in a comprehensive and comprehensible format. The system involves the use of a hierarchical matrix structure that allows for the selection and evaluation of related groups of clinical trials. The format of the data is tailored to the requirements of metaanalysis. An example is presented using the treatment of acute Crohn's disease and including a sample metaanalysis of immunosuppressive therapy for this condition. The hierarchical matrix structure in conjunction with a comprehensive database of clinical trials holds the potential to facilitate access to and interpretation of clinical research.


Trimethoprim-sulfamethoxazole compared with ciprofloxacin for the prevention of urinary tract infection in renal transplant recipients. A double-blind, randomized controlled trial. Prophylaxis with low-dose trimethoprim-sulfamethoxazole has been shown to be cost-effective in the prevention of urinary tract infections, pyelonephritis, urosepsis, and pneumocystis pneumonia in renal transplant recipients. Ciprofloxacin, effective against almost all urinary tract pathogens in this patient population, represents a promising alternative prophylactic agent for patients unable to tolerate trimethoprim-sulfamethoxazole due to toxicity. We conducted a randomized, double-blind trial to compare low-dose trimethoprim-sulfamethoxazole with ciprofloxacin for the prevention of urinary tract infections in renal transplant recipients. Patients received either ciprofloxacin (250 mg) or trimethoprim-sulfamethoxazole (80 mg trimethoprim, 400 mg sulfamethoxazole) daily for 6 months following transplantation. Treatment was considered successful if patients completed the 6-month course and 3-month follow-up period without evidence of urinary tract infection or drug-related toxicities. Of 103 eligible patients, 51 received ciprofloxacin and 52 received trimethoprim-sulfamethoxazole. At 6 months, treatment was successful in 75% (38 of 51) receiving ciprofloxacin and 71% (37 of 52) treated with trimethoprim-sulfamethoxazole (P = 0.87, relative risk 1.04, 95% confidence limits 0.83 to 1.33). Thirteen patients (25%) receiving trimethoprim-sulfamethoxazole withdrew from the study-4 for resistant urinary tract infection and 9 for drug-related toxicity, while 3 (6%) of the patients receiving ciprofloxacin withdrew because of drug-related toxicity (P = 0.016, relative risk of urinary tract infection or adverse event 0.24, 95% confidence limits 0.07 to 0.78). At 9 months, all 38 patients who completed the 6-month course of ciprofloxacin remained free of urinary tract infection, while an additional 4 patients who had received trimethoprim-sulfamethoxazole prophylaxis (total of 8 patients over the 9 months) developed urinary tract infections (P = 0.006, Fisher's exact test for urinary tract infection alone). Pneumocystis pneumonia occurred in a total of 7 (14%) patients who were randomized to ciprofloxacin, but 2 of the 7 had withdrawn from the study at least 2 weeks prior to the diagnosis of pneumocystis pneumonia. There were no cases of pneumocystis pneumonia in patients receiving trimethoprim-sulfamethoxazole (P = 0.006). Following completion of the study, monthly aerosolized pentamidine administered in conjunction with ciprofloxacin has provided complete protection against urinary tract infection and pneumocystis pneumonia in 30 transplant recipients unable to tolerate trimethoprim-sulfamethoxazole therapy. Ciprofloxacin is at least as effective as trimethoprim-sulfamethoxazole in the prevention of urinary tract infection in renal transplant recipients, and is better tolerated. Ciprofloxacin prophylaxis is associated with a higher incidence of pneumocystis pneumonia than is trimethoprim-sulfamethoxazole therapy. An uncontrolled follow-up study suggests that ciprofloxacin prophylaxis combined with monthly aerosolized pentamidine may be efficacious in preventing both urinary tract infection and pneumocystis pneumonia in renal transplant recipients.


Episiotomy. To cut or not to cut?

Episiotomy. To cut or not to cut? Episiotomy is performed in over half of the hospital-based deliveries in the US, despite the dearth of scientific data demonstrating its usefulness in uncomplicated cases. After roughly 70 years of widespread use in the US, the first randomized clinical trial of episiotomy conducted in North America (and the first worldwide involving median episiotomy) found no evidence for better outcomes in deliveries assigned to "liberal" than those assigned to "restricted" use of episiotomy. These results lend support to the many health professionals and lay persons calling for further reduction in the use of this procedure.


