The Kallikrein-Kinin system and muscle metabolism—Clinical aspects

The influence of synthetic bradykinin (BK) on disturbed protein and carbohydrate metabolism was studied in chemical and manifest maturity-onset diabetics, in surgical patients and in alloxan diabetic rats. BK,mixed with insulin and injected subcutaneously twice daily in alloxan diabetic rats lowered the morning blood glucose concentration in a dose-dependent way, whereas in a control group treated with insulin only no decrease was seen. Accelerated local blood flow or enhanced vascular permeability as a cause of increased glucose uptake could be ruled out by control experiments using papaverine and eledoisin. Better metabolic control in the BK/insulin-treated group was also indicated by lower arterial levels of free fatty acids and of -hydroxybutyrate, normalized hepatic glycogen content and better growth of body weight. In healthy man an intravenous infusion of BK (80 g/h) did not influence normal fasting blood glucose concentrations, whereas elevated glucose levels in maturity-onset diabetics were continuously reduced within 100 min by 12.2±1.4%. A comparable diabetic group receiving saline alone showed no spontaneous drop of blood glucose concentration. An improvement of pathological carbohydrate metabolism by infusion of BK i.v. could also be demonstrated using the intravenous glucose tolerance test in chemical and manifest maturity-onset diabetics and in surgical patients: in all groupsk values of the glucose tolerance test were significantly increased by BK. This effect was neither due to stimulated insulin release nor to changed glucose pool or to increased renal glucose loss, which was even reduced by BK. Interestingly, normalk values in healthy volunteers were not further improved by BK. A stimulated protein breakdown, which occurs after surgery due to peripheral insulin resistance, can also be restricted by intravenous infusion of BK: in surgical patients urinary nitrogen excretion was reduced by 50% during infusion of BK and was accelerated again after cessation of the infusion. These results indicate that BK can improve the efficacy of exogenous insulin in insulin-deficient animals and depressed insulin sensitivity in maturity-onset diabetics and surgical patients.     

Energetics of karate kumite

It is speculated that anaerobic metabolism is the predominant source of energy in karate kumite. However, no experimental proof is currently available. The metabolic cost and fractions of aerobic and anaerobic energy of karate kumite fighting were investigated. Ten male nationally or internationally ranked karateka [means (SD) age 26.9 (3.8) years, height 1.80 (0.08) m, mass 77.2 (12.8) kg] performed two to four fights scheduled and judged like a championship. Oxygen uptake was measured continuously with a portable spirometric device. Blood lactate was determined immediately before, and minute by minute after, each fight. Aerobic, anaerobic alactic and anaerobic lactic energy were calculated from oxygen uptake during the fight (VO₂), the fast component of the post-fight oxygen uptake (VO_2PCr) above resting values and changes in blood lactate concentration (Net-BLC), respectively. Altogether, 36 fights lasting 267 (61) s were analysed. The referees decisions caused an activity-to-break ratio of approximately 2:1. VO₂, VO_2PCr, and Net-BLC per fight were 165.3 (52.4) ml^.kg^–1, 32.2 (7.2) ml^.kg^–1and 4.2 (1.9) mmol^.l^–1; the overall energy cost above rest was 334.3 (86.3) kJ per fight. Fractions of aerobic, anaerobic alactic, and lactic energy sources were 77.8 (5.8)%, 16.0 (4.6)%, and 6.2 (2.4)%, respectively. The results indicate a high metabolic rate in karate kumite. However, the acyclic activity profile implies that aerobic metabolism is the predominant source of energy and there is anaerobic supplementation, mainly by high-energy phosphates.     

