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Zusammenfassung: Hintergrund: Wir untersuchten die prophylaktische präoperative Implantation einer intraaortalen Ballonpumpe (IABP) in herzchirurgischen Hochrisikopatienten mit einer additiven EuroSCORE-Summe ≥8. Material und Methoden: Randomisierte Studie mit 104 Patienten, denen prophylaktisch keine IABP (Gruppe A, n=52) oder eine IABP (Gruppe B, n=52) implantiert wurde. Primärer Endpunkt war die 30-Tagessterblichkeit. Ergebnisse: Das mediane Alter der Patienten betrug 74 Jahre und 43% der Patienten waren Frauen. Die 30-Tagessterblichkeit unterschied sich nicht (Gruppe A 17,3% versus Gruppe B 13,4%, p=0,78). Die mediane Klinikaufenthaltsdauer betrug in beiden Gruppen 14 Tage. In Gruppe A benötigten 13 Patienten (21%) intra- und postoperativ eine IABP-Unterstützung. Mediane Beatmungszeit (14 h versus 13 h), medianer Katecholaminbedarf, Häufigkeit eines akuten dialysepflichtigen Nierenversagens (28 versus 18%), kardiale Indizes und Häufigkeit eines „Low-cardiac-output“-Syndroms (26 versus 25%) waren zwischen den Gruppen nicht signifikant verschieden. Schlussfolgerung: Die präoperative prophylaktische IABP-Implantation in EuroSCORE-stratifizierten Patienten ist nicht mit einer reduzierten 30-Tagessterblichkeit assoziiert.

Zusammenfassung: Hintergrund: Zunehmend werden ltere Patienten herzchirurgisch versorgt. Postoperativ fhren Rhythmusstrungen, Myokardinfarkte aber auch atypische Symptomatiken zu erneuten rztlichen Konsultationen und stationren Einweisungen. Telemedizinisches Monitoring kann eine Methode zur genauen und schnellen Analyse der Beschwerden darstellen und diese zeitnah sowie entsprechend des Therapiebedarfs charakterisieren helfen. Wir untersuchten, ob telemedizinisches EKG-Monitoring fr den gealterten herzchirurgischen Patienten ein praktikables Verfahren und darber hinaus im Rahmen der postklinischen Betreuung eine verlssliches Verfahren zur Kosten- und Risikoreduzierung darstellen kann.Methode & Ergebnisse: Zweihundertacht Patienten (46 Frauen, 162 Mnner) wurde nach herzchirurgischen Eingriffen ein portables 12-Kanal-EKG ausgehndigt. Die Gerte wurden durch einen Arzt whrend einer ausfhrlichen Einweisung des Patienten angepasst. ber einen Zeitraum von drei Monaten ab Entlassung wurden alle eingehenden Anrufe und Elektrokardiogramme im Monitorzentrum aufgenommen und analysiert. Insgesamt wurden von 165 Teilnehmern (80% Nutzungsgrad) 1387 Anrufe mit EKG-bermittlung (8,4 Anrufe pro Patient) registriert, davon 235 (17%) mit Beschwerdesymptomatik, von denen 51% in der Zeit von 18 bis 8 Uhr gefhrt wurden. Insgesamt 14 (6%) dieser Anrufe mit Beschwerdesymptomatik fhrten zu einer sofortigen Klinikeinweisung (n=5) bzw. zu einem rztlichen Konsil am Folgetag (n=9), bei 221 Anrufen (94%) hingegen mit subjektiven Beschwerden konnten keine pathologischen EKG-Vernderungen nachgewiesen werden. Hier konnten die Patienten durch telefonische Beratung, Beruhigung, und Kontrolle im Verlauf ausreichend medizinisch betreut werden. Kriterien fr eine Klinikeinweisung waren Angina pectoris, uncharakteristischer Brustschmerz, kardiale Dekompensation (n=3) sowie Herzrhythmusstrungen (n=2). Der Kontakt zum telemedizinischen Zentrum erfolgte sehr zeitnah. Knapp 75% aller Anrufe wurden innerhalb der ersten Stunde nach Beginn der Beschwerden gefhrt.Schlussfolgerung: Auch ltere herzchirurgische Patienten sind nach technischer Einweisung reproduzierbar in der Lage telemedizinische Diagnostik selbstndig durchzufhren. Bei insgesamt niedriger Inzidenz subjektiver Beschwerden ist telemedizinisch eine sofortige und effektive Diagnostik der Beschwerdesymptomatik und damit Objektivierung der Befunde mglich. Durch die zeitnahe Diagnostik erhhte sich die subjektive und objektive poststationre Sicherheit des Patienten und kann Folgeschden durch Zeitverzug verhindern helfen. Die Reduktion von Arztbesuchen und Klinikaufenthalten zur gezielten Therapie bereits objektivierter pathologischer Befunde kann zur Kostenreduktion im Gesundheitswesen beitragen. Die Reduktion nicht notwendiger Arzt- und Krankenhausbesuche kann weiterhin zur Optimierung des Zeitmanagements in den behandelnden Einrichtungen beitragen.

