Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury.

The mechanism of immunodepression after brain injury is not yet clear. Here we demonstrate rapid systemic release of the immunoinhibitory cytokine interleukin-10, monocytic deactivation and a high incidence of infection in patients with 'sympathetic storm' due to acute accidental or iatrogenic brain trauma. In vitro studies showed that within minutes catecholamines trigger the secretion of interleukin-10 from unstimulated monocytes through a beta-adrenoreceptor-mediated, cAMP/protein kinase A-dependent pathway. We found that in a rat model of acute brain injury, the beta-receptor antagonist propranolol prevented the increase of interleukin-10 plasma levels. Rapid monocytic interleukin-10 release after sympathetic activation may represent a common pathway for immunodepression induced by stress and injury.

Dexmedetomidine oromucosal gel for noise-associated acute anxiety and fear in dogs-a randomised, double-blind, placebo-controlled clinical study.

The aim of this randomised, double-blind, placebo-controlled, clinical-field study was to evaluate the effect of dexmedetomidine oromucosal gel at subsedative doses in alleviation of noise-associated acute anxiety and fear in dogs. On New Year's Eve, 182 dogs with a history of acute anxiety and fear associated with fireworks received treatment as needed up to five times: 89 dogs received dexmedetomidine and 93 dogs received placebo. For the primary efficacy variables, dog owners assessed the overall treatment effect as well as signs and extent of anxiety and fear. The overall treatment effect was statistically significant (P<0.0001). An excellent or good treatment effect was reported for a higher proportion of dogs treated with dexmedetomidine (64/89, 72 per cent) than those receiving placebo (34/93, 37 per cent). Additionally, dexmedetomidine-treated dogs expressed significantly (P<0.0314) fewer signs of fear and anxiety despite the noise of fireworks. No local tolerance or clinical safety concerns occurred during the study. This study demonstrated that oromucosal dexmedetomidine at subsedative doses alleviates noise-associated acute anxiety and fear in dogs.

Mechanisms of brain-mediated systemic anti-inflammatory syndrome causing immunodepression.

Overwhelming inflammatory immune response can result in systemic inflammation and septic shock. To prevent excessive and deleterious action of proinflammatory cytokines after they have produced their initial beneficial effects, the immune system can release several anti-inflammatory mediators, including interleukin-10, interleukin-1 receptor antagonist, and soluble tumor necrosis factor receptors, thus initiating a compensatory anti-inflammatory response syndrome. However, in vivo the delicate balance between pro- and anti-inflammatory responses is additionally controlled by the central nervous system. Therefore, proinflammatory cytokines stimulate the hypothalamic-pituitary-adrenal axis and enhance sympathetic nerve system activity. The mediators of these neuroimmune pathways can again suppress immune cell functions to control systemic inflammation. The question is, however, what happens if the immunoinhibitory CNS pathways are activated without systemic inflammation? This can result from production of cytokines in the brain following infection, injury, or ischemia or in response to various stressors (e.g., life events, depression, anxiety) or directly from brainstem irritation. The answer is that this may generate a brain-mediated immunodepression. Many animal and clinical studies have demonstrated a stress and brain cytokine mediated decrease in the cellular immune response at the lymphocyte level. More recently, the importance of monocytes in systemic immunocapacity has been shown. Monocytic inactivation with decreased capability of antigen presentation and depressed secretion of proinflammatory cytokines increases the risk of infectious complications. Interestingly, cytokines in the brain and other stressors can also generate systemic immunodepression at the monocyte level. In this scenario the catecholamine-induced release of the potent anti-inflammatory cytokine interleukin-10 is a newly discovered mechanism of the brain-mediated monocyte deactivation in addition to the "well known" immunosuppressive action of glucocorticoids. Furthermore, other neuropeptides such as alpha-melanocyte-stimulating hormone and beta-endorphin which can be released in stressful situations have also inhibitory effects on immune cells. Thus mediators of the CNS are implicated in the regulation of immune functions and may play a role in both conditioning the host's response to endogenous or exogenous stimuli and generating a "brain-mediated" immunodepression.

Diminished monocytic HLA-DR expression and ex vivo cytokine secretion capacity in patients with glioblastoma: effect of tumor extirpation.