The water jet as a new tool for endoprosthesis revision surgery--an in vitro study on human bone and bone cement

In revision surgeries of endoprostheses, the interface between implant and bone cement or bone must be loosened. Conventional tools have many disadvantages because of their size and limited range. Taking advantage of the selective and athermic cutting process, a plain water jet is already used in order to cut soft tissues. This study investigates the possibilities of both a plain and an abrasive water jet as cutting tools for revision surgery. Samples of the mid-diaphysis of human femora and bone cement (CMW3) were cut with a plain water jet (PWJ) and an abrasive water jet (AWJ) at two different jet-to-surface angles (30 degrees,90 degrees ) and at five different pressure levels (30, 40, 50, 60, 70 MPa). For a PWJ a selective pressure range was identified, where only bone cement was cut. Injecting a bio-compatible abrasive (lactose) to the jet stream resulted in significantly higher cut depths in both materials. Material removal in bone was significantly less at the smaller jet-to-surface angle for both techniques. No clear selectivity between bone and bone cement was observed for application of the AWJ. However, the material removal rate was significantly higher for bone cement than for bone at all pressure levels. The results indicate that an AWJ might be an alternative tool for cement removal. The possibility for localised cutting at interfaces could be an advantage for revision of a non-cemented prosthesis.     

Chondroitin sulfate A released from platelets blocks RANTES presentation on cell surfaces and RANTES-dependent firm adhesion of leukocytes

The sequestration of chemokines on the surface of microvascular endothelium is an early event in the selective recruitment of leukocytes. The sequestration and presentation of chemokines must be tightly controlled to confine the extravasation of leukocytes and to prevent uncontrolled inflammation. We investigated whether soluble molecules released under physiological conditions could control chemokine immobilization on cell surfaces and function as regulatory chemokine binding molecules. We determined that human serum contains a molecule that suppresses RANTES (CCL5) binding to endothelial cells, PBMC and CHO cells. Using platelet-rich and platelet-free plasma, serum from patients with thrombocytopenia, and purified platelets, we identified platelets as the source of the chemokine-binding molecule and further identified it as chondroitin sulfate A. In contrast to platelet-derived fully-sulfated chondroitin sulfate A, low-sulfated chondroitin sulfate A present in plasma was almost inactive. Under physiological flow conditions chondroitin sulfate A was found to block RANTES-mediated firm adhesion of monocytes to endothelial cells. It also prevented RANTES-mediated influx of calcium in CCR5-transfected CHO cells while internalization of CCR5 was only marginally reduced. Taken together, chondroitin sulfate A released from platelets appears to act as an important regulatory molecule for cellular responses to chemokines.     

Lipooligosaccharide of Campylobacter jejuni prevents myelin-specific enteral tolerance to autoimmune neuritis--a potential mechanism in Guillain-Barre syndrome?

Campylobacter jejuni-induced enteritis is the most common infection preceding Guillain-Barre syndrome (GBS), an immune-mediated polyradiculoneuritis. The acute autoimmune attack is thought to be based on C. jejuni antigens which may mimick antigens of the peripheral nervous system. Additional pathomechanisms, like disturbance of natural T cell immunoregulation by C. jejuni, have not been evaluated so far. In experimental autoimmune neuritis (EAN), a T lymphocyte-mediated animal model of human GBS, tolerance to myelin-derived autoantigens can be induced by oral feeding of the respective antigen. Here we investigated whether the lipooligosaccharide (LOS) fraction of C. jejuni may directly alter immunologic tolerance through gastrointestinal pathways. While EAN, actively induced by immunization with bovine peripheral nerve myelin could be ameliorated by precedent feeding of myelin, feeding of C. jejuni LOS along with the myelin antigen not only prevented the tolerizing effects of oral myelin but even accelerated the onset of overt EAN and augmented the myelin-specific B cell response. These findings provide evidence that LOS of C. jejuni, as produced in the gut during C. jejuni-induced enteritis, can disturb natural tolerance to definite proteins which may be or may mimic peripheral nerve antigens. In human patients this may be one of the potential mechanisms to explain why C. jejuni enteritis is a common trigger of GBS.     

A Mott cell hybridoma

A hybridoma is described that exhibits all the characteristic features of Mott cells. It has spherules (Russell bodies) in the cytoplasm made up of dilated rough endoplasmatic reticulum and containing condensed immunoglobulin (λ₁ light chains). Some of the cells appear to be very fragile, and free spherules are often found on cell smears. Cells with the Mott cell characteristics are still able to divide, but they do not secrete immunoglobulin. Hybridomas of this kind should be useful for determining the place of the Mott cell within the scheme of B cell differentiation.     