Sternumwundinfektionen (SWI) nach herzchirurgischen Eingriffen sind selten, stellen aber auf Grund hoher Morbidität und Mortalität eine schwere Komplikation dar. Das Ziel der Studie war die multivariate Evaluierung von Risikofaktoren, um somit geeignete Präventionsmaßnahmen zu etablieren. 6 895 Patienten, die sich in der Zeit von 1988–1999 einer kardiochirurgischen Operation unter extrakorporaler Zirkulation (ECC) unterzogen haben, wurden hinsichtlich der Entwicklung einer SWI untersucht. Den Patienten mit SWI (Untersuchungsgruppe, n = 112) wurde zur Auswertung von Risikofaktoren eine repräsentative Kontrollgruppe (n = 241) gegenüber gestellt. Der Vergleich von potenziellen Risikofaktoren zwischen diesen Gruppen erfolgte uni- und multivariat (logistisches Regressionsmodell). Die Inzidenz von SWI betrug 1,6%. In der Untersuchungsgruppe sind 26 Patienten (23,2%) verstorben. Diese Mortalitätsrate lag signifikant (p < 0,001) über der der Kontrollgruppe (6,7%). Als unabhängige Risikofaktoren konnten multivariat das Low-Cardiac-Output-Syndrom [odds ratio 13,0; 95% Konfidenzintervall, (1,84, 92,6)], die Adipositas [8,9; (4,0, 19,8)], das Rauchen [5,0; (1,84, 92,6)], das Alter [0,96; (0,93, 0,99)], die respiratorische Insuffizienz [5,0; (1,47, 17,3)] und die Art des Sternumverschlusses [0,22; (0,10, 0,52)] evaluiert werden. Die evaluierten Risikofaktoren beweisen, dass Sternuminstabilitäten (ineffektiver Sternumverschluss), mechanische Belastungen der Sternotomie (Adipositas) und systemische Faktoren wie die verminderte Gewebeperfusion (LCOS) SWI fördern. Gezielte Maßnahmen zur Bekämpfung dieser Risikofaktoren sind indiziert. Although sternal wound infection (SWI) after cardiac surgery is infrequent, its consequences are serious. The aim of this study was multivariate risk factor analysis for more effective preventive measures. Retrospective analysis of 6 895 patients who underwent cardiac surgery from 1988 to 1999 was performed. The patients were divided into the SWI group (n = 112) and a representative non-infection comparison group (n = 241). Preoperative, operative, and postoperative variables were compared between the two groups using univariate and multivariate logistic regression analysis. The incidence of SWI was 1.6%. Twenty-six (23.6%) of the 112 patients of the SWI group died. The mortality rate in the control group was significantly lower (6.7%) than in the SWI group. The main independent predictors for SWI after multivariate analysis were postoperative Low-Cardiac-Output Syndrome (LCOS) [odds ratio 13.0; 95% confidence interval (1.84, 92.6)], obesity [8.9; (4.0, 19.8)], smoking [5.0; (1.84, 92.6)], age [0.96; (0.93, 0.99)], respiratory insufficiency [5.0; (1.47, 17.3) and sternal wound closure [0.22; (0.10, 0.52)]. The evaluated risk factors suggesting that sternal instability (ineffective sternal closure), mechanical strain (obesity) on the sternotomy and poor systemic perfusion (LCOS) may precede infection. Targeted preventive procedures for these risk factors could be justified.

Some physico-chemical properties of NiO–ThO2mixed oxides of various compositions have been investigated. The presence of strongly bound constitutional water in the hydrogel of reactive forms of thorium dioxide, determined by their origin (thermal decomposition of mixed hydroxides) caused the different reduction behaviour as compared with other mixed oxide systems containing the only, thermodynamically less stabile reducible component. The significant effects of the thermal treatment in oxygen atmosphere, pre-irradiation by the gamma rays or accelerated electrons under various conditions (in air or in water suspension) as well as of surface chemical activation with a platinum complex on the reactivity of mixed oxides or reoxidized samples during their hydrogen reduction have been also proved.

Zusammenfassung: Die steigende Lebenserwartung der Bevölkerung führt dazu, dass sich zunehmend Patienten im fortgeschrittenen Lebensalter einer Herzoperation unterziehen. Es stellt sich nun die Frage, inwieweit fortgeschrittenes Alter und Multimorbidität das Früh- und Langzeitergebnis nach Herzoperationen beeinflussen. Die vorliegende Studie ist eine retrospektive Untersuchung. Sie erfasst zwei Kollektive (je 96 Patienten). Gruppe I sind Patienten mit 75 Jahren und älter. Gruppe II sind Patienten im Alter von höchstens 65 Jahren. Um die Aussagefähigkeit zu verbessern, wurde das Vergleichskollektiv so ausgewählt, dass es mit Gruppe I bzgl. der Geschlechtsverteilung und Therapieart identisch ist. Der mittlere Beobachtunszeitraum betrug zwischen 12 und 71 Monaten. Die perioperative Mortalität der älteren Patienten betrug 2,1% (n=2) und die der jüngeren 0% (n=0). Innerhalb des fünfjährigen Beobachtungszeitraumes sind 13,54% (n=13) der über 75-jährigen und 6,25% (n=6) des Vergleichskollektives verstorben. Eine kardiale Todesursache wiesen 53,85% (n=7) der älteren und 66,66% (n=4) der jüngeren auf. Postoperative Komplikationen, wie Herzrhythmusstörungen, neurologisches Defizit, Nachblutung und Infarkt, traten bei den älteren Patienten mit einer Häufigkeit von 17,71% und bei den Jüngeren mit 14,58% auf. Praeoperativ befanden sich 81% der älteren und 63% der jüngeren Patienten im NYHA-Stadium III und IV. Postoperativ waren es in beiden Kollektiven jeweils nur noch 20%. Die Befragung unserer Patienten ergab, dass sich die Selbständigkeit und Mobilität durch die Operation entschieden gebessert hatte, lediglich 6,02% (n=5) der älteren und 4,44% (n=4) der jüngeren Patienten konnten sich aufgrund der Herzerkrankung nicht mehr selbständig versorgen. Insgesamt gesehen beurteilten die älteren Patienten ihr Allgemeinbefinden subjektiv besser als die jüngeren. 92% der älteren und 84% der jüngeren Patienten waren der Meinung, dass ihnen die Herzoperation eine wesentliche Besserung gebracht hat. Die Patienten im Alter von 75 Jahren und älter sprachen sich einstimmig für die Operation aus, bei den Jüngeren würden sich nur 96,66% erneut für die Operation entscheiden. Ziel der operativen Therapie der koronaren Herzerkrankung ist die Reduktion der Beschwerdesymptomatik, die Verbesserung der Lebensqualität und die Erhaltung der Selbständigkeit. Anhand unserer Ergebnisse ist ersichtlich, dass uns dies vorallem auch bei den älteren Patienten gelungen ist. Trotz eines erhöhten prae- und perioperativ Risikoprofils und eines vermehrten pflegerischen Aufwandes bei älteren Patienten werden gute Ergebnisse erreicht.

