Serotonin Receptors in Myocardial Infarction: Friend or Foe?

Acute myocardial infarction (AMI) is one of the leading causes of death worldwide and treatment costs pose a major burden on the global health care system. Despite the variety of treatment options, individual recovery can be still poor and the mortality rate, especially in the first few years after the event, remains high. Therefore, intense research is currently focused on identifying novel target molecules to improve the outcome following AMI. One of the potentially interesting targets is the serotonergic system (5-HT system), not at least because of its connection to mental disorders. It is known that patients suffering from AMI have an increased risk of developing depression and vice versa. This implicates that the 5-HT system can be affected in response to AMI and might thus represent a target structure for patients' treatment. This review aims to highlight the importance of the 5-HT system after AMI by describing the role of individual serotonin receptors (5-HTR) in the regulation of physiological and pathophysiological responses. It particularly focuses on the signaling pathways of the serotonin receptors 1, 2, 4, and 7, which are expressed in the cardiovascular system, during disease onset, and the following remodeling process. This overview also emphasizes the importance of the 5-HT system in AMI etiology and highlights 5-HTRs as potential treatment targets.

Otto Hilgenfeldt (1900-1983): tribute to an important pioneer of European hand surgery.

The German surgeon Otto Hilgenfeldt (1900-1983) was a great innovator in European hand surgery in the 20th century, particularly in respect of the tactile (sensate) thumb and grip reconstruction in amputation injuries. His experience, beginning in the 1930s, helped him to treat hundreds of soldiers with mutilating hand injuries from 1941 to 1945 during World War II. While totally isolated and without any access to international publications, he devised many innovative ideas such as a neurovascular middle finger transposition for pollicization (first case done in July 1943) and a sensory dorsoradial first metacarpal flap for thumb resurfacing. His book Operative thumb replacement and substitution of finger losses published in 1950 is regarded as one of the most important German contributions to modern hand surgery. Hilgenfeldt's life and work remain fascinating and exemplary from a historical and surgical point of view. Many of his pragmatic surgical solutions remain valid despite the advent of microsurgery.

Interleukin 6--a potential mediator of lethal sepsis after major thermal trauma: evidence for increased IL-6 production by peripheral blood mononuclear cells.

We studied the plasma levels of the acute phase mediator interleukin 6 (IL-6) in 21 severely burned patients (burn injuries ranging from 24% to 75% total body surface area). The posttraumatic course of the IL-6 plasma levels was closely related to the clinical outcome. The nonseptic survivors as well as survivors with suspected sepsis (n = 14) exhibited maximal amounts of IL-6 (251 +/- 32 pg/mL) during the first 3 days post-burn, which subsequently returned to values within the normal range (days 30 to 50; 26 +/- 8 pg/mL). In the nonsurvivors (n = 7) IL-6 concentrations permanently increased (up to 1,921 +/- 356 pg/mL) until death (days 10 to 19) resulting from sepsis with consecutive multiple organ failure. Peripheral blood mononuclear cells (PBMCs) of patients expressed IL-6-specific mRNA in vivo at high levels in contrast to the PBMCs of healthy donors. In addition, the spontaneous and PHA-induced in vitro production of IL-6 by patients' PBMCs was enhanced compared with healthy controls, whereas no significant differences were obtained with bacterial endotoxin (LPS). The findings suggest that interleukin 6 is a potential mediator of lethal sepsis after major thermal trauma.

Serum CD14 levels in polytraumatized and severely burned patients.

Recently it has been demonstrated that the CD14 molecule which is expressed on monocytes and macrophages serves as a receptor for lipopolysaccharide (LPS) bound to LPS-binding protein (LBP) and thus mediates LPS-induced tumour necrosis factor (TNF) production. Here we report that CD14 is found as a soluble (s) molecule in serum. In healthy volunteers sCD14 levels (mean +/- s.e.m.) were 3.7 +/- 0.05 micrograms/ml (n = 30, 25-50 years of age) as determined by ELISA (detection limit 20 ng/ml serum) using two monoclonal antibodies in a sandwich technique. In polytraumatized patients (n = 16) significantly decreased levels (1.7 +/- 0.3) were detected immediately after the trauma, which increased to 4.9 +/- 0.3 micrograms/ml within the first 6 days post trauma. sCD14 remained elevated during the first 14 days post trauma in patients with the most severe injuries (injury severity score greater than 45 points), whereas a return to normal levels was observed in patients with an injury score of less than 45 points. In addition, the levels of the high-density lipoproteins that partially inactivate free endotoxin are significantly decreased post trauma. No correlation between parameters of inflammation (C3a and neopterin levels, leucocyte counts, amount of band cells), liver function and sCD14 levels was established. Comparable to polytraumatized patients, increased sCD14 serum levels were observed in five patients with burn trauma (burned area greater than 35%) within the second week post trauma when clinical signs of septicaemia were evident.