Quantitative analysis of gene expression in human articular chondrocytes in monolayer culture

Human articular chondrocytes (HACs) were isolated from cartilage samples of normal joints and cultivated in monolayer for 56 days. Collagen type I, II, IX, aggrecan, and versican expression was quantified by real-time polymerase chain reaction (PCR). The expression of the genes was highly time-dependent and changed over the culture time. Collagen type I was not present at the beginning of the culture and increased 100-fold during the culture time. Collagen type II and IX expression was found during the entire culture period and decreased more than 100-fold. Aggrecan expression was downregulated 100-fold whereas versican expression increased 10 times. Indices of cell differentiation, defined as ratios of collagen type II to I (CII/I), collagen type IX to I (CIX/I), and aggrecan to versican (Agg/Ver), were significantly higher at the beginning of the culture and decreased over the culture period. The CII/I and CIX/I ratios formed three phases, with a plateau at the beginning, followed by a transition phase and a steady state at the end of the culture time, whereas the Agg/Ver ratio declined constantly. The accurate quantitative assessment of extracellular matrix gene expression in samples of chondrocytes taken from monolayer culture can be used to monitor chondrocyte metabolism as well as changes in the cell differentiation status.     

Differences in maintenance of CD8+ and CD4+ bacteria-specific effector-memory T cell populations

Our knowledge about the kinetics and dynamics of complex pathogen-specific CD8(+) T cell responses and the in vivo development of CD8(+) memory T cells has increased substantially over the past years; in comparison, relatively little is known about the CD4(+) T cell compartment. We monitored and directly compared the phenotypical changes of pathogen (Listeria monocytogenes)-specific CD8(+) and CD4(+) T cell responses under conditions leading to effective and long-lasting protective immunity. We found that the general kinetics of bacteria-specific CD8(+) and CD4(+) T cells during the effector and post-effector phases are synchronized. However, later during the memory phase, CD8(+) and CD4(+) T cell populations differ substantially. Whereas CD8(+) memory T cell populations with immediate effector function are readily detectable in lymphoid and non-lymphoid tissues and remain remarkably stable in size, antigen-specific CD4(+) effector-memory T cells decline continuously in frequency over time. These findings have important implications for the better understanding of the in vivo development of protective immunity towards intracellular pathogens.     

Association between atrial fibrillation and central sleep apnea

BACKGROUND: We previously described an association between atrial fibrillation and central sleep apnea in a group of patients with congestive heart failure. We hypothesized that the prevalence of atrial fibrillation might also be increased in patients with central sleep apnea in the absence of other cardiac disease. METHODS AND RESULTS: We compared the prevalence of atrial fibrillation in a series of 60 consecutive patients with idiopathic central sleep apnea (apnea-hypopnea index > 10 events per hour, > 50% central events) with that in 60 patients with obstructive sleep apnea (apnea-hypopnea index > 10, > 50% obstructive events) and 60 patients without sleep apnea (apnea-hypopnea index < 10), matched for age, sex, and body mass index. Subjects with a history of congestive heart failure, coronary artery disease, or stroke were excluded from the study. The prevalence of atrial fibrillation among patients with idiopathic central sleep apnea was found to be significantly higher than the prevalence among patients with obstructive sleep apnea or no sleep apnea (27%, 1.7%, and 3.3%, respectively, P < .001). However, hypertension was most common and oxygen desaturation most extreme among patients with obstructive sleep apnea. CONCLUSIONS: We conclude that there is a markedly increased prevalence of atrial fibrillation among patients with idiopathic central sleep apnea in the absence of congestive heart failure. Moreover, the high prevalence of atrial fibrillation among patients with idiopathic central sleep apnea is not explainable by the presence of hypertension or nocturnal oxygen desaturation, since both of these were more strongly associated with obstructive sleep apnea.