Abstract.: The employment of the heart-lung machine to assisting the circulatory system for the resection of extracardial tumors is increasing because of their location, growth and infiltration. We report on three patients in whom the resection of the tumor was only possible with extracorporeal circulation (ECC). In the first patient sarcoma of the pulmonary artery and valve was resected under ECC. Artery and valve were replaced with a cryopreserved valved bifurcation homograft. In the other patients ECC was used on the basis of tumorinfiltration of the inferior vena cava and tumor embolus of the pulmonary artery in a case of primary renal cell carcinoma, and tumor infiltration of the superior vena cava and right atrium in a case of follicular thyroid carcinoma. All patients had a good postoperative course and excellent long term survival.

In human right atrium, endothelin A (ETA) receptors couple to both inositol phosphate formation and inhibition of adenylylcyclase, whereas in human left ventricle, ETAreceptors couple only to inositol phosphate formation. To find out whether this might be of functional relevance, we studied, in right atria obtained from 32 patients undergoing coronary bypass grafting without apparent heart failure, and in right atria and left ventricles from eight patients with end-stage heart failure (NYHA IV) undergoing heart transplantation, the effects of endothelin-1 (ET-1) on basal force of contraction or on force of contraction increased by 1 μMforskolin. ET-1 (0.1 μM) exerted a positive inotropic effect in atrial and ventricular tissue; this could be antagonized by the ETA-receptor antagonist BQ 123, but not by the ETB-receptor antagonist BQ 788. In atrial, but not in ventricular tissue, this positive inotropic effect was preceded by a transient negative inotropic effect. This negative inotropic effect was inhibited by BQ 123, but not by BQ 788. It was significantly prolonged in forskolin-prestimulated atria, and was significantly larger in atria from failing hearts. We conclude that, because ET-1 inhibits adenylylcyclase and causes negative inotropic effects in atria but not in ventricles, adenylylcyclase inhibition might be responsible for the transient negative inotropic effect of ET-1.

We investigated the expression of adherence molecules lymphocyte function-associated antigens-1 alpha and -beta (LFA-1 alpha, -beta) and p150, 95 in 103 well-characterized non-Hodgkin's lymphomas (NHLs) and lymphoid leukemias (LLs). We found that NHLs and LLs differentially express LFA-1 molecules according to their lineage derivation, degree of clinical aggressiveness, and anatomic site of involvement. Specifically, (a) T-cell neoplasms nearly always express these molecules; (b) diffuse aggressive B-cell NHLs and mature LLs often lack LFA-1 alpha molecules; and (c) B-cell chronic lymphocytic leukemia (CLL) is often LFA-1 alpha-negative while B-cell small lymphocytic lymphomas (SLLs) are nearly always LFA-1 alpha-positive. Furthermore, the low expression of LFA-1 alpha in CLL is related to the low degree of homotypic lymphocyte adhesion after tumor promoter antigen stimulation that does not modulate the expression of LFA-1 alpha in vitro. The differential expression of LFA-1 by B-cell CLL and SLL and their degree of homotypic lymphocyte adhesion may account for the distinct anatomic compartmentalization and characteristic clinical behavior of these two morphologically and immunologically similar lymphoid malignancies.

We compared the effect of adenosine and adenosine analogues on the phytohemagglutinin-induced proliferative response of blood lymphocytes from normal subjects and patients with chronic lymphocytic leukemia. As measured by the inhibition of thymidine or leucine incorporation, adenosine was more toxic to chronic lymphocytic leukemia (CLL) than to normal lymphocytes. This difference was not affected by the removal of adherent cells. The patients' B lymphocytes were more susceptible to adenosine toxicity than normal B lymphocytes. Similar responses were noted in T lymphocytes from both sources. Differential susceptibility was also observed with deoxyadenosine and adenosine analogues, including 5'deoxyadenosine. Uridine rescue from adenosine toxicity was observed for normal and CLL lymphocytes. In the presence of uridine, there was no difference in the residual inhibition of CLL as compared to normal lymphocytes. Intact CLL lymphocytes metabolized 14C-adenosine at a much lower rate than normal lymphocytes. While it appears that the greater toxicity of adenosine to CLL lymphocytes reflects the impaired catabolism of this nucleoside by these cells, evidence is presented that this is not the only mechanism underlying the differential susceptibility. These results may serve as the basis for further pharmacologic investigations of adenosine and adenosine deaminase inhibitors in chronic lymphocytic leukemia.