Differential regulation of T- and B-lymphocyte activation in severely burned patients.

We studied the in vitro expression and regulation of the CD23 and CD25 (Tac) surface antigens by peripheral blood lymphocytes (PBL) from severely burned patients (burn injuries ranging from 25% to 72% TBSA) in order to evaluate T- and B-lymphocyte activation processes after thermal trauma. The spontaneous and cytokine (IL-4, IL-2)-induced expression of CD23 which represents a B-cell activation marker was significantly reduced during the second to fifth week postburn when compared to healthy donors. In contrast, CD25, which is expressed on activated T cells, showed a marked increase both spontaneously, indicating an in vivo activation, and after stimulation with IL-2 or PHA. Concomitantly, T-cell proliferation induced by PHA or Con A was suppressed. However, the number of T and B cells remained unchanged. The data demonstrate the impairment of early events in the lymphocyte program in severely burned patients. The activation of B cells is downregulated, since they become refractory to external helper signals. In addition, T cells are highly activated but fail to proceed to proliferation in response to mitogenic stimuli.

Metabolism of platelet activating factor (PAF) and lyso-PAF in polymorphonuclear granulocytes from severely burned patients.

We studied the metabolism of 3H-platelet activating factor (PAF) and lyso-PAF in human polymorphonuclear granulocytes (PMN) from severely burned patients (n = 6) on days 1, 5, 9, 15, and 25 post-trauma. All patients suffered from a severe burn trauma of more than 30% total body surface area. Stimulation of PMN in healthy donors (n = 10) with the Ca-ionophore resulted in the conversion of 3H-lyso-PAF into PAF (18 +/- 2% of total radioactivity) and alkyl-acyl-glycero-phosphorylcholine (alkyl-acyl-GPC, 50 +/- 6%). In burned patients a significantly reduced formation of 3H-PAF was observed between days 1 and 15 post-trauma (day 9: 1 +/- 1%, p less than 0.0001). This pattern was normalized again in patients (n = 5) who survived the trauma after septic periods and was observed during the second week post-trauma. In one patient who succumbed to his injuries a sustained inhibition of PAF formation was observed up to his death. The decreased formation of PAF correlated weakly with the appearance of immature granulocytes within the analyzed cell fraction (ratio of immature cells versus PAF-formation, r = -0.55, p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Basophil releasability in severely burned patients.

Thermal injury is known to induce dysregulation of the immune system; however, the precise mechanisms have to be clarified. We investigated the histamine release of basophil granulocytes from severely burned patients (n = 12) after stimulation with anti-IgE or the Ca-ionophore A 23187, respectively. The anti-IgE-induced basophil histamine release of all patients was reduced in comparison to healthy donors beginning at day one postburn (p.b.) (5.0 +/- 2.3% vs. 30.5 +/-3.4%), while the Ca-ionophore-induced release was not decreased before day two p.b. Basophils of patients who finally succumbed to their injuries showed poor responsiveness (to zero levels) over the total time. In contrast, the basophil releasability of surviving patients returned to nearly normal levels (fifth to seventh week p.b.). Already in the second week p.b. there was a significant difference in histamine release between survivors and nonsurvivors [e.g., days 6-9 p.b.: 23.7 +/- 4.0 vs. 6.9 +/- 2.7 (p less than 0.005) after Ca-ionophore stimulation]. The altered basophil histamine release was neither due to a diminished dose- or a delayed time-response to the stimuli nor due to differences in the basophil counts or the cellular histamine content. Our data indicate that the decrease of the basophil releasability, which may be secondary to altered signal transduction pathways in severely burned patients correlates with the clinical outcome.

Studies on B-lymphocyte dysfunctions in severely burned patients.

We studied in vitro functional parameters of peripheral blood B-lymphocytes from severely burned patients (n = 10; burn injuries ranging from 25 to 72% TBSA). While the number of B-cells remained unchanged, B-cell proliferation induced by Staphylococcus aureus strain Cowan I (SAC) was normal or even enhanced at early and late phases postburn, but showed a marked suppression during the second to fourth week. A similar pattern was observed for the pokeweed mitogen (PWM)- or SAC-stimulated synthesis of immunoglobulin M (IgM), whereas IgG production was decreased over the whole postburn period monitored. Cytokine (interleukin 4)-induced B-cell activation as indicated by the expression of the CD23 surface antigen was impaired throughout the second to fifth week. In parallel, the release of the proteolytic cleavage product sCD23 which represents a B-cell growth and differentiation factor was reduced. Our data provide evidence that activation, proliferation, and differentiation processes of B-lymphocytes are impaired in severely burned patients, which may contribute to their enhanced susceptibility to infection and sepsis.