Severe immunodysregulation on lymphocyte level has been described in patients with glioblastoma and is likely involved into its unfavorable prognosis. Although the major importance of monocytic cells for immunoregulation is well established, only very limited data exist regarding the monocyte status in glioblastoma patients. Here we demonstrate a markedly diminished monocytic HLA-DR expression and ex vivo cytokine secretion capacity (TNF-alpha, IL-1beta, IL-10) as signs for monocyte deactivation in glioblastoma patients but not in patients with astrocytoma. As known in immunocompromised patients from other reasons, monocyte deactivation indicate global immunodepression associated with an enhanced risk of infectious complications. Interestingly, tumor resection resulted in partial recovery from the monocytic deactivation. This suggests that the glioblastoma itself contributed to this phenomenon. However, IL-10 and the active forms of transforming growth factor-beta2 and -beta1, which are produced by glioblastoma cells and known to inhibit monocyte function, were not detectable in plasma in our patients. Moreover, low levels of the adrenocorticotropic hormone and cortisol excluded hypothalamo-pituitary-adrenal axis involvement. So, further investigations are necessary to clarify the mechanism. The demonstrated severe glioblastoma-associated monocytic deactivation may contribute to its unfavorable prognosis. Therefore, monocytes may represent target cells for new adjuvant immunotherapies in glioblastoma.

Brain-IL-1beta induces local inflammation but systemic anti-inflammatory response through stimulation of both hypothalamic-pituitary-adrenal axis and sympathetic nervous system.

It is well established that systemic inflammation induces a counter-regulatory anti-inflammatory response particularly resulting in deactivation of monocytes/macrophages. However, recently we demonstrated a systemic anti-inflammatory response without preceding signs of systemic inflammation in patients with brain injury/surgery and release of cytokines into the cerebrospinal fluid (CSF). In order to analyze the mechanisms and pathways of systemic immunodepression resulting from sterile cerebral inflammation we established an animal model using continuous intra-cerebroventricular (i.c.v.) or intra-hypothalamic (i.h.) infusion of rat recombinant (rr) tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta for 48 h. Controls received intra-venous (i.v.) cytokine administration. Interestingly, i.c.v. and i.h. infusion of IL-1beta but not TNF-alpha produced distinct signs of central nervous system (CNS) inflammation. Correspondingly, i.c.v. infusion of IL-1beta particularly diminished the TNF-alpha but increased the IL-10 concentration in whole blood cultures after endotoxin stimulation. All parameters normalized within 48 h after termination of the infusion. Blocking the hypothalamic-pituitary-adrenal (HPA) axis by hypophysectomy (HPX) led to complete recovery of the diminished TNF-alpha concentration and temporarily inhibited the IL-10 increase. Blocking the sympathetic nervous system (SNS) transmission by application of the beta2-adrenoreceptor antagonist propranolol not only inhibited the increase but further downregulated the endotoxin induced IL-10 concentration in the media of whole blood cell cultures, whereas the TNF-alpha decrease was only partially prevented. Interestingly, HPX and propranolol also diminished the cell invasion into the CSF. In summary, activation of both the HPA axis and the SNS plays an important role in systemic anti-inflammatory response resulting from cytokines in brain and cerebral inflammation.

Temporal profile of cerebrospinal fluid glutamate, interleukin-6, and tumor necrosis factor-alpha in relation to brain edema and contusion following controlled cortical impact injury in rats.

Traumatic brain injury is associated with release of the excitotoxin glutamate and production of pro-inflammatory cytokines IL-6 and tumor necrosis factor-alpha (TNF-alpha). Following controlled cortical impact injury, cerebrospinal fluid (CSF) glutamate, IL-6, and TNF-alpha concentrations were measured to investigate their relationship to evolving tissue damage. Compared to non-traumatized rats CSF glutamate, IL-6 and TNF-alpha levels were significantly increased by 8 h after trauma (P<0.005). Parallel to increasing brain swelling and contusion CSF glutamate was significantly elevated over time, reaching highest levels by 48 h (33+/-4 microM) while IL-6 and TNF-alpha showed maximum values at 24 h after trauma (42+/-7 and 4.7+/-1 pg/ml) (P<0.005). The observed different temporal profile of CSF glutamate, IL-6, and TNF-alpha following focal traumatic brain injury could be of therapeutic importance.

Continuous infusion of proinflammatory cytokines into the brain to study brain cytokine induced local and systemic immune effects.