The electrophoretic mobility distributions of hairy cells, normal monocytes. CLL, and normal lymphocytes isolated from blood were determined by electrophoretic light scattering. Values obtained for hairy cells, 1.52 X 10(-4) cm2/V . sec, were indistinguishable from that of normal monocytes. The mobility of CLL lymphocytes was similar to that of normal B cells. After exposure to neuraminidase, hairy cells revealed a homogeneous distribution with a reduced mobility of 0.55 X 10(-4) cm2/V . sec, while normal monocytes showed a heterogeneous distribution of electrophoretic mobilities suggestive of subpopulations. The electrokinetic behavior of hairy cells thus differs from that or normal and CLL lymphocytes before, and from that of monocytes after, treatment with neuraminidase. The hairy cell therefore possesses a distinct pattern of surface charge properties that clearly distinguish it from the circulating B cells, T cells, or monocytes.

In a comparative study, we investigated whether or not removed and non-beating hearts could be preserved in vitro by continuous perfusion with oxygen-carrying solutions (blood, perfluoro-carbon emulsion) and simultaneous substitution with specific substrates. We used 18 mongrel dogs subdivided into 2 groups (1st group: perfluorocarbon emulsion; 2nd group: blood); the perfusion time was 9 h. In addition to parameters to control the medium of the perfusion solution, we measured parameters that would allow us to assess the success of the extended perfusion. These parameters were high-energy phosphates and, in particular, electron optical analysis. At the end of the perfusion period, electron optical analysis revealed a mild and reversible ischemic reaction by the myocardial cells in both groups. However, statistical analysis showed (1) a significant increase in the ischemic reaction for both groups over the perfusion period (P=0.02), and (2) a significant, even more pronounced ischemic reaction in the subendocardial myocardium (P=0.025). It should be noted that distinctly interstitial edema developed during the perfusion period and that this would appear to be a fairly critical problem with extended continuous isolated heart perfusion.

Chemosensitivity of B lymphocytes, obtained from 65 patients with B- cell chronic lymphocytic leukemia (B-CLL), Rai stages 0 through IV, was determined using the MTT assay. The results were expressed by the drug concentration required for 50% inhibition of cell viability (IC50). The cytotoxicity of chlorambucil (CLB) was compared with that of fludarabine and the DNA topoisomerase I inhibitors, camptothecin, 9- aminocamptothecin, 10,11-methylenedioxy-20(S)-camptothecin (10,11-MDC) and 9-amino-10,11-methylenedioxy-20(S)-campthothecin (9-A-10,11-MDC), and topotecan. Considerable heterogeneity in sensitivity to CLB was observed, with a median IC50 of 40.5 mumol/L in untreated patients. B- CLL cells from patients treated with CLB had a significantly higher median IC50 of 86.0 mumol/L (P < .01). Untreated as well as CLB-treated patients were divided into two subsets. For the purpose of this study, B-CLL lymphocytes with an IC50 CLB of less than 61.0 mumol/L were designated as “sensitive” and those with an IC50 CLB of > or = 61.0 mumol/L were designated as “0resistant.” After baseline assays, 15 untreated patients received CLB; after treatment, the IC50 increased in B-CLL lymphocytes from 13 of 15 patients. The response to CLB treatment, determined by its effect on the absolute lymphocyte count and by the Eastern Cooperative Oncology Group clinical criteria, was significantly better in patients whose lymphocytes had an IC50 CLB of less than 61.0 mumol/L before therapy (P < .01). B-CLL lymphocytes also had a variable degree of sensitivity in vitro to each of the other drugs. There was significant cross-resistance between CLB and fludarabine (P < 0.01). Whereas only 29% of CLB-resistant B-lymphocyte specimens obtained from individual patients were sensitive to fludarabine in vitro, 52% and 67% of CLB-resistant lymphocyte samples were sensitive to 10,11-MDC and 9-A-10,11-MDC, respectively. We have previously reported that p53 gene mutations were associated with aggressive B-CLL and a poor prognosis. B lymphocytes from seven patients with these mutations were resistant to CLB, and five of six were resistant to fludarabine. Lymphocytes from four of seven were resistant to 10,11-MDC, and three of four were resistant to 9-A-10,11- MDC. This study implies that the MTT assay may be useful in identifying subsets of CLL patients resistant to conventional chemotherapy. However, definitive conclusions can not be drawn in view of the small number of patients studied prospectively. In addition, these results suggest the potential of camptothecin-based therapy for patients unresponsive to standard treatment.

We studied 53 patients with B-cell chronic lymphocytic leukemia (B-CLL) and found mutations of the p53 gene in 15%. Patients with p53 gene mutations were found to have an aggressive form of B-CLL disease characterized by advanced Rai stage, rapid lymphocyte doubling time (LDT), and resistance to chemotherapy. While 27 of 29 treated patients (93%) without p53 mutations achieved a partial remission, only one of seven treated patients (14%) with p53 mutations achieved a partial remission (P = .00009). Adjusting for prognostic factors (age, sex, race, and Rai stage), patients with p53 gene mutations had a 13-fold greater risk of death than patients without p53 mutations (P = .013). In addition to examining the clinical relevance of p53 gene mutations in B-CLL, we investigated the possible role of p53 gene regulation in the expression of the multidrug resistance genes MDR1 and MDR3. We quantitated MDR1 and MDR3 mRNA expression by reverse transcription- polymerase chain reaction (RT-PCR). Expression of both the MDR1 and MDR3 genes was independent of p53 gene mutation or prior drug treatment, and did not predict for clinical response. Our findings indicate that p53 gene mutations in B-CLL are associated with a poor clinical outcome and may be a prognostic indicator for drug resistance.

