Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity,delayed FHL,and a predisposition to cancer

The pore-forming protein perforin is critical for defense against many human pathogens and for preventing a catastrophic collapse of immune homeostasis, manifested in infancy as Type 2 familial hemophagocytic lymphohistiocytosis (FHL). However, no evidence has yet linked defective perforin cytotoxicity with cancer susceptibility in humans. Here, we examined perforin function in every patient reported in the literature who lived to at least 10 years of age without developing FHL despite inheriting mutations in both of their perforin (PRF1) alleles. Our analysis showed that almost 50% of these patients developed at least 1 hematological malignancy in childhood or adolescence. The broad range of pathologies argued strongly against a common environmental or viral cause for the extraordinary cancer incidence. Functionally, what distinguished these patients was their inheritance of PRF1 alleles encoding temperature-sensitive missense mutations. By contrast, truly null missense mutations with no rescue at the permissive temperature were associated with the more common severe presentation with FHL in early infancy. Our study provides the first mechanistic evidence for a link between defective perforin-mediated cytotoxicity and cancer susceptibility in humans and establishes the paradigm that temperature sensitivity of perforin function is a predictor of FHL severity.     

Dietary energy restriction-induced modulation of protein kinase C ζ isozyme in the hamster pancreas

Dietary restriction in experimental animals enhances life span, delays disease, inhibits immunological perturbations, and ameliorates cancer. Protein kinase C(a) isozymes mediate signals generated by hormones, growth factors, and neurotransmitters for cell proliferation and differentiation. The results of our study showed that a C-terminally directed anti-PKC ζ antibody detected an 81–kDa band in the pancreases of control and energy-restricted hamsters. Syrian golden hamsters were fed energy-restricted diets formulated such that the hamsters received 90%(10% energy restriction(a) ), 80%(20% ER), or 60%(40% ER) of the total energy consumed by control hamsters, with the energy reduced proportionally from fat and carbohydrate. ER decreased PKC ζ isozyme levels by 40–75% in hamsters fed 10, 20, and 40% ER diets for 8 wk. PKC ζ isozyme expression was decreased by 75–80% in hamsters fed ER diets for 15 wk. Although ER caused significant decreases in PKC ζ isozyme levels compared with those of control hamsters at both time points, the relative differences in PKC ζ levels between the dietary ER groups(10, 20, and 40%) were small and not significant. A significant decrease in the body weights of ER animals compared with those of controls was observed at both time points. No differences in tomato lectin and phytohemagglutinin reactivity were observed between control animals and animals fed 10, 20, and 40% ER diets. Furthermore, the cellular expression of PKC ζ in the hamster pancreas did not differ among hamsters fed the various ER diets. These observations may be important for understanding not only the role of dietary ER in pancreatic cancers but also PKC ζ signal transduction mechanisms in normal pancreatic physiology.© 1995 Wiley-Liss, Inc     

Aziridines and aziridinium ions in the practical synthesis of pharmaceutical intermediates--a perspective

Recent methods for the synthesis of aziridines and aziridinium ions, the mechanisms of their nucleophilic ring-opening reactions and applications to the practical synthesis of pharmaceutical intermediates are reviewed.     

Timing of chest tube removal after coronary artery bypass surgery

AIM: Assessing the impact of chest tube removal timing following a coronary artery bypass grafting surgery on the clinical outcome. METHODS: Eighty-three consecutive patients were randomly assigned to either have the chest tube removed 24 hours (Group A) or 48 hours (Group B) postoperatively. Chest tubes were removed on the condition that drainage was less than 100 cc for the last 8 hours. Pre- and postoperative data were analyzed. RESULTS: The following preoperative and intraoperative risk factors were more prevalent among Group A patients: previous MI (60.5% vs 40.7%, p = 0.11), previous CVA (9.1% vs 0%, p = 0.11), hypertension (72.7% vs 55.6%, p = 0.14), pump time (111.6 min vs 96.8 min, p = 0.07), and cross-clamp time (73.8 min vs 64.4 min, p = 0.07). Postoperatively, there was a lower demand for analgesics in Group A (2.1 times for 12 hours at 36 hours vs 3.6 p = 0.09), lower white blood cell count (10,947 at 48 hours vs 11,576, p = 0.39) a higher oxygen saturation (91.9% at 48 hours vs 88.9%, p = 0.07), higher expiratory volumes (594 mL at 36 hours vs 514 mL p = 0.08) and earlier mobilization (23% walking at 48 hours vs 4%, p = 0.01). Pleural effusion and atelectasis were less frequent in Group A in both chest X-rays (66% vs 73%, p = 0.6 and 64% vs 75%, p = 0.47, respectively) and CT scans (19% vs 41%, p = 0.1 and 84% vs 96%, p = 0.42, respectively). There was no difference between the two groups in the prevalence of serous wound discharge and the length of hospital stay and there were no reported cases of pneumonia throughout the study. CONCLUSION: In cases where no excessive drainage accumulates, early removal of the chest tubes was found to be a policy that improves the postoperative outcome and decreases the need for supportive treatment such as analgetics, physiotherapy, nurse care, and oxygen. This policy did not involve significant residual effusions.     

Cytokine dysregulation, inflammation and well-being

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute-phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1 versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic 'overshooting' with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor-alpha and C-reactive protein production and through activation of the corticotropin-releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases.