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In the postgenomic era new technologies are emerging for global analysis of protein function. The introduction of active site-directed chemical probes for enzymatic activity profiling in complex mixtures, known as activity-based proteomics has greatly accelerated functional annotation of proteins. Here we review probe design for different enzyme classes including serine hydrolases, cysteine proteases, tyrosine phosphatases, glycosidases, and others. These probes are usually detected by their fluorescent, radioactive or affinity tags and their protein targets are analyzed using established proteomics techniques. Recent developments, such as the design of probes for in vivo analysis of proteomes, as well as microarray technologies for higher throughput screenings of protein specificity and the application of activity-based probes for drug screening are highlighted. We focus on biological applications of activity-based probes for target and inhibitor discovery and discuss challenges for future development of this field.In the postgenomic era new technologies are emerging for global analysis of protein function. The introduction of active site-directed chemical probes for enzymatic activity profiling in complex mixtures, known as activity-based proteomics has greatly accelerated functional annotation of proteins. Here we review probe design for different enzyme classes including serine hydrolases, cysteine proteases, tyrosine phosphatases, glycosidases, and others. These probes are usually detected by their fluorescent, radioactive or affinity tags and their protein targets are analyzed using established proteomics techniques. Recent developments, such as the design of probes for in vivo analysis of proteomes, as well as microarray technologies for higher throughput screenings of protein specificity and the application of activity-based probes for drug screening are highlighted. We focus on biological applications of activity-based probes for target and inhibitor discovery and discuss challenges for future development of this field.

Implantable cardioverter-defibrillators were investigated for their impact on mortality in 228 consecutive heart transplant candidates on the waiting list for transplantation (207 patients without and 21 with implantable cardioverter-defibrillator therapy). The mortality rate in 207 patients without implantable cardioverter-defibrillator therapy was 23.2% and in 21 patients with implantable cardioverter-defibrillator therapy was 4.7%. In a Cox proportional hazards model for all 228 study patients (mortality while on the waiting list: 21.5%; transplantation rate: 54.8%), the absence of an implantable cardioverter-defibrillator was only a marginally significant predictor of mortality ( p = 0.079). However, the absence of an implantable cardioverter-defibrillator was a powerful predictor of mortality for a subgroup of 134 patients with high-grade ventricular arrhythmias on Holter electrocardiography (mortality while on the waiting list: 26.1%; transplantation rate: 54.5%; p = 0.022) and for a subgroup of 58 survivors of sudden cardiac death (mortality while on the waiting list: 22.4%; transplantation rate: 56.9%; p = 0.018). Implantable cardioverter-defibrillator therapy can be strongly recommended in transplant candidates with a history of sudden cardiac death. Recommendations for an expanded, prophylactic use of implantable cardioverter-defibrillator therapy in heart transplant candidates cannot be given. (J THORAC CARDIOVASC SURG 1995;110:532-9)

Zusammenfassung Eiweißfrei ernährte Ratten zeigen im Hunger einen Aktivitätsanstieg der Glutamat-Aspartat-Transaminase in der Leber, der bei adrenalektomierten Tieren noch gesteigert ist. Im Gegensatz zur Serin-Dehydratase läßt sich diese Hungerinduktion nicht durch Verabreichung von Glucose hemmen. In Ratten mit Alloxan-Diabetes finden sich erhöhte Enzymspiegel der Serin-Dehydratase, der Glutamat-Alanin-Transaminase und der Glutamat-Aspartat-Transaminase. Dieser Effekt läßt sich im Falle der Serin-Dehydratase und der Glutamat-Aspartat-Transaminase durch zusätzliches Hungern erheblich steigern, während die Aktivität der Glutamat-Alanin-Transaminase unter den gleichen Bedingungen leicht abnimmt. Die Glucokinase-Aktivivität sinkt im Hunger und beim Alloxan-Diabetes gegenüber der Kontrollgruppe deutlich ab.

Summary The aim of these experiments was to examine the time-difference in the induction of the amino-transferases (GOT, GPT) and the serine-dehydratase after starvation in rat liver. The activity of alaninketoglutarate-amino-transferase increased 10 hours after the aspartat-ketoglutarate-aminotransferase and the serine-dehydratase. Both aminotransferases increased significantly after 7-days protein-free diet and showed a decrease 24 hours later. An increase in the enzyme activity of the amino-transferases was detected although glucose was given, while the serin-dehydratase did not increase under the same conditions.

Malignant cardiac arrhythmias are reported during prolonged drastic weight reduction with very low calorie diets (VLCD). Moreover, we could monitor potentially cardiac arrhythmias in a previously healthy obese adolescent girl treated with a alxed low calorie diet (2400 KJ) for only two weeks.Therefore we studied cardiac function in 36 grossly obese adolescents (aged 12.1±0.6 years, overweight 54±4% mean±SE) who were treated with a 2000 KJ diet for weight reduction by 24 hour Holter monitoring before and during the treatment at one week interals (Del Mar Avionics, Model 500, USA). Weight loss during the low calorie treataent was 5.7±0.3 kg.Analysis of variance showed a significant decrease of average heart rate (HRavg), minimal heart rate (HRmin) and maximal heart rate (HRmax) during the weight reduction. However, the number of patients who revealed ventricular (VES) and supraventricular (SVES) extrasystoles did not change significantly.Neither before nor during the period of weight loss dysarrhythmias were seen.