Studies on the contact system of coagulation during therapy with high doses of recombinant IL-2: implications for septic shock

Patients treated with high doses of interleukin-2 (IL-2) because of cancer, develop hemodynamic and vasopermeability changes, that resemble those observed in sepsis. These patients thus provide a unique opportunity to study the early events in the development of septic shock. We analysed the changes that occurred in the contact system of coagulation in plasma from 4 patients, who together received seven 12-day cycles of high doses of IL-2. Levels of factor XII and prekallikrein during the cycles progressively fell to 50 and 30% of their initial levels, respectively, whereas significant increases in plasma factor XIIa- and kallikrein-C1-inhibitor complexes were not observed (in 3 out of 211 samples slightly increased levels of both complexes were found). The reductions in factor XII and prekallikrein were only in part due to protein leakage, since levels were still significantly lower, i.e., 80 and 50%, respectively, when corrected for albumin decreases. Levels of high molecular weight kininogen (HMWK) also decreased during IL-2 therapy, however, this decrease paralleled that of albumin. SDS-PAGE analysis of plasma HMWK did not reveal increased cleavage of this protein. The reduction of factor XII and prekallikrein, corrected for protein leakage, significantly correlated with albumin levels and inversely with daily cumulative weight gain in the patients. Thus, we demonstrate that factor XII and prekallikrein decrease during IL-2 therapy. As these decreases, already observed after 1 day treatment, were disproportional to that of albumin, a negative acute phase reactant, and correlated with signs of the vascular leak syndrome, we favor the explanation that they reflected activation rather than a decreased synthesis of the contact system proteins.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mice with neonatally induced inactivation of the vascular cell adhesion molecule-1 fail to control the parasite in Toxoplasma encephalitis

Under various inflammatory conditions, cell adhesion molecules are up-regulated in the central nervous system (CNS) and may contribute to the recruitment of leukocytes to the brain. In the present study, the functional role of vascular cell adhesion molecule (VCAM)-1 in Toxoplasma encephalitis (TE) was addressed using VCAM(flox/flox MxCre) mice. Neonatal inactivation of the VCAM-1 gene resulted in a lack of induction of VCAM-1 on cerebral blood vessel endothelial cells, whereas the constitutive expression of VCAM-1 on choroid plexus epithelial cells and the ependyma was unaffected; in these animals, resistance to T. gondii was abolished, and VCAM(flox/flox MxCre) mice died of chronic TE caused by a failure to control parasites in the CNS. Although leukocyte recruitment to the CNS was unimpaired, the B cell response was significantly reduced as evidenced by reduced serum levels of anti-T. gondii-specific IgM and IgG antibodies. Furthermore, the frequency and activation state of intracerebral T. gondii-specific T cells were decreased, and microglial activation was markedly reduced. Taken together, these data demonstrate the crucial requirement of VCAM-1-mediated immune reactions for the control of an intracerebral infectious pathogen, whereas other cell adhesion molecules can efficiently compensate for VCAM-1-mediated homing across cerebral blood vessels.     

Dietary control of pathogenesis in C57BLKsJdbdb diabetes mice

Weanling $\text{C57BL}\text{KsJ}$ homozygous diabetic ($\text{db}\text{db}$) and normal littermate (+/+ or +/db) mice were maintained for 5 mon on isocaloric diets containing either 60% sucrose, 23% casein, 8% corn oil (diet C) or 0% sucrose, 83% casein, 8% corn oil (diet B). Diabetic homozygotes consumed more diet C than normals, but ate control amounts of diet B. Diabetic mice fed diet C exhibited 57% mortality between 4 and 5 mo of age. All diabetic mutants fed the carbohydrate-free diet B appeared healthy at 6 mo of age; mutant females were normoglycemic and mutant males were only moderately hyperglycemic. Histological examination of pancreatic islets confirmed the absence of islet degeneration. In diet B maintained mutants, increased carcass fat composition, plasma and pancreatic content of insulin and glucagon, and thymidine incorporation into islets, all established that the db gene was being fully expressed. These results indicate that dietary protein stimulates islet growth and function in $\text{db}\text{db}$ mice, while high levels of refined carbohydrate in the diet predispose islet beta cells to undefined changes that culminate in necrosis. Restricting mutants' intake of a carbohydrte-containing diet to one-half the caloric intake of normal mice failed to block onset of beta cell necrosis. Thus, dietary composition rather than total caloric intake appears to be critical in the induction of islet necrosis and atrophy in this animal model of genetically transmitted diabetes.     