Human lymphocyte extracts analyzed by high-performance liquid chromatography reveal a major UV-absorbing peak that was shown to be ascorbic acid by spectral, chemical, and enzymatic criteria. Because this peak appeared very prominent in the elution profile of chronic lymphocytic leukemia (CLL) lymphocyte extracts, we measured the ascorbic acid content in lymphocytes from the blood of normal subjects and untreated patients with chronic lymphocytic leukemia. A significantly higher concentration of 111 +/- 15.3 nmol per 10(8) cells (mean +/- SEM) was found in CLL lymphocytes than in normal blood lymphocytes, which contained 42.2 +/- 3.3 nmol per 10(8) cells. Selective enrichment with B and T cells showed that this difference was limited to the chronic lymphocytic leukemia B cell, which had a 5- to 15-fold higher content of ascorbic acid than normal B cells had. In contrast, the ascorbic acid level was similar in normal and CLL T cells. The very high ascorbic acid content provides the chronic lymphocytic leukemia B cell with a reducing substance that could react with oxidants or free radicals.

Chronic lymphocytic leukemia (CLL) lymphocytes manifest anomalous motility and cap formation. Since these processes involve cytoskeletal proteins, vimentin from intermediate filaments of normal and CLL lymphocytes was investigated using hetero- and monoclonal antisera. The antisera reacted predominantly with a 60-kD polypeptide, following sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of total lymphocyte proteins. When lymphocytes were stained by indirect immunofluorescence, normal lymphocytes demonstrated well defined cytoplasmic fibrils that capped spontaneously after contact with a glass surface and incubation at 37 degrees C. This capping was dependent on energy and intact microfilaments. Lymphocytes from patients with CLL showed several patterns. In one group, the initial staining was weak, and few capped cells were present after incubation. Lymphocytes from other patients had either normal or aberrantly organized fibrils in which capping was diminished. In another group, a fibrillar pattern with normal or increased capping was seen. In total, 47% +/- 5.1% (mean +/- SE) of normal lymphocytes capped after a 1-hr incubation at 37 degrees C (n = 12) compared to 21% +/- 5.1% for CLL lymphocytes (n = 20, p less than 0.002). Purified subpopulations of normal B and T cells did not differ from unfractionated normal lymphocyte populations. These results demonstrate an anomalous vimentin capping response in CLL lymphocytes. They also show that the arrangement of vimentin in these cells differs from that of normal lymphocytes.

Two patients with progressive hairy cell leukemia following splenectomy were treated with low-dose daily chlorambucil. Both had an objective hematologic response as determined by a return to normal hematocrit and platelet count. This was also reflected in the mononuclear cell fraction by the normalization of cholesterol content, cholesterol/phospholipid ratio, and the lymphocyte subpopulations. This article confirms previous reports on the efficacy of chlorambucil in this setting and describes some morphological, and biochemical concomitant events.

One hundred ninety-five patients were entered into a multi-institutional study of interferon alfa 2b from 1983-1986; follow-up was completed through June 1989. A complete remission was documented in 7 patients, a partial remission in 152 patients, a minor response in 10 patients, and no response in 26 patients. One-hundred fifty-nine of the 195 patients treated (81%) had a normalization of their peripheral blood counts by the criteria used. To date, 17 patients have died. Only 3 of the 159 patients (2%) with a PR or CR have expired. Three of 10 MR patients have expired and 11 of 26 NR patients have expired. Of the 11 who expired, 7 did so before receiving an adequate duration of treatment. Three of the NR patients died within 1 week of starting interferon from intracranial hemorrhages secondary to severe thrombocytopenia (present prior to initiation of interferon) and 4 NR patients died of infectious deaths within 2 months of initiating interferon therapy secondary to severe neutropenia (present prior to initiation of interferon). Of the 17 NR's who remained alive and on-study for at least 6 months, only 2 eventually died, both after failing subsequent pentostatin therapy. Systemic therapy with agents that induce a more rapid response such as pentostatin or 2-chlorodeoxy-adenosine, or the combination of interferon plus growth factor are indicated in these severely cytopenic patients.

Summary Using different perfusion regimes and orthograde implantation, some investigators have found sufficient heart function after extracorporeal perfusion of hearts for 24 and even 72h. However, we found no significant improvement of perfused hearts compared to cold stored hearts after a 9-h extracorporeal period. A possible explanation for this finding could be the excessive liberation of catecholamines during ischemia, as has been demonstrated in isolated perfused hearts. Therefore, the aim of this study was to investigate whether concentrations of noradrenaline and dihydroxyphenylglycol (DOPEG) — a noradrenaline metabolite — increased pathologically during continuous extracorporeal heart perfusion for 5 h in pigs, in comparison to hearts stored at 4°C. The venoarterial differences in noradrenaline and DOPEG were not significantly different in the two groups. Concentrations of lactate and pyruvate decreased substantially after 3-h hypothermic perfusion. The lactate/pyruvate ratio remained at a value of 25–35. Only after the end of the extracorporeal circulation did this ratio reach a value of 40–65. In our model, these findings demonstrate that the excessive liberation of catecholamines is not a reason for heart failure after cold storage or perfusion.