Low-dose (7.5 mg) oral methotrexate for chronic progressive multiple sclerosis. Design of a randomized, placebo-controlled trial with sample size benefits from a composite outcome variable including preliminary data on toxicity. To present a detailed description of (1) the study design of this ongoing trial, (2) advantages of using a composite outcome variable instead of multiple individual outcome measures, (3) treatment group characteristics at baseline, and (4) observed short-term methotrexate (MTX) toxicity. Randomized, double-masked, placebo-controlled intervention study. Referral-based outpatient multidisciplinary multiple sclerosis (MS) clinic. Participation offered to all clinically definite chronic progressive multiple sclerosis (CPMS) patients attending clinic ages 21 to 60, disease duration > 1 year, Expanded Disability Status Scale (EDSS) score 3.0 to 6.5 (ambulatory with moderate disability). Patients first stratified by EDSS 3.0 to 5.5 and 6.0 to 6.5, then randomized to MTX or placebo treatment. Weekly oral low-dose (7.5 mg) MTX or identical-appearing placebo for 2 years followed by a 1-year observation period. Sample size calculations undertaken prior to enrolling patients based upon a composite outcome variable consisting of designated change in any of the following functional measures: (1) EDSS, (2) Ambulation Index (AI), (3) Box and Block Test (BBT), and (4) 9-Hole Peg Test (9HPT). (1) Treatment group characteristics were comparable at baseline, (2) no patient has been withdrawn for adverse effects or lost to follow-up, (3) no significant short-term MTX toxicity has been observed. (1) The use of a composite outcome measure in the design of MS clinical trials is a promising alternative to multiple individual outcome measures that are relatively insensitive to detecting clinical change, (2) low-dose oral weekly MTX does not appear to be associated with significant short-term toxicity in CPMS. Conclusions regarding therapeutic efficacy of MTX in MS must await completion of this clinical trial.


Analgesia for the reduction of Colles fracture. A comparison of hematoma block and intravenous sedation. An alternative to general anesthesia was tested against conventional sedation by a double-blind, randomized clinical trial in reduction of Colles fracture. A large teaching hospital where cases of Colles fracture are not different from those seen in district hospitals. Sixty-six out of 80 consecutive cases with this fracture were selected from March to August 1990 on the basis of: 1) informed consent; 2) no contraindication to any method of analgesia; 3) no analgesic during the past 8 hours; 4) injury duration less than 96 hours; 5) no mental, auditory, or visual impairment; and 6) no associated injury. Patients were randomized into 2 equal groups. After tests for Xylocaine (Astra brand of lidocaine hydrochloride) sensitivity in both groups, the A group received 30 mg of pentazocine with 5 mg of diazepam intravenously on the dorsum of the affected wrist (sedation group), whereas the B group received 20 cc of 1.5% Xylocaine into the fracture hematoma. Five minutes later the fracture was reduced and immobilized by Lakhtakia or A. Singh. Thirteen to 15 hours later Manglik, blinded to the analgesia status of the patient, recorded pain before, during, and after reduction using Visual Analogue Scale (VAS). Statistically, randomization and blinding were found to be effective. The pain scores during reduction in the local anesthetic group (median = 1.8) were significantly less than those in the sedation group (median = 8.7), P < 0.001 using the Wilcoxon rank sum test. The difference persisted in regression analysis. The 2 methods proved comparable in safety and other measures of effectiveness. Hematoma block by local anesthetic is a safe and effective alternative to sedation in reduction of Colles fracture.


The Monitored Atherosclerosis Regression Study (MARS). Design, methods and baseline results. The Monitored Atherosclerosis Regression Study (MARS) was designed to evaluate the effect of cholesterol lowering by monotherapy with an HMG-CoA reductase inhibitor on progression/regression of atherosclerosis in subjects with angiographically documented coronary artery disease. The purpose of this paper is to present the design, methods, and baseline results of MARS. MARS is a prospective, randomized, double-blind, placebo-controlled trial with baseline, 2-year, and 4-year coronary angiography as well as carotid, brachial, and popliteal ultrasonography. Outpatient clinics at the University of Southern California School of Medicine and the University of Wisconsin School of Medicine. Two hundred seventy participants of both sexes were recruited directly from the cardiac catheterization laboratory or by chart review of patients having undergone cardiac catheterization in the past. Subjects were considered eligible if they had angiographically demonstrable atherosclerosis in 2 or more coronary artery segments, unaltered by angioplasty, with at least 1 lesion > or = 50% but < 100% diameter stenosis (%S). The inclusion range for total cholesterol (TC) was between 190 and 295 mg/dL. Exclusion factors were: triglycerides > or = 500 mg/dL; premenopausal females; uncontrolled hypertension; diabetes mellitus; untreated thyroid disease; liver dysfunction; renal insufficiency; congestive heart failure; major arrhythmia; left ventricular conduction defects; or any life-threatening disease. Subjects were placed on a low-fat, low-cholesterol diet and either 40 mg b.i.d. lovastatin (Mevacor) or placebo. Randomization was stratified by sex, smoking status, and TC. Per-subject average change in %S as determined by quantitative coronary angiography (QCA) is the primary angiographic endpoint. Secondary endpoints are: categorical analyses of the proportion of subjects with progression; human panel reading of coronary angiograms; and change in minimum lumen diameter (MLD) in mm by QCA. Carotid, brachial, and popliteal ultrasonography is also being performed. The subjects randomized into MARS are 91.5% male with an age range of 37 to 67 years (mean age 57.9 years). For the cohort, baseline lipids are (mean +/- SD): TC, 231 +/- 24 mg/dL; low-density lipoprotein cholesterol (LDL-C) by ultracentrifugation, 153 +/- 24 mg/dL; LDL-C, by calculation, 157 +/- 23 mg/dL; high-density lipoprotein cholesterol (HDL-C), 43 +/- 10 mg/dL; and triglycerides, 160 +/- 73 mg/dL. There were no significant differences between treatment groups in baseline lipid levels or baseline angiographic characteristics. MARS baseline data show adequacy of randomization with comparability of lovastatin and placebo groups in demographic, lipid, and angiographic characteristics.


Early or selective surfactant (colfosceril palmitate, Exosurf) for intubated babies at 26 to 29 weeks gestation. A European double-blind trial with sequential analysis. European Exosurf Study Group. To compare a policy of giving surfactant to all intubated babies of gestational age 26 to 29 weeks with a policy of treating only those babies developing respiratory distress syndrome (RDS). Randomized, double-blind, placebo-controlled. Twenty-two neonatal intensive care units in 5 countries. Blinded administration of either surfactant (colfosceril palmitate, Exosurf) or air placebo, within 2 hours of birth. Babies in either group developing RDS during the following 18 hours received 2 unblinded doses of surfactant 12 hours apart. Babies without RDS received a 2nd dose of surfactant or air as originally randomized 18 hours after the 1st dose. Primary: survival to 28 days without brain damage (cysts or hydrocephalus-blinded ultrasound assessment with central review). Secondary: incidence of RDS; durations of intubation, intensive care, and oxygen therapy. incidences of pneumothorax, pulmonary interstitial emphysema, persistent ductus arteriosus, infection, and necrotizing enterocolitis. Two hundred twelve babies randomized to early and 208 to selective surfactant. One hundred five early babies and 142 selective babies developed RDS requiring unblinded surfactant (50% versus 68%; 95% CI of difference, 9% to 27%). At age 28 days, 175 early and 163 selective babies survived (83% versus 78%, 95% CI, -3% to 12%), 140 early and 131 selective without brain damage (66% versus 63%, 95% CI, -6% to 12%, P = 0.41). Significant reductions were seen in the incidence of pneumothorax (18% early versus 26% selective) and pulmonary interstitial emphysema (14% versus 22%) (95% CI for both, 1% to 16%). Early surfactant reduces short-term morbidity, but any difference in outcome at 28 days is likely to be small.


Is the medical world ready for electronic journals? New technologies offer new ways to deliver scholarly information, perhaps advantageously compared with paper journals, which have been an accustomed mode of scholarly communication for 300 years. Paper journals offer conveniences in handling and reading, and the economic constraints on their length tend to ensure that this constraint is important. Electronic journals are not yet as easy to use. But paper journals are economically cost effective and these space constraints prevent their publishing information not important to most readers but important to some. Electronic journals offer new advantages for readers, including the capacity to carry more and longer papers, linkages between related documents, and hypertext functions. The editors of The Online Journal of Current Clinical Trials welcome comments on its features and content; these should be sent to Dr. María L. Lebrón, Managing Editor, CCT, AAAS, 1333 H Street, NW, Washington, DC 20005 USA, FAX 202-842-2868.


The publisher's perspective.

The publisher's perspective. The Online Journal of Current Clinical Trials (CCT) represents a publishing milestone in the history of the American Association for the Advancement of Science. The historical background and institutional considerations leading to the establishment of CCT are discussed in this editorial.