Proinflammatory cytokines are produced in the brain after various kinds of insult (ischemia, trauma, infection). In this process interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha are most important. These cytokines are key mediators of inflammation. Furthermore, these cytokines can act as neurotransmitters and develop direct effects on the central nervous system (CNS) including fever, sleep and stimulation of the neuroendocrine as well as sympathetic nervous system. Moreover, IL-1beta and TNF-alpha may also be involved in brain repair and regenerating processes. However, most of the data about the role of cytokines in the brain have been obtained from either in vitro studies or bolus injections into the brain parenchyma or cerebroventricular system. On the other hand, it is known that cytokines are released continuously into the brain after a cerebral insult over a period of 24 to 48 h. In order to further complete the knowledge about the interactions between neural and immune cells to overcome the primary insult and initiate repair and regeneration in the CNS, a new animal model of local inflammation reaction was established using chronic intracerebral infusion of rat recombinant cytokines.

Effects of tacrolimus on hemispheric water content and cerebrospinal fluid levels of glutamate, hypoxanthine, interleukin-6, and tumor necrosis factor-alpha following controlled cortical impact injury in rats.

OBJECT: Disturbance of calcium homeostasis contributes to evolving tissue damage and energetic impairment following traumatic brain injury (TBI). Calcium-mediated activation of calcineurin results in production of tissue-damaging nitric oxide and free oxygen radicals. Inhibition of calcineurin induced by the immunosuppressant tacrolimus (FK506) has been shown to reduce structural and functional damage after ischemia. The aims of the present study were to investigate time- and dose-dependent short-term antiedematous effects of tacrolimus following TBI. METHODS: A left temporoparietal contusion (controlled cortical impact injury [CCII]) was induced in 51 male Sprague-Dawley rats. Tacrolimus (1 or 3 mg/kg body weight) was administered by a single intraperitoneal injection at 5 minutes, 30 minutes, or 4 hours after CCII occurred. Control rats received physiological saline. Water contents of traumatized and nontraumatized hemispheres, as well as cerebrospinal fluid (CSF) levels of mediators reflecting tissue damage (the proinflammatory cytokines interleukin [IL]-6 and tumor necrosis factor [TNF]-alpha, the excitotoxin glutamate, and the adenosine triphosphate-degradation product hypoxanthine), were determined 24 hours after trauma. Although CSF levels of IL-6 and TNFalpha were completely suppressed by tacrolimus at all time points and at both concentrations, CSF levels of glutamate and hypoxanthine, as well as edema formation, were only marginally influenced. Significant reduction of cerebral water content was confined to nontraumatized hemispheres. In addition, the higher dose of tacrolimus failed to exert significant antiedematous effects on traumatized hemispheres. CONCLUSIONS: Under the present study design, the potency of tacrolimus in reducing edema formation following CCII seems limited. However, its immunosuppressive effects could be of value in influencing the posttraumatic inflammatory response known to aggravate tissue damage.

Prevention of allergoid (cutaneous anaphylactoid) reactions to polygeline (Haemaccel) in orthopaedic patients by premedication with H1- and H2-receptor antagonists.

"Purified" polygeline (Haemaccel) was examined for its anaphylactoid and allergoid reactions in a controlled clinical trial on a homogenous sample of orthopaedic patients. In two test groups histamine H1- and H2-receptor antagonists were applied, in the control group saline as a placebo premedication. Unexpectedly no anaphylactoid reaction associated with histamine release greater than or equal to 1 ng/ml plasma occurred in the trial. Clinically unimportant allergoid reactions restricted to the skin occurred with a lower frequency (18%) than observed in previous trials. The specific premedication was highly effective in preventing these reactions in the two test groups (p less than 0.0005). Due to the apparent improvement of the product a general premedication with histamine H1- and H2-receptor antagonist seems not to be necessary before polygeline is administered to patients. For reasons of safety, however, it seems to be indicated in patients at risk, such as those with carcinoma, a proven allergic diathesis and in those who have already suffered from an incident to plasma substitutes.

