Single-cell fate mapping reveals widespread clonal ignorance of low-affinity T cells exposed to systemic infection

T cell ignorance is a specific form of immunological tolerance. It describes the maintenance of naivety in antigen-specific T cells in vivo despite the presence of their target antigen. It is thought to mainly play a role during the steady state, when self-antigens are presented in absence of costimulatory signals and at low density or to T cells of low affinity. In how far antigen-specific T cells can also remain clonally ignorant to foreign antigens, presented in the inflammatory context of systemic infection, remains unclear. Using single-cell in vivo fate mapping and high throughput flow cytometric enrichment, we find that high-affinity antigen-specific CD8⁺ T cells are efficiently recruited upon systemic infection. In contrast, most low-affinity antigen-specific T cells ignore the priming antigen and persist in the naïve state while remaining fully responsive to subsequent immunization with a high-affinity ligand. These data establish the widespread clonal ignorance of low-affinity T cells as a major factor shaping the composition of antigen-specific CD8⁺ T cell responses to systemic infection.     

Urinary excretion of adenosine deaminase binding protein in neonates treated with tobramycin

The potential tubulotoxicity of tobramycin and cefotaxim were assessed in neonates by measuring the urinary level of adenosine deaminase binding protein (ABP) and urinary ₁-microglobulin and ₂-microglobulin. In a prospective study, 33 neonates who received tobramycin and cefotaxim for suspected neonatal sepsis were compared with 48 untreated newborns during the first 10 days of life. The urinary concentrations of ABP and its excretion rates, corrected for body weight and body surface area, were significantly increased from the 1st day of treatment. Urinary ₁-microglobulin and ₂-microglobulin were not elevated under tobramycin and cefotaxim during the first 2 days of treatment. We conclude that ABP may be a sensitive marker for the detection of proximal renal tubular injury during tobramycin and cefotaxim treatments of neonates. The increase in urinary ABP which occurs before an elevation of urinary ₁-microglobulin and ₂-microglobulin may reflect earlier structural than functional alterations. However, since none of the treated infants had signs of electrolyte disorders or glomerular dysfunction, the clinical relevance of ABP measurement should be reevaluated.     

A noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders

Noradrenergic and/or serotonergic deficits, as well as other abnormalities, may contribute to predisposition to some epilepsies and depressions. Evidence for this hypothesis stems from several sources. Epidemiological investigations are intriguing but incomplete. Pharmacological studies show that noradrenergic and/or serotonergic transmission are both anticonvulsant and antidepressant. Therapeutically pertinent investigations show that antidepressant drugs have anticonvulsant properties, whereas antiepileptic drugs are effective in the management of affective disorders. Additional investigations demonstrate that seizures, whether spontaneously occurring or therapeutically induced, protect against depression. Through studies of innate pathophysiology, noradrenergic and serotonergic deficits have been identified in individuals with depression and in animal models of epilepsy, as well as in some humans with epilepsy. Vagal nerve stimulation, a treatment already known to be effective in the epilepsies, is presently under investigation for effectiveness in affective disorder. New evidence suggests that vagal nerve stimulation exerts at least some of its therapeutic effects through its capacity to increase noradrenergic and serotonergic transmission. Finally, emerging evidence supports the concept that some genetic mammalian models of the human epilepsies exhibit analogous manifestations of depression.     

Effects of Extracorporeal Shock Wave Lithotripsy on Plasma Concentrations of Endothelin and Renin in Humans

Purpose

There is ongoing controversy regarding blood pressure changes after extracorporeal shock wave lithotripsy (ESWL*). Experimental data suggest a role for renin but only few data are relevant to humans. It has been shown that renin secretion is stimulated by endothelin, a recently discovered peptide with strong vasoconstrictive properties and stimulating effects on renin secretion. Endothelin is relevant in the development of hypertension and acute renal failure.*Dornier Medical Systems, Inc., Marietta, Georgia.