We compared the effect of adenosine and adenosine analogues on the phytohemagglutinin-induced proliferative response of blood lymphocytes from normal subjects and patients with chronic lymphocytic leukemia. As measured by the inhibition of thymidine or leucine incorporation, adenosine was more toxic to chronic lymphocytic leukemia (CLL) than to normal lymphocytes. This difference was not affected by the removal of adherent cells. The patients' B lymphocytes were more susceptible to adenosine toxicity than normal B lymphocytes. Similar responses were noted in T lymphocytes from both sources. Differential susceptibility was also observed with deoxyadenosine and adenosine analogues, including 5'deoxyadenosine. Uridine rescue from adenosine toxicity was observed for normal and CLL lymphocytes. In the presence of uridine, there was no difference in the residual inhibition of CLL as compared to normal lymphocytes. Intact CLL lymphocytes metabolized 14C-adenosine at a much lower rate than normal lymphocytes. While it appears that the greater toxicity of adenosine to CLL lymphocytes reflects the impaired catabolism of this nucleoside by these cells, evidence is presented that this is not the only mechanism underlying the differential susceptibility. These results may serve as the basis for further pharmacologic investigations of adenosine and adenosine deaminase inhibitors in chronic lymphocytic leukemia.

Activity of the ectoenzyme 5’-nucleotidase is markedly reduced or absent in the lymphocytes from most patients with chronic lymphocytic leukemia. Experiments were designed to determine whether the absence of activity stems from a lack of enzyme protein or is the result of a functionally abnormal molecule. An antibody to purified rat liver 5’-nucleotidase was raised in rabbits. The antiserum was strongly inhibitory to human lymphocyte 5’-nucleotidase activity. Absorption of the antiserum with 5’-nucleotidase positive lymphocytes removed the inhibitory activity, while absorption with 5’-nucleotidase negative lymphocytes had no effect. When cells which had been incubated with the rabbit anti-5’-nucleotidase serum were exposed to fluorescein-labeled goat anti-rabbit IgG, diffuse fluorescence was noted at the cell surface of lymphocyte populations shown to contain 5’-nucleotidase by chemical or histochemical assay. No fluorescence was observed under these conditions with 5’-nucleotidase negative chronic lymphocytic leukemia lymphocytes. The percent of positive cells in normal subjects or in 5’-nucleotidase positive chronic lymphocytic leukemia patients determined by immunofluorescence corresponded to the percentage positive cells by histochemical assay and was closely related to the specific activity of 5’-nucleotidase determined chemically (p< 0.001). These studies show that the distribution of enzyme protein corresponds to that of enzyme activity in 5’-nucleotidase positive cells. The results also indicate that the 5’-nucleotidase immunoreactive protein is not detectable in lymphocytes from most patients with chronic lymphocytic leukemia.

Actin, a major cytoskeletal protein, was quantitated in normal and chronic lymphocytic leukemia lymphocytes. The actin content of normal human blood lymphocytes was 2.2 +/- 0.4 mg/10(9) cells and represented 6.6% +/- 1.8% of the total cellular protein. A significant decrease (p less than 0.001) was noted in chronic lymphocytic leukemia lymphocytes that contained 1.4 +/- 0.3 mg actin/10(9) cells, constituting 4.3% +/- 1.1% of the total protein. Normal T and B cells did not differ in actin content. Reduced actin levels were found in the T as well as in the B lymphocytes of “B-cell” chronic lymphocytic leukemia. The possible importance of the decreased actin level in the anomalous capping response and motility of chronic lymphocytic leukemia lymphocytes is discussed.

Experiments were performed to characterize the protein kinase activity in blood lymphocytes from patients with chronic lymphocytic leukemia (CLL). Using histone as a substrate, the average specific activity was 397 pmole/min/mg protein. The Km for ATP was 8 muM and for histone 0.3 mg/ml. The addition of optimal concentrations of cyclic adenosine monophosphate (cAMP) (1 muM) or cyclic guanosine monophosphate (cGMP) (10muM) resulted in a 2.2-fold stimulation in activity but had no effect on the Km for ATP or histone. Most of the properties of the CCL protein kinase were similar to those of the normal lymphocyte enzyme. These include the pH response, substrate affinity, as well as rates of phosphorylation and dephosphorylation. The phosphorylation pattern of endogenous proteins was determined using intact lymphocytes incubated with 32P and cell-free homogenates with AT32P. These results indicate that: (1) the cyclicnucleotide-protein kinase interactions are unimpaired in CLL lymphocytes; and (2) a sharply defined cyclic nucleotide concentration response occurs for CLL (as well as normal) lymphocytes, which may explain the reports of variable inhibitory (and stimulatory) effects on mitogenesis by these agents.

Decay-accelerating factor (DAF) is a 70,000 Mr protein that has been isolated from the membrane of red cells. The function of DAF is to inhibit the assembly of amplifying enzymes of the complement cascade on the cell surface, thereby protecting them from damage by autologous complement. We raised monoclonal antibodies to DAF and used them to study its distribution in cells from the peripheral blood of normal individuals and of patients with paroxysmal nocturnal hemoglobinuria (PNH), a disease characterized by the unusual susceptibility of red cells to the hemolytic activity of complement. The results of immunoradiometric assays and of fluorescence-activated cell sorter analysis showed that DAF was present not only on red cells but was widely distributed on the surface membrane of platelets, neutrophils, monocytes, and B and T lymphocytes. By Western blotting, we observed small but consistent differences in the Mr of DAF from the membranes of various cell types. Quantitative studies showed that phagocytes and B lymphocytes, which presumably enter more frequently in contact with immune complexes and other potential activators of complement, had the highest DAF levels. As previously reported by others, the red cells from PNH patients were DAF deficient. When the patients' red cells were incubated in acidified serum (Ham test), only the DAF-deficient cells were lysed. In addition, we detected defects in DAF expression on platelets and all types of leukocytes. The observed patterns of DAF deficiency in these patients were consistent with the concept that the PNH cells were of monoclonal origin. In one patient, abnormal and normal cells were found only in the erythroid, myeloid, and megakaryocytic lineages. In two other patients, the lymphocytes were also DAF deficient, suggesting that a mutation occurred in a totipotent stem cell. It appears, therefore, that the lesion leading to PNH can occur at various stages in the differentiation of hematopoietic cells.