[Randomised study on histaminelike side-effects of 5 common plasmasubstitutes in orthopedic surgery (author's transl)]. / Pathergiequote verschiedener Plasmasubstitute an Haut und Respirationstrakt orthopädischer Patienten

Preceding anaesthesia 750 randomised patients, sub-divided into 5 different age groups, were given 500 ml of a standard plasma-substitute at a flow rate of 25-30 ml/min. There was direct correlation (p=0.1%) of the frequency of side-effects to the substance used; none, however, to the age or general surgical risk. Side-effects were observed in 21.3% with derivates of gelatin as compared to 3.7% with Macrodex and Plasmasteril combined. The rate of more serious anaphylactoid reactions was 6% with Haemaccel, 1.3% with Gelifundol-S, 0.67% with Macrodex and less than 0.67% with Neo-Plasmagel. The study reveals that serious side-effects may be expected in orthopaedictic patients after application of plasma substitutes. As a prophylactic procedure for those patients we recommend, therefore, the application of these substances only after careful consideration of the indications for their use.

[Reducing of unwanted side effects of modified fluid gelatin by promethazine: controlled clinical trial with orthopaedic patints (author's transl)]. / Suppression der Nebenwirkungsquote von Neo-Plasmagel durch Promethazin.

In order to determine the undesirable side effects of standard commercially available plasma substitutes, 450 stationary patients covering 5 age groups were randomly allocated to various methods of pre-medication and 3 batches of modified fluid gelatin (Neo-Plasmagel). The incidence of allergoid and anaphylactoid reactions depended on the pre-medication (p less than 0.025). Atosil proved to be an strong histamine blocker: the incidence of reactions between the control and the promethazine group was p less than 0.005. Seen as a whole reactions among females were greater than with males (p less than 0.025). No relationship could be determined statistically between the different batches and the incidence of side-effects. -The prophylactic use of Neo-Plasmagel in orthopaedic patients is therefore dependent on a sufficient blockade of histamine receptors.

Binding of native and denatured collagen to immunoglobulins and cold insoluble globulin in serum of patients undergoing orthopedic surgery.

Native and denatured 125-I-collagen were reacted with sera from 366 patients undergoing orthopedic surgery. Complexes consisting of native or denatured collagen and immunoglobulins or of denatured collagen and cold insoluble globulin were precipitated with secondary antibodies to either immunoglobulins or CIG. Only approximately 10% of the patients' sera bound more than 5 ng native collagen/10 microliter serum. Binding of denatured collagen to immunoglobulins occurred more frequently and in larger amounts. Binding of denatured collagen to CIG was determined in some of the sera and found to occur in all of them and in substantial amounts. Some of the subjects developed pathergic reactions upon subsequent infusion of a gelatin based plasma substitute. There was no correlation between the severity of such adverse reactions and any of the parameters measured. Therefore, the observed clinical reactions are not likely to be caused by true immunological mechanisms.

[The incidence of hepatitis following orthopedic operations with massive blood-loss in adolescents (author's transl)]. / Die Hepatitisquote nach orthopädischen Operationen mit grossem Blutverlust bei Jugendlichen.

Blood replacement in 527 thoracic spinal grafts (n=295) was greater (F=17.99; 1.116; 0.01) when grafting had to be done in two stages. Between 1953 and 1972 3 cases of postoperative jaundice were seen, negative to Australia-Antigen. Transfusion hepatitis appears to be rarer in this operative material of adolescent orthopedic patients then in other disciplines published. The reasons may be: homogenous material, intact youthful immunity reactions, thorough prevention of infection in orthopedic departments. More could be said only in polycentric prospective study. Preventive measures for hepatitis prophylaxis are discussed.

Lack of evidence for immunological reactions to polygelatin.

Gelatin-based plasma substitutes resemble denatured collagen in that sequence dependent antigenic sites of collagen may be preserved in these preparations and cause side reactions of such plasma substitutes. We have measured the binding of 125I-collagen in denatured conformation to antibodies and to cold-insoluble globulin (CIG) in sera of patients undergoing orthopedic surgery. About two thirds of the sera bound significant amounts of denatured collagen to immunoglobulins and to CIG. Yet, there was no correlation in individual patients or in groups of patients between the collagen binding capacity of sera and the occurrence of allergic reactions upon infusions of Haemaccel. Furthermore, antibodies to denatured collagen induced in animals did not cross-react with gelatin-based plasma substitutes. Thus, it is not likely that side reactions after infusion of gelatin-based plasma substitutes are caused by immunological reactions between antigens and performed antibodies.

Characterization of the 18-kDa apple allergen by two-dimensional immunoblotting and microsequencing.