Retraining automatic action‐tendencies to approach alcohol in hazardous drinkers

Aims The main aim of this study was to test whether automatic action‐tendencies to approach alcohol can be modified, and whether this affects drinking behaviour. Design and participants Forty‐two hazardous drinkers were assigned randomly to a condition in which they were implicitly trained to avoid or to approach alcohol, using a training variety of the alcohol Approach Avoidance Test (AAT). Participants pushed or pulled a joystick in response to picture‐format (landscape or portrait). The pictures depicted alcoholic or non‐alcoholic drinks. Participants in the avoid‐alcohol condition pushed most alcoholic and pulled most non‐alcoholic drinks. For participants in the approach‐alcohol condition these contingencies were reversed. After the implicit training, participants performed a taste test, including beers and soft drinks. Automatic action tendencies at post‐test were assessed with the AAT, including both trained and untrained pictures, and with a different test (Implicit Association Test, IAT). We further tested effects on subjective craving. Results Action tendencies for alcohol changed in accordance with training condition, with the largest effects in the clinically relevant avoid‐alcohol condition. These effects occurred outside subjective awareness and generalized to new pictures in the AAT and to an entirely different test using words, rather than pictures (IAT). In relatively heavy drinking participants who demonstrated changed action tendencies in accordance with their training condition, effects were found on drinking behaviour, with participants in the approach‐alcohol condition drinking more alcohol than participants in the avoid‐alcohol condition. No effect was found on subjective craving. Conclusions Retraining automatic processes may help to regain control over addictive impulses, which points to new treatment possibilities.     

Design and pharmacology of N-[(3R)-1,2,3,4-tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H-1,2,4-triazol- 1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a potent,selective, melanocortin subtype-4 receptor agonist

Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.     

Spirituality and effective leadership in healthcare: is there a connection?

Does the level of a leader's spirituality affect his or her effectiveness as a leader? The existence or nonexistence of a link between leadership and spirituality is an emerging issue in the healthcare leadership and management literature. This article defines effective leadership and spirituality and reviews the literature for both healthcare and other organizations in the discussion of this link. It concludes that healthcare leaders who are more developed in terms of their actualized spirituality simultaneously implement the five practices of effective leaders: challenge the process, inspire a shared vision, enable others to act, model the way, and encourage the heart. Moreover, they achieve more positive results for their organizations.     

Sequential organ failure predicts mortality of patients with a haematological malignancy needing intensive care

OBJECTIVES: Poor survival of patients with a haematological malignancy admitted to the intensive care unit (ICU) prompts for proper admission triage and prediction of ICU treatment failure and long-term mortality. We therefore tried to find predictors of the latter outcomes. METHODS: A retrospective analysis of charts and a prospective follow-up study were done, of haemato-oncological patients, admitted to our ICU in a 7-year period with a follow-up until 2 yr thereafter. Clinical parameters during the first four consecutive days were taken to calculate the simplified acute physiology (SAPS II) and the sequential organ failure assessment (SOFA) scores, of proven predictive value in general ICU populations. RESULTS: From a total of 58 patients (n = 47 with acute myelogenous leukaemia or non-Hodgkin lymphoma), admitted into ICU mostly because of respiratory insufficiency, sepsis, shock or combinations, 36 patients had died during their stay in the ICU. Of ICU survivors (n = 22), 20 patients died during follow-up so that the 1-year survival rate was only 12%. The SAPS II and particularly the SOFA scores were of high predictive value for ICU and long-term mortality. CONCLUSIONS: Patients with life-threatening complications of haematological malignancy admitted to ICU ran a high risk for death in the ICU and on the long-term, and the risk can be well predicted by SOFA. The latter may help us to decide on intensive care in individual cases, in order to avoid potentially futile care for patients with a SOFA score of 15 or higher.     

Domestic violence: no place for a smile

Because dentists routinely assess a patient's head, neck and mouth, they have a unique and excellent opportunity to recognize whether or not a patient is being abused. This article seeks to enlist the collaboration of the dental community in the effort to prevent domestic/intimate partner violence and provide more information about the signs and symptoms of domestic violence injuries, including strangulation, which is often overlooked by medical and dental professionals. Strangulation has only been identified in recent years as one of the most lethal forms of domestic violence. Unconsciousness may occur within seconds and death within minutes. It is known that victims may have no visible injuries whatsoever yet because of underlying brain damage by a lack of oxygen from being strangled, victims may have many serious internal injuries or die days or several weeks later. Strangulation is often indicative of a high level of domestic violence in a relationship. Attempted strangulation may cause physiological changes evident in the course of a dental examination. For these reasons, dentists should be vigilant in looking for its symptoms.