Materials and Methods

In a prospective study of 48 normotensive patients undergoing ESWL for renal stones the influence of high energy shock waves on plasma endothelin and active renin was analyzed. These substances are secreted by renal cells in response to hemodynamic alterations, and inflammatory and traumatic processes. Peripheral blood samples were analyzed for active renin and endothelin before, and immediately, 1, 3 and 5 days after ESWL. Blood pressure was measured before, and 1, 3 and 5 days after ESWL.

Results

Only a slight and transient increase was noted in active renin, which was in the same range as that found after mental stress. Endothelin and blood pressure were not significantly influenced by ESWL. There was no correlation between endothelin and active renin. Thus, the increase in active renin was not mediated by endothelin.

Conclusions

The transient increase in active renin cannot be attributed to the development of hypertension. The lack of influence of ESWL on endothelin indicates that ESWL, at least in the routine clinical setting, does not cause severe renal trauma.     

Dopamine,dopexamine and dobutamine in liver transplant recipients: a comparison of their effects on hemodynamics,oxygen transport and hepatic venous oxygen saturation

The purpose of this study was to determine the effects of vasoactive treatment with dopamine (DO), dopexamine (DX), and dobutamine (DOB) on hemodynamics, oxygen transport and hepatic venous oxygen saturation (SvhO₂) after orthotopic liver transplantation (OLT). A pulmonary artery catheter was inserted into the right hepatic vein of 17 OLT patients. Timed infusion of DO, DX, and DOB was performed at the following rates: DO at 4 and 8 g/kg per minute, and DOB at 5 and 10 g/kg per minute. Hemodynamics, oxygen transport variables, and SvhO₂ were assessed. Each catecholamine induced a significant increase in cardiac index, oxygen delivery, and SvhO₂. Mean arterial pressure was increased during DO and DOB, but significantly reduced during DX. Each inotrope increased oxygen delivery in parallel with SvhO₂, suggesting a corresponding increase in hepatic oxygen supply. Therefore, it appears that each vasoactive drug may be utilized in OLT patients to provide oxgen delivery without impairment of splanchnic oxygenation.     

Stimulus-evoked release of tritiated monoamines from rat periaqueductal gray slices in vitro and its receptor-mediated modulation

Summary The periaqueductal gray is a brain region of considerable interest. It is innervated by monoamine-containing neurons as well as by a variety of peptidergic fiber systems, and it participates in the regulation of various functions. Virtually nothing is known about monoamine release in the periaqueductal gray and its receptor-mediated modulation. We therefore studied the release of radioactivity from periaqueductal gray slices preloaded with tritriated monoamines, using an in vitro superfusion method.The release of radioactivity from superfused periaqueductal gray slices after preloading of the tissue with [³H]noradrenaline increased upon electrical stimulation in a frequency-dependent manner. The stimulus-evoked release of radioactivity was Ca²⁺-dependent. Clonidine reduced and yohimbine enhanced the release. The inhibition curve for the effect of clonidine was shifted to the right in the presence of 10^–6 M yohimbine. While phenylephrine, isoprenaline, SK&F 38393, quinpirole, carbachol, [Arg⁸]vasopressin, -MSH and ACTH-(1-24), at a concentration of 10^–6 M, did not influence the electrically evoked release of radioactivity, [Leu⁵]enkephalin reduced it. The selective -opioid receptor agonists [d-Ala²,NMePhe⁴,Gly-ol⁵]enkephalin and [d-Arg²,Lys⁴]-dermorphin-(1–4)-amide reduced the release of radioactivity, whereas the selective opioid receptor agonist [d-Pen²,d-Pen⁵]enkephalin and the selective K opioid receptor agonist U-69593 had no effect. In the presence of naloxone, which by itself had no effect on the release of radioactivity, the effect of [d-Arg²,Lys⁴]dermorphin-(1–4)-amide was abolished. These results show that the release of noradrenaline from periaqueductal gray slices is via a Ca²⁺-dependent. exocytotic process, and that it is modulated through ₂-adrenoceptors as well as via -opioid receptors. Though the overflow of radioactivity from slices preloaded with [3H]dopamine in the presence of desipramine was measurable, there are reasons to assume that we are dealing here with the release of tritiated catecholamines from a population of nerve endings consisting of noradrenergic and dopaminergic terminals.The release of radioactivity from periaqueductal gray slices preloaded with [³H]5-hydroxytryptamine upon elevation of the K⁺ concentration in the superfusion medium was much more pronounced than that induced by electrical stimulation. The K⁺-evoked release of radioactivity was almost completely abolished in the absence of Cat²⁺; showing that the release is via a Ca²⁺-dependent process. 5-Hydrotryptamine reduced the K⁺-evoked release of radioactivity in a concentration-dependent manner.Some of these data were presented at the XIth International Congress of Pharmacology, 1–6 July 1990, Amsterdam, The Netherlands (Eur J Pharmacol 183:408) Send offprint requests to D. H. G. Versteeg at the above address     

