Primed B cells present type-II collagen to T cells.

Development of type-II collagen (CII)-induced arthritis (CIA) is dependent on a T-cell mediated activation of autoreactive B cells. However, it is still unclear if B cells can present CII to T cells. To investigate the role of B cells as antigen-presenting cells (APCs) for CII, we purified B cells from lymph nodes of immunized and nonimmunized mice. These B cells were used as APC for antigen-specific T-cell hybridomas. B cells from naïve mice did present native, triple-helical, CII (nCII) but also ovalbumin (OVA) and denatured CII (dCII) to antigen-specific T-cell hybridomas. In addition, B cells primed with nCII or OVA, but not dCII, activated the antigen-specific T-cell hybridomas two to three times better than naïve B cells. We conclude that antigen-primed B cells have the capacity to process and present CII to primed T cells, and antigen-primed antigen-specific B cells are more efficient as APC than naïve B cells. We further conclude that B cells have the potential to play an important role as APC in the development of CIA.

Guidelines for the treatment of acidaemia with THAM.

THAM (trometamol; tris-hydroxymethyl aminomethane) is a biologically inert amino alcohol of low toxicity, which buffers carbon dioxide and acids in vitro and in vivo. At 37 degrees C, the pK (the pH at which the weak conjugate acid or base in the solution is 50% ionised) of THAM is 7.8, making it a more effective buffer than bicarbonate in the physiological range of blood pH. THAM is a proton acceptor with a stoichiometric equivalence of titrating 1 proton per molecule. In vivo, THAM supplements the buffering capacity of the blood bicarbonate system, accepting a proton, generating bicarbonate and decreasing the partial pressure of carbon dioxide in arterial blood (paCO2). It rapidly distributes through the extracellular space and slowly penetrates the intracellular space, except for erythrocytes and hepatocytes, and it is excreted by the kidney in its protonated form at a rate that slightly exceeds creatinine clearance. Unlike bicarbonate, which requires an open system for carbon dioxide elimination in order to exert its buffering effect, THAM is effective in a closed or semiclosed system, and maintains its buffering power in the presence of hypothermia. THAM rapidly restores pH and acid-base regulation in acidaemia caused by carbon dioxide retention or metabolic acid accumulation, which have the potential to impair organ function. Tissue irritation and venous thrombosis at the site of administration occurs with THAM base (pH 10.4) administered through a peripheral or umbilical vein: THAM acetate 0.3 mol/L (pH 8.6) is well tolerated, does not cause tissue or venous irritation and is the only formulation available in the US. In large doses, THAM may induce respiratory depression and hypoglycaemia, which will require ventilatory assistance and glucose administration. The initial loading dose of THAM acetate 0.3 mol/L in the treatment of acidaemia may be estimated as follows: THAM (ml of 0.3 mol/L solution) = lean body-weight (kg) x base deficit (mmol/L). The maximum daily dose is 15 mmol/kg for an adult (3.5L of a 0.3 mol/L solution in a 70kg patient). When disturbances result in severe hypercapnic or metabolic acidaemia, which overwhelms the capacity of normal pH homeostatic mechanisms (pH < or = 7.20), the use of THAM within a 'therapeutic window' is an effective therapy. It may restore the pH of the internal milieu, thus permitting the homeostatic mechanisms of acid-base regulation to assume their normal function. In the treatment of respiratory failure, THAM has been used in conjunction with hypothermia and controlled hypercapnia. Other indications are diabetic or renal acidosis, salicylate or barbiturate intoxication, and increased intracranial pressure associated with cerebral trauma. THAM is also used in cardioplegic solutions, during liver transplantation and for chemolysis of renal calculi. THAM administration must follow established guidelines, along with concurrent monitoring of acid-base status (blood gas analysis), ventilation, and plasma electrolytes and glucose.

Xylocain (lidocaine, lignocaine), its discovery and Gordh's contribution to its clinical use.

Hans v. Euler, while investigating how genes and enzymes were chemically related in some chlorofylldefective mutants of barley, isolated gramine, an indole. Erdtman synthetized isogramine and found it to have weak anesthetic properties. He then together with Löfgren synthetized other amino-amides, but no one of them could compete with the existing local anesthetics of the ester-type, derivatives of para-aminobenzoic acid, e.g. procaine. Later Löfgren and Lundqvist followed up these studies and found an amid compound lidocaine (2-dimethylaminoacet-2, 6-xylidide). Lidocaine represented such a significant advance over procaine in clinical tests preformed by T. Gordh that it was introduced for clinical use. It has now during a half century been the standard local anesthetic drug. All local anesthetics are neurotoxic in high enough doses. Xylocain, however, has had an excellent record of safety. Only during the last years have there been reports on possible toxic irritation and damage by Xylocain used for spinal anesthesia. The aetiology is still not clear In this connection two early observations by Gordh and his coworkers are discussed.

The clinical relevance of the interaction between carbamazepine and dextropropoxyphene in elderly patients in Gothenburg, Sweden.