Intensive therapy with cisplatin, interleukin-2 and interferon-alpha-2a in patients with metastatic melanoma. A phase II Study. Based upon their individual clinical activity and combined effects in animal models or in vitro, we wished to evaluate a regimen of cisplatin, interferon-alpha, and IL-2 in patients with metastatic melanoma. Phase II pilot study. Referral-based US Government clinical research unit. Nine patients with metastatic malignant melanoma. Cisplatin 75-100 mg/m2 was administered intravenously over 30 minutes on days 1 and 8. Interferon-alpha 2a 5 Mu/m2 body surface area (BSA) was given subcutaneously for 4 days beginning 1 day before each dose of cisplatin. Beginning on day 15 and day 22, IL-2 was administered by intravenous continuous infusion at 3 Mu/m2 BSA/d for 96 hours and by daily intravenous bolus concurrent with daily subcutaneous doses of interferon-alpha 2a. Antitumor response and toxicities. The study was stopped due to renal and hematopoietic toxicity and severe, delayed nausea and vomiting associated with the cisplatin-interferon treatment. Three of 9 patients achieved a partial response (duration 2.5, 4, 14+ months), and an additional patient had a 50% reduction in measurable tumor volume before undergoing resection of residual disease. Overall response rate was 45%. This regimen was associated with excessive toxicity, and the lack of complete responses in a patient cohort with favorable characteristics for response (good performance status, predominance of skin and lymph node metastatic sites) suggests that it had no advantage over less toxic treatment regimens. National Cancer Institute/Cancer Therapy Evaluation Program T89-0137.


Developmental theories for the 1990s: development and individual differences. Understanding both typical human development and indivdual differences within the same theoretical framework has been difficult because the 2 orientations arise from different philosophical traditions. It is argued that an evolutionary perspective can unite the study of both species-typical development and individual variation. Research on determininants of development from many perspectives can be understood within an evolutionary framework in which organism and environment combine to produce development. Species-normal genes and environments and indidividual variations in genes and environments both affect personality, social, and intellectual development. These domains are used as examples to integrate theories of normal development and individual differences. Within the usual samples of European, North American, and developed Asian countries, the results of family and twin studies show that environments within the normal species range are crucial to normal development. Given a wide range of environmental opportunities and emotional supports, however, most children in these societies grow up to be individually different based on their individual genotypes. Understanding the ways in which genes and environments work together helps developmentalists to identify children in need of intervention and to tailor interventions to their particular needs.


Salivary excretion of drugs in children: theoretical and practical issues in therapeutic drug monitoring. Studies suggest that saliva could be used instead of blood in the therapeutic monitoring of many drugs. This has distinct advantages in pediatrics and neonatology as saliva sampling is painless and spares blood. Stimulation of saliva secretion with a chemical stimulus (i.e. citric acid applied over the tongue) facilitates the study of younger patients. Secretory and reabsorptive processes which take place in the ductal system of the salivary glands, and the rate of flow of the secretion play major roles in the determination of the concentration of solutes in saliva. Drug passage into saliva follows the general principles of movement of drugs across biologic membranes. Only the unbound fraction of the drug in plasma is available for diffusion into saliva and a relationship exists between saliva pH and the saliva/plasma concentration ratio of many polar drugs (tolbutamide, propranolol, procainamide, etc.). However, deviations from the pH theory exist and the inter -and intra-individual variations in saliva/plasma concentration ratios of salicylate and procainamide cannot be explained solely on the basis of fluctuations of salivary pH; on the other hand, a useful relationship exists between plasma and saliva phenobarbital concentrations with no need to correct for saliva pH. The use of stimulated saliva has several advantages over resting saliva: a larger volume of the sample is obtained, the pH gradient between plasma and saliva is smaller, the variability in saliva/plasma concentration ratios of some drugs is narrowed, and less specimens are too viscous or discolored to allow drug analysis. Thorough rinsing of the mouth is required prior to saliva sampling as remnants of orally administered medicines may contaminate saliva specimens and give spuriously high values. Deviation from a simple but strict methodology accounts for some of the discrepancies found in the literature. Studies in children uniformly recommend saliva for therapeutic monitoring of phenytoin, carbamazepine and phenobarbital. Saliva sampling for therapeutic monitoring of ethosuximide, primidone and digoxin in infants and children, and of theophylline and caffeine in the neonate is promising, but little pediatric experience is available as yet. The value of saliva in therapeutic monitoring of theophylline in children is still controversial. Little of highly polar compounds such as aminoglycosides, and of polar highly protein bound drugs such as valproic acid is present in saliva. More data are still needed on the excretion of drugs in saliva in infants and in acutely ill children, and few data exist in the premature and full-term neonate.