[Prognostic significance of macroscopic and microscopic findings in acute inhalation damage in the most severely burned patients]. / Prognostische Bedeutung makroskopischer und mikroskopischer Befunde bei der akuten Inhalationsschädigung schwerstbrandverletzter Patienten.

The bronchoscopic examination of the upper respiratory tract is thought to be of major value recognizing and determining the severity of an inhalation injury in burn patients. From clinical observation however it can be questioned if the initial bronchoscopic aspect has indeed any prognostic significance concerning soon or later developing pulmonary complications in those patients. In 15 burn patients with inhalation injury the endoscopically evident lesions of the respiratory tract were classified and documented by photography. Additionally bronchus biopsies for histological examination were taken from different levels of the bronchus tree and a bronchoalveolar lavage (BAL) was performed to gather lung cells of peripheral lung areas. Summarizing the results no firm relations between macroscopically classified degrees of respiratory damage and histopathological diagnosed destructions were found; patients, however, whose differentiation of BAL cells showed an extreme neutrophilia developed progressive lung insufficiency (ARDS) a few days later.

Induction of inflammatory mediators (histamine and leukotrienes) from rat peritoneal mast cells and human granulocytes by Pseudomonas aeruginosa strains from burn patients.

Clinical isolates of Pseudomonas aeruginosa from severely burned patients were analyzed with regard to their capacity to induce inflammatory-mediator release from rat mast cells or human granulocytes. The bacterial strains were characterized according to their cell-associated hemolysin activity as well as their secreted hemolysin and phospholipase C activities. P. aeruginosa expressing heat-labile hemolysin and phospholipase C induced histamine release from rat mast cells and leukotriene formation from human granulocytes, while bacterial strains expressing heat-stable hemolysin were potent releasers of histamine but did not lead to leukotriene formation. The mediator-inducing capacity was dependent on the growth characteristics of the bacterial strains. The purified glycolipid (heat-stable hemolysin) of P. aeruginosa was a potent inducer of histamine release but did not initiate leukotriene formation. Exotoxin A did not affect inflammatory-mediator release. P. aeruginosa with leukotriene-inducing capacity also enhanced omega oxidation of endogenous leukotriene B4, suggesting an additional inactivation of the chemotactic potential. Our data suggest that both hemolysins of P. aeruginosa contribute to the pathogenicity of P. aeruginosa by inducing and modulating inflammatory-mediator release from various cells.

Studies on the mechanisms of granulocyte dysfunctions in severely burned patients--evidence for altered leukotriene generation.

The leukotriene generation (LTB4, 20-OH-LTB4, 20-COOH-LTB4) from PMNs of severely burned patients (n = 6) was studied by reversed-phase HPLC. Granulocytes from all patients showed a decrease in leukotriene generation which only returned to normal levels when the patients recovered from their injuries. The leukotriene generation induced by different stimuli, i.e., the Ca++-ionophore A23187 (7.3 microM) or opsonized zymosan (2 mg) in the presence of exogenous arachidonic acid (60 microM) showed similar stimulation profiles. The cellular differentiation of the respective granulocyte fractions revealed that the decreased leukotriene generation was accompanied by the occurrence of immature granulocytes in the peripheral blood. Furthermore, the studies in the presence of exogenous arachidonic acid showed that the defect in leukotriene generation from granulocytes of surviving patients was due to the availability of metabolizable substrate (i.e., free arachidonic acid). Granulocytes from one nonsurviving patient showed in addition a defect in the metabolic ability of arachidonic acid to generate the respective leukotrienes. The generation of reactive oxygen species did not correlate with the observed alterations in the formation of the leukotrienes.

[In vitro virulence of wound infecting staphylococcal isolates from severely burned patients]. / In vitro Virulenz wundinfizierender Staphylokokken-Isolate von schwerbrandverletzten Patienten.

The hemolysin and histamine releasing activity of 30 S. aureus strains isolated from third degree burns of heavily burned patients was detected. The culture supernatants (cs) of Staphylococcus aureus isolated during episodes of invasive burn wound infection displayed significantly lower amounts of hemolysin and histamine releasing activity as compared to cs of bacteria isolated when no sign of septicemia was present. In contrast, when washed bacterial cells were analysed, a reversed ratio could be observed. These data clearly indicate that in strains isolated during invasive burn wound infection pathogenicity factors remain attached to the bacterial surface of the staphylococci investigated.

Decreased expression of leukotriene B4 receptor sites on polymorphonuclear granulocytes of severely burned patients.

Polymorphonuclear granulocytes were isolated from patients with burn injury and the specific binding of (3H)leukotriene B4 was assessed. We observed a decreased receptor expression as compared to healthy donor cells, which may be the result of receptor downregulation as a consequence of cellular preactivation. In addition, leukotriene B4-synthesis was also reduced and differential cell counts demonstrated a shift from segmented neutrophils to immature cells. In survivors the values returned to normal parameters whereas nonsurvivors who succumbed in the course of generalized sepsis showed depressed cellular functions up to their death.