OBJECTIVES: To evaluate the clinical importance of the interaction between carbamazepine (CBZ) and dextropropoxyphene in elderly patients. METHODS: All patients (n = 7263) in Gothenburg, Sweden, who were part of a drug-dispensing programme, were included in the study. Eight per cent of the patients took CBZ and 18% took dextropropoxyphene, continuously. Patients who used a combination of these drugs were compared with patients who took only CBZ or dextropropoxyphene or neither of the two drugs. These four groups of patients were matched to each other with reference to gender, age and concomitant medication, which finally resulted in 21 patients in each group. A questionnaire with 30 symptoms of well-being, including symptoms typical of adverse effects of CBZ, were answered by the patients with the help of a registered nurse. Venous blood samples were drawn from the patients for the analysis of CBZ, its metabolite CBZ 10,11-epoxide (CBZ-E) and dextropropoxyphene. RESULTS: The doses of CBZ and dextropropoxyphene were lower among patients who used the combination of the two drugs than among those who only used one of the drugs. The mean level of CBZ in serum (S-CBZ) was, however, significantly higher and the level of CBZ-E in serum (S-CBZ-E) significantly lower among the patients who used the combination of CBZ and dextropropoxyphene, thus indicating an inhibition of the metabolism of CBZ. The prevalence of symptoms indicating side effects of CBZ was significantly higher in the group of patients who used both drugs. CONCLUSION: This study has shown that the combination of CBZ and dextropropoxyphene is hazardous in elderly patients and should be used with caution.

Macrophages, but not dendritic cells, present collagen to T cells.

Dendritic cells, such as epidermal Langerhans cells, play a crucial role for the antigen-specific priming of T cells. We have addressed the question whether dendritic cells present collagen, a major protein component in tissues through which dendritic cells migrate, i.e. the basement membrane, dermis, and synovial tissue. Langerhans cells, spleen cells and peritoneal macrophages were compared for antigen-presenting capacity using a panel of mouse T cell hybridomas reactive with different determinants on type II collagen, myelin basic protein, ovalbumin and pepsin. Langerhans cells did not present any of the type II collagen determinants, unless the antigen was administered as a 15-mer peptide, but did present myelin basic protein, ovalbumin and pepsin. Spleen cells and peritoneal macrophages, in contrast, presented all type II collagen determinants. This biased antigen presentation was also observed when Langerhans cells were pulsed with antigen in vivo. The inability to present type II collagen is related to the collagen sequence as such, since both native type II collagen, type II collagen alpha chains, as well as a type II collagen determinant incorporated in type I collagen, were not presented by Langerhans cells. In addition, granulocyte/macrophage colony-stimulating factor-expanded blood dendritic cells displayed the same biased antigen presentation, suggesting that the inability to present collagen is not restricted to dendritic cells localized in epidermis. B cell-deficient mice could prime a type II collagen-reactive T cell response, thus excluding B cells as obligatory antigen-presenting cells for the priming of collagen-reactive T cells. We suggest that neither Langerhans cells nor B cells, but macrophages are the primary antigen-presenting cells in the immune response towards type II collagen.

Chronicity of arthritis induced with homologous type II collagen (CII) in rats is associated with anti-CII B-cell activation.

DA rats develop chronic arthritis after immunization with native rat type II collagen (CII) emulsified in incomplete Freund's adjuvant (IFA) (= collagen-induced arthritis, CIA). The same rat strain develops an acute, self-limited form of arthritis after injection with IFA alone (= oil-adjuvant-induced arthritis, OIA). The induction of a chronic course of arthritis, as well as an anti-CII antibody response, was dependent on the dose of CII; 30 micrograms induced a self-limited disease course and no B-cell response, while 150 micrograms induced a chronic disease course and a strong B-cell response. Immunization with denatured rat CII induced only acute arthritis, similar to OIA. To investigate why IFA or denatured CII/IFA induced only acute disease while native CII/IFA induced chronic disease, we analysed the immune responses to CII. Both native and denatured CII induced a weak but significant autoreactive T-cell response while only native CII induced a strong B-cell response to CII. IFA did not produce a significant immune response to CII. Interestingly, rats that had developed acute arthritis after immunization with denatured CII/IFA were vaccinated against CIA, but not rats that had developed arthritis induced with IFA only. Rats vaccinated against CIA after pretreatment with denatured CII/IFA had an anti-CII antibody response that was almost eliminated. In addition, pretreatment of rats with denatured or native rat CII in olive oil, which does not induce arthritis, vaccinated against a subsequent induction of arthritis with native rat CII. Again, the vaccination suppressed the anti-CII B-cell response. We suggest that activated B-cells, reactive with conformational epitopes on CII, are of importance for the chronic development of CIA.

Patient controlled analgesic therapy in the early postoperative period.

Fourteen patients with postoperative pain were allowed to self-administer preset doses of pethidine intravenously via a logic-controlled motor syringe. Plasma samples were collected during anaesthesia and the postoperative self-administration period, and the concentrations of pethidine and nor-pethidine were determined. Separate single-dose studies in eight patients yielded pharmacokinetic parameters which made possible computer simulations of continuous plasma concentration curves for the anaesthesia and postoperative self-administration period. The consumption of pethidine showed great interindividual variations with a mean consumption for the entire group of 26 mg per hour. The patients established steady-state plasma concentrations with far less than the maximum amount of pethidine allowed. The mean measured plasma concentration of pethidine which provided adequate analgesia was 738 +/- 149 ng/ml. Simulated and measured plasma concentrations were in close agreement. The individual mean drug consumption per hour during self-administration correlated closely with the individual elimination rate of pethidine. No serious side effects were observed. Thus, patient-controlled analgesic therapy offers an individualized analgesic supply to meet an analgesic demand which is governed by each patient's appreciation of pain.

The role of regional block versus parenteral analgesics in patient management with special emphasis on the treatment of postoperative pain.

Based upon a series of clinico-physiological investigations, the usefulness of regional anaesthetic techniques such as extradural, intercostal and splanchnic blocks are stressed. Main emphasis is put on the relief of postoperative pain after some common types of operations such as prostatectomies, total hip replacements and cholecystectomies. Compared with parenteral analgesics, regional anaesthetic techniques offer several advantages such as a more favourable situation of oxygen transport and a more effective treatment of pain without depressing the sensorium.