Glutathione (GSH) content may be the major determinant of a cell's sensitivity to cytotoxic alkylating agents. In the present study, the GSH concentration was determined in lymphocytes isolated from the blood of normal subjects and patients with chronic lymphocytic leukemia (CLL). Comparable levels were found in both types of cells. Incubation for 20 hours led to a decrease in GSH to 51% of baseline values in CLL B cells. Under the same conditions, normal B- or T-lymphocyte GSH content remained constant. GSH depletion was shown to be a characteristic of the B-CLL B lymphocyte. It was not found in the T cells of patients with B-CLL or in cells from patients with T-CLL. Chlorambucil (CLB) contributes to the decrease in GSH in B-CLL lymphocytes; after incubation with the drug, lower levels of GSH were found than in the normal B or T lymphocytes, B-CLL T cells, or T-CLL (CD4 or CD8) cells. GSH depletion of CLL B lymphocytes may be related to the greater therapeutic efficacy of CLB in B-CLL than in T-CLL.

Erythrocytes shed membrane vesicles in response to many stimuli. It has been previously demonstrated that glycan phosphatidylinositol-linked (GPI-linked) proteins such as decay accelerating factor and acetylcholinesterase are concentrated in these vesicles relative to the erythrocyte membrane. We have examined the requirement for GPI-linked proteins for the process of vesiculation. Erythrocytes that do not express GPI-linked proteins, obtained from patients with paroxysmal nocturnal hemoglobinuria (PNH), release between 10% and 50% of the quantity of vesicles as normal cells in response to the Ca2+ ionophore A23187. Platelets from the same patients produced 10% to 20% of the amount of vesicles as normal platelets. In addition, a mutant B- lymphoblastoid cell line that lacks GPI-linked molecules produces about half of the number of vesicles as compared with the wild-type cell line in response to the Ca2+ ionophore. Prior findings indicate that vesiculation is one of the mechanisms that the cell uses to remodel the plasma membrane, as well as protect itself from membrane-damaging agents such as the terminal complement components C5b-9. On the basis of the present results, we conclude that GPI-linked proteins play an important role in membrane vesiculation.

Purified decay-accelerating factor (DAF), from the stroma of normal human erythrocytes, was incorporated into the membranes of erythrocytes of patients with paroxysmal nocturnal hemoglobinuria (PNH), and its effect on the complement sensitivity of the cells was investigated. Reconstitution with exogenous DAF restored the ability of the affected PNH cells to resist assembly of the homologous C3 convertase, C4b2a, on their surfaces, and decreased the susceptibility of the cells to lysis in acidified serum. Conversely, treatment of normal erythrocytes with monoclonal or polyclonal anti-DAF antibodies abrogated the capacity of the normal cells to circumvent C4b2a assembly and rendered the cells sensitive to acid lysis. These findings show that the previously reported association of DAF deficiency with PNH is causally related to the lytic abnormalities of the cells and clarify the molecular basis for restriction of autologous convertase formation on normal human erythrocytes.

Lymphocyte function-associated antigen 3 (LFA-3) is a widely distributed cell surface glycoprotein that binds to the T lymphocyte CD2 surface glycoprotein. This interaction mediates CTL-target cell conjugate formation and adhesion of thymocytes to thymic epithelial cells. CD2 is also the E rosette receptor of T lymphocytes and mediates rosetting with autologous E by binding to LFA-3. We describe deficient expression of LFA-3 on E from paroxysmal nocturnal hemoglobinuria (PNH) patients. PNH is an acquired defect affecting phosphatidylinositol-anchored membrane proteins, of which decay-accelerating factor (DAF) is most important in the clinical symptoms of PNH. LFA-3-negative, weakly positive, and positive populations were found among PNH E. There was a good correlation with DAF deficiency. PNH E exhibited decreased binding of 125I-CD2 and rosetting with a human T lymphoma cell line. PNH E readily incorporated purified LFA-3, restoring LFA-3 expression and the CD2 binding and rosetting activity to normal levels. The expression of DAF was not restored after the incorporation of purified LFA-3 into PNH E, showing that LFA-3 and DAF are different molecules. Phosphatidylinositol-specific phospholipase C (PIPLC) treatment of a B lymphoma cell line released 35% of the cell surface LFA-3 and 62% of DAF. LFA-3 on E was resistant to PIPLC. However, when LFA-3 purified from human E was reconstituted in sheep E or human E and subjected to PIPLC treatment, 40-50% of LFA-3 was released from the cell membrane. The results show that LFA-3 is attached to the cell membrane by a phosphatidylinositol glycolipid moiety, and confirm previous findings (37-41) that LFA-3 is a cell adhesion molecule that mediates adhesion by interacting with CD2 antigen.

To identify mannosyl (Man)-containing intermediates of the human glycoinositol phospholipid (GPI) anchor pathway and examine their expression in paroxysmal nocturnal hemoglobinuria (PNH), mannolipid products deriving from in vitro guanosine diphosphate [3H]Man labeling of HeLa cell microsomes were characterized. The defined GPI species were correlated with products deriving from in vivo [3H]Man labeling of normal and (GPI-anchor defective) affected leukocytes. In vitro analyses in HeLa cells showed dolichol-phosphoryl (Dol-P)-[3H]Man and a spectrum of [3H]Man lipids exhibiting TLC mobilities approximating those of Trypanosoma brucei (Tryp) GPI precursors. Iatrobead HPLC separations and partial characterizations of the major isolated [3H]Man species (designated H1-H8) showed that all but H1 (Dol-P-Man) were sensitive to HNO2 deamination and serum GPI-specific phospholipase D digestion but were resistant to phosphatidylinositol-specific phospholipase C digestion unless previously deacylated with mild alkali. [3H]Man label in H3, H4, and H6 but not in H5 or H7 was efficiently released into the aqueous phase by jack bean alpha-mannosidase digestion. BioGel P-4 and AX-5 sizing of the dephosphorylated core glycan fragments of H6 and H7 gave values that coincided precisely with the corresponding glycan fragments from the fully assembled Tryp anchor donor A' (P2). Affected leukocytes from four patients with PNH supported formation of GlcNAc- and GlcN-PI but all failed to express H6 and H7 as well as H8 and two showed complete absence of earlier Man-containing intermediates. These findings argue that human intracellular GPI mannolipids are built on acylated inositol phospholipids, that H6 and H7 contain differentially phosphoethanolamine-substituted Man3-GlcN-inositol cores, and that PNH cells are defective in conversion of GlcN-PI into these more mature mannolipid structures.

1. A case of pseudotumor of the ilium in a PTC deficient patient is reported. 2. The natural history and treatment of this serious complication of hemophilia are reviewed.

The effect of several simple sugars on the mitogenic and binding properties of PHA has been investigated. N acetyl D-galactosamine in concentration of 3-10 mg./ml. inhibited the incorporation of uridine-2-C14 and thymidine-2-C14 into the acid precipitable fraction of human tonsil cells stimulated by phytohemagglutinin. No inhibition, or a significantly lesser degree of inhibition was observed with N acetyl D-glucosamine or glucose. The binding of I131 labeled PHA to cells was decreased by NAGAL or EDTA. The EDTA inhibition, unlike the NAGAL inhibition was overcome by magnesium.

Ohne Zusammenfassung:

Abstract.: Pulmonary sequestration is a rare anomaly. An accurate pre-operative evaluation of its vascular supply is essential for the surgeon's operative approach. We describe here an intrapulmonary sequestration with vascular arterial supply via the left circumflex and the right coronary artery. This case demonstrates that if aortography is unrevealing, then a coronary source should be considered in the preoperative search for the arterial supply to a pulmonary sequestration. Moreover, pulmonary sequestration should be listed in the differential diagnosis of aberrant coronary arteries.

The tocopherol content of lymphocytes, erythrocytes, and plasma from patients with chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), and normal subjects was measured by a sensitive high performance liquid chromatographic method. Lymphocytes from patients with CLL had lower values of tocopherol (1.7 +/- 1.0 micrograms/10(9) cells) than lymphocytes from normal subjects (3.8 +/- 0.7 micrograms/10(9) cells). Mononuclear cells from patients with HCL had an increased tocopherol content of 6.2 +/- 1.0 micrograms/10(9) cells. Subfractionation of the lymphocytes from patients with CLL into T- and B-cell subgroups showed that the tocopherol content of T cells was the same as in normal subjects (4.1 +/- 0.5 micrograms/10(9) cells versus 3.5 +/- 1.2), but that the tocopherol content of the B cells was markedly reduced compared to normals (2.6 +/- 1.0 versus 6.0 +/- 1.3).

The activity of the ectoenzyme 5'-nucleotidase (5'N) was determined in the T lymphocyte subpopulations from patients with chronic lymphocytic leukemia (CLL). 5'N could be detected only in the T cells from patients whose B cells also had enzyme activity. The specific activity of CLL T4 cells was 0.17 +/- 0.02 micron/h/mg protein, similar to that of normal T4 cells, which was 0.13 +/- 0.08 micron/h/mg. The CLL T8 cells, however, had a significantly lower 5'N activity (0.17 +/- 0.02 micron/h/mg) than normal T8 cells (0.41 +/- 0.11 micron/h/mg) (P = .003). Normal null cells had very low activity, while much higher levels were found in the null cells of CLL patients whose B cells had activity. These findings document a difference in activity of an enzyme between the T8 cell population of patients with CLL and that of normal subjects.

The tocopherol content of lymphocytes, erythrocytes, and plasma from patients with chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), and normal subjects was measured by a sensitive high performance liquid chromatographic method. Lymphocytes from patients with CLL had lower values of tocopherol (1.7 ± 1.0 μg/109cells) than lymphocytes from normal subjects (3.8 ± 0.7 μg/109cells). Mononuclear cells from patients with HCL had an increased tocopherol content of 6.2 ± 1.0 μg/109cells. Subfraction-ation of the lymphocytes from patients with CLL into T- and B-cell subgroups showed that the tocopherol content of T cells was the same as in normal subjects (4.1 ± 0.5 μg/109cells versus 3.5 ± 1.2), but that the tocopherol content of the B cells was markedly reduced compared to normals (2.6 ± 1.0 versus 6.0 ± 1.3).