A low-temperature extract taken from Golden Delicious apples was separated by two-dimensional polyacrylamide gel electrophoresis. By means of two-dimensional immunoblotting with patients' serum containing IgE specific to Bet v I, a rabbit polyclonal antiserum raised against Bet v I, and two Bet v I specific monoclonal antibodies, epitopes cross-reactive to Bet v I were identified on an apple allergen with a molecular mass of 18 kDa and pI 5.5. Furthermore, certain antibody reactivities with 4 isoproteins of a molecular mass of 16 kDa and pIs ranging from 4.9 to 5.5 were observed, which may indicate the presence of Bet v I related epitopes on these proteins. Based on 26 amino acid residues, N-terminal sequencing of the 18-kDa apple allergen revealed 62% sequence identity between Bet v I from birch pollen and the apple allergen. Our results therefore support the view that both proteins express common as well as non-related IgE-reactive epitopes.

Prophylaxis of anaphylactoid reactions to a polypeptidal plasma substitute by H1- plus H2-receptor antagonists: synopsis of three randomized controlled trials.

To demonstrate the efficacy of a premedication with H1- + H2-receptor antagonists against histamine-release responses in anaesthesia and surgery 3 randomized controlled trials were conducted in patients, volunteers and experimental animals (dogs). Cutaneous anaphylactoid reactions following infusion of polygeline (Haemaccel) in orthopedic patients were successfully abolished by premedication with 0.1 mg/kg dimethpyrindene (Fenistil) and 5 mg/kg cimetidine (Tagamet). Chlorpheniramine (Piriton) was also useful, but dimethpyrindene was more effective in the doses recommended and used. Side-effects of the premedication were not observed when the 2 drugs were slowly administered (2 min each). Systemic anaphylactoid reactions following infusion of polygeline were completely prevented in volunteers by the same premedication (0.1 mg/kg dimethpyrindene and 10 mg/kg cimetidine). Life-threatening reactions could not be tested in human subjects, but were elicited in experimental animals (dogs). In this species which resembles man in its sensitivity against histamine, in plasma histamine levels and in response to polygeline life-threatening reactions were prevented or in especially severe cases diminished to such an extent by the premedication with H1- + H2-blockers that this premedication was finally judged to be very effective against histamine-release responses of any grade of severity. To confirm this clinically very important hypothesis more clinical trials in patients at risk for anaphylactoid reactions to drugs are urgently needed.

[Heart arrest during dextran infusion despite hapten blockade]. / Herzstillstand unter Dextraninfusion trotz Haptenhemmung.

In a running clinical prospective study on the incidence of adverse reactions to colloidal polysaccharides (randomised, single blind, n = 300) a bronchospasm followed by cardiac arrest occurred during dextran infusion although the necessary hapten blockage with monovalent dextran-1 had been effected. Resuscitation was successful. Directly after this, surgery was carried out as planned under general anaesthesia. The 69-year-old patient was discharged without noticeable sequelae. For the first time in the literature on dextran the studied sample allows a generalisation: The event occurred with an incidence of about 0.9% (of 116 patients who had received dextran infusion). This incidence corresponds to a confidence interval ranging from 0.02 to 4.96%. If the study would be continued as planned, the upper limit of this interval signals the probability of another case of severe intolerance. The diagnosis "dextran adverse reaction" can be made in this case by clinical symptoms. Since no previous or concomitant medication had been administered as provided in the protocol to confirm the diagnosis as an adverse reaction to dextran by determination of the titer of dextran antibodies prior to infusion is not required and it may be concluded that dextran was the causative agent.

[Notes on the indication of corrective osteotomy in Perthes' disease (author's transl)]. / Zur Indikation der Varisierungsosteotomie beim Morbus Perthes. (Ein morphologischer Vergleich zweier Behandlungsverfahren).

The results of surgical (corrective osteotomy) and conservative therapy (Thomas splint treatment) are compared in 88 patients suffering from Perthes' disease. It is attempted to show whether the age of the patients, the stage of disease, centric or excentric head of femur, Cattherall's stage or any risk factors influence the results. Statistics show that only young children profit from surgical treatment whereas it offers no advantage to children over six years of age. Among the young children only those with excentric head of femur, show significantly better results as opposed to conservative splint treatment. Surgery is otherwise only indicated when it is seen as an alternative to prolonged splint treatment.