The Effect of Parenterally Administered Cyclodextrins on Cholesterol Levels in the Rat

The inclusion complex formation of intravenously administered hydroxypropyl--cyclodextrin and -cyclodextrin with endogenous lipids was studied. We tested the hypothesis that complex formation of endogenous cholesterol with cyclodextrins in the bloodstream leads to extraction of cholesterol from the large lipoprotein particles. The relatively small cholesterol–cyclodextrin complexes then leave the bloodstream via capillary pores, and dissociation of the complex in the extravascular compartment finally causes redistribution of cholesterol from blood to tissue. This hypothesis is supported by the following experimental findings. Intravenous administration of cyclodextrins led to a transient decrease in plasma cholesterol levels in a dose-dependent manner, and in vitro cholesterol-cyclodextrin complexes passed dialysis membranes with a molecular weight cutoff of 6000–8000. Further, cyclodextrins increased protein binding of the steroidal drug spironolactone, probably through removal of cholesterol from plasma protein binding sites. Finally, extravascular redistribution was directly demonstrated in histological studies of the kidneys. Glomerular filtration of the cholesterol–cyclodextrin complex is followed by dissociation of the complex in the ultrafiltrate, resulting in cholesterol accumulation in the proximal tubule cells. The cholesterol--cyclodextrin complex has a limited aqueous solubility. Crystallization of this complex in renal tissue might explain the nephrotoxicity of parenterally administered -cyclodextrin. The absence of such crystallization might explain the lower nephrotoxicity of hydroxypropyl--cyclodextrin after intravenous administration.     

Familiale Beziehungsmuster und Patientenkarriere männlicher schizophrener Kranker

Zusammenfassung Mit Hilfe eines Persönlichkeitsfragebogens (Gießen-Test), der von beiden Eltern und dem schizophrenen Kranken bei dessen Entlassung aus der ersten stationären psychiatrischen Behandlung ausgefüllt worden war, wurde die Personenwahrnehmung und damit mittelbar die Beziehung in der Familie untersucht. Über alle drei Selbstbilder und sechs Fremdbilder von insgesamt 28 Familien mit einem schizophrenen Sohn sowie von 29 als Vergleichsgruppe dienenden Familien mit einem chirurgisch kranken Sohn wurde eine Clusteranalyse berechnet, die die Abgrenzung von fünf Clustern erlaubte, von denen zwei vor allem durch Familien mit Schizophrenen und zwei vor allem durch solche mit organisch kranken Söhnen gebildet wurden; ein Cluster war unspezifisch. Ein 2-Jahres-follow-up ergab, daß 13 schizophrene Kranke erneut die Klinik aufsuchen mußten. Es fand sich keine statistisch bedeutsame Beziehung zwischen den untersuchten psychiatrischen und soziodemographischen Parametern und dem Rehospitalisierungsrisiko. Als besonders gefährdet erwiesen sich jedoch Familien, in denen sich nach den Ergebnissen der Clusteranalyse ein Konflikt zwischen Eltern und Sohn um die Definition als Kranker auf dem Hintergrund rigider Normvorstellungen abbildete. Die Übernahme der Krankenrolle durch den Patienten ging hingegen nur in der Hälfte der Fälle mit einer Rehospitalisierung einher, führte also nicht zwangsläufig zur Ausgrenzung aus dem Familienverband. Söhne aus Familien, die als besonders gesund imponierten, aber auch Söhne aus Familien mit dominanten Müttern wurden im Untersuchungszeitraum nicht erneut in die Klinik aufgenommen.