Generation of leukotrienes from human polymorphonuclear granulocytes of severely burned patients.

The Ca ionophore A23187-induced leukotriene (LT) release (LTC4, LTB4, 20-OH-LTB4, 20-COOH-LTB4) of human PMN's from severely burned patients (n = 6) was studied by reversed-phase HPLC. The patients' granulocytes demonstrated a decrease (to zero levels) in LT generation postburn. The level of generated LT's resembled that of healthy donors when the patients recovered from their trauma (after day 40 postburn). In contrast, the granulocytes of patients who finally succumbed to their injuries showed poor responsiveness over the total time. An enhanced LTC4 production by granulocytes correlated with an increase in eosinophils within the granulocyte fraction. In addition, the reduced LTB4 production was accompanied by an enhanced LTB4 metabolism to biologically less active products (omega-oxidated metabolites). Thus, the capacity of patients' PMN's to release chemotactic substances was further decreased. The onset of this PMN dysfunction correlated with the onset of invasive microbial growth as determined by the quantitative bacterial analysis of full-thickness biopsy specimens. Our data provide evidence that the altered mediator release of patients' PMN's is closely related to a depressed host defense.

[Epidemiologic studies of the microbial colonization of severely burned patients]. / Epidemiologische Studien zur mikrobiellen Kolonisation von schwerverbrannten Patienten.

Bacteria isolated between 1/1/1983 and 12/31/1984 from the burns of 122 patients in a burns unit at the Ruhr-Universität Bochum were studied. Grampositive bacteria were predominant in colonizing the burn wounds (62.5% of all strains isolated). In the patients with more than 40% of total body surface area (TBSA) burn, isolation of Staph aureus was most frequent. The exogenous colonization rate with Staph. aureus was 86%. Coagulase negative Staphylococci were identified in 89.6% of all patients (71.4% of the patients with more than 40% TBSA burn). There was a constant decline in detecting Pseudomonas aeruginosa from the second half of 1983. Microbial sensitivity testing was performed in 834 cases. Gramnegative strains of bacteria resistant to Ampicillin, Mezlocillin, Piperacillin and Ticarcillin were found in 10 up to 97% of the tested strains. Acinetobacter calcoaceticus var. antitratus and Enterobacter cloacae usually displayed a wide resistant pattern. Some strains were resistant as to 16 antibiotics. The incidence of multiresistant Staph. aureus was studied. The time course of multiresistance was paralleled by the incidence of a 6-fold resistance to Benzylpenicillin, Oxacillin, Tetracyclin(T), Gentamycin(G), Erythromycin(E), and Sulfadiacin(S). The probability of simultaneous resistance to 2 of the 4 antibiotics (T, G, E, S) ranged between 0.7 and 0.98. 98 out of 336 Staph. aureus isolates showed a simultaneous resistance to T, G, E and S (29%).

[Comparison of 4 methods of bacterial count determination in burn wounds]. / Vergleich von vier Methoden zur Keimzahlbestimmung auf Verbrennungswunden.

The present study includes twelve patients with second and third degree fresh burns involving 10-70 per cent total body surface area. Standardized surface swab, gaze pad contact, Rodac plates, and burn wound biopsy cultures were obtained twice per week. The various techniques were compared by 48 independent measurements. Confluent growth occur in more than 70 per cent of the Rodac agar plates. There was a significant (alpha less than 1%) correlation between the results of the surface swab and the gaze pad method. A comparison of the number of viable bacteria detected with the burn wound biopsy technique and the surface methods (gaze pad and surface swab) showed no significant correlation. In addition, the number of colony forming units in 8 parallel cultures obtained from different sites of the burn wound was determined. The standard error of mean (SEM) varied between 1.01 log (biopsy), 0.91 log (gaze pad) and 0.61 log (surface swab). Several case reports emphasize that the quantitative biopsy culture seems to give most reliable data in predicting burn wound sepsis.

[Late results of 1,046 breast reduction-plasties]. / Spätergebnisse von 1046 Mammareduktionsplastiken.

Between 1971 and 1985 1046 reduction mammaplasties were performed using the Strömbeck technique with personal modifications and also subtotal amputations with free nipple grafting were carried out in 162 cases. Late results of these patients show in detail the age, the amount of weight resected, the histology and the complications.

[Facial burns]. / Gesichtsverbrennungen.

Deep partial and full thickness facial burns require early skin grafting. Pressure face masks and local steroids reduce hypertrophic scarring. Split skin and Z-plasties are used for early reconstructive surgery. Only after softening of the scar tissue definite reconstructive work should be undertaken. For this period full thickness skin grafts and local flaps are preferred. Special regional problems require skilled plastic surgery. Reconstructive surgery is the most essential part of the rehabilitation of severe facial burns.