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Summary Patterns of personal relationships within the families of male schizophrenic patients, and their relationship to clinical course and outcome, were examined by means of a personality questionnaire (Gießen-Test), completed by both parents and by the schizophrenic patient himself at the time of discharge from his first psychiatric in-patient treatment. The test yields scores related to the self-perceptions of the individual and to his perceptions of the other nuclearfamily members. A cluster analysis was performed on all three self-perception scores and six scores of the perceptions the three family members had of each other, for a total of 28 families each with a schizophrenic son and for a control group of 29 families each with a surgically-ill son. This analysis allowed five clusters to be distinguished, two of which consisted predominantly of families with schizophrenic sons and two predominantly of families with surgically-ill sons. The remaining cluster comprised a mixed group. A two-year follow-up showed that 13 schizophrenic patients had been readmitted to hospital. There was no statistically significant relationship between the psychiatric and sociodemographic parameters examined and the re-hospitalization rate. Readmissions were, however, more frequent from families in which the research findings had indicated conflicting mutual perceptions of parents and sons, against a background of rigid notions of normality. Acceptance by the patient of the notion of being ill was associated with re-hospitalization in only about half of the cases, so that it had not necessarily led to rejection by the family unit. No patients were readmitted during the follow-up period from families which had represented themselves as particularly healthy, or from families with dominant mothers.

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Teil des von der Deutschen Forschungsgemeinschaft unterstützten Projektes Interaktion in Familien mit Schizophrenen     

Eight month follow-up of delinquent adolescents: predictors of short-term outcome

Clinicians working with young delinquents are concerned with finding methods to predict recidivism in these subjects. It has not been investigated yet to what extent psychiatric assessment can be of any help in this field. In this study, we investigated whether psychiatric assessment can help to predict recidivism in already delinquent adolescents. By means of semi-structured psychiatric assessment (Child Assessment Schedule), developmental interview of the parents and self-report instruments, we assessed the psychiatric status of 72 delinquent adolescents, adjudicated before the Juvenile Court of Antwerp (Belgium). A follow-up of criminal status after eight months was conducted. Self-report questionnaires by the subjects did not differentiate recidivists from non-recidivists, while parent questionnaires did. Through a semi-structured interview, we found that a diagnosis of conduct disorder significantly predicts recidivism, while subjects with ADHD and substance abuse show a tendency towards more recidivism. We were unable, however, due to the small number of subjects showing a psychiatric disorder (e. g. ADHA and PTSD) unrelated to conduct disorder, to assess the relative contribution of these disorders to the recidivism rate. This study found that psychiatric assessment of delinquent adolescents could be of help in predicting recidivism. The necessity of gathering information from parents and teachers is demonstrated. Future research should include a more extensive group of a delinquent adolescent and should focus on the effect of therapeutic interventions. Received: 29 June 1999 / Accepted: 1 February 2000     

A simple theoretical verification of monitor unit calculation for intensity modulated beams using dynamic mini-multileaf collimation.

A spreadsheet based program is presented to perform an independent Monitor Unit (MU) calculation verification for the Quality Assurance (QA) of Intensity Modulated Radiation Therapy (IMRT) using Dynamic MultiLeaf Collimation (DMLC). The computed dose value is compared to the planned dose by calculating the percent dose difference per Intensity Modulated Beam (IMB) and absolute dose difference per IMB. The proposed acceptability levels are +/-5.0% or +/-2.0 cGy for the percent dose difference per IMB and the absolute dose difference per IMB, respectively. For percent dose difference per treatment, an acceptability level of +/-2.0% is proposed. The presented program is considered adequate for checking the treatment plans calculated for IMRT treatments using DMLC as a part of the QA procedure.