Feasibility of reaching world health organization targets for hepatitis C and the cost-effectiveness of alternative strategies.

New drugs for treating hepatitis C have considerably increased the probability of being cured. Treatment uptake, however, is still low. The objectives of this study were to analyse the impact of initiatives that may increase the proportion of infected people on treatment and interventions aimed at reducing the incidence of new infection among people who inject drugs. A compartmental model for Norway was used to simulate hepatitis C and related complications. We analysed 2 different screening initiatives aimed to increase the proportion of infected people on treatment. Interventions aiming at reducing the hepatitis C incidence analysed were opioid substitution therapy (OST), a clean needle and syringe programme and a combination of both. The most cost-effective strategy for increasing hepatitis C treatment uptake was screening by general practitioners while simultaneously allowing for all infected people to be treated. We estimated that this intervention reduces the incidence of hepatitis C by 2030 by 63% compared with the current incidence. The 2 harm reduction strategies both reduced the incidence of hepatitis C by about 70%. Combining an increase in the current clean needles and syringe programme with OST was clearly the most cost-effective option. This strategy would reduce the incidence of hepatitis C by 80% compared with the current incidence by 2030. Thus, interventions to reduce the burden and spread of hepatitis C are cost-effective. Reaching the WHO target of a 90% reduction in hepatitis C incidence by 2030 may be difficult without combining different initiatives.

Definition and estimation of an actual reproduction number describing past infectious disease transmission: application to HIV epidemics among homosexual men in Denmark, Norway and Sweden.

Prevalence and incidence measures are the common way to describe epidemics. The reproduction number supplies information on the potential for growth or decline of an epidemic. We define an actual reproduction number for infectious disease transmission that has taken place. An estimator is suggested, based on the number of new infections observed in a given time-interval, the number of those infected at the start of the interval, and the length of the infectious period. That estimator is applied to HIV among men having sex with other men over the period, 1977-1995, in Scandinavia. The actual reproduction number was estimated with acceptable certainty from the period, 1981-1982, yielding a value of 15 secondary cases. A value of less than one secondary case was assessed for the period, 1988-1995, in Denmark and Sweden. The actual reproduction number gives us some additional understanding of the dynamics of epidemics, compared with prevalence and incidence curves.

Back-calculation based on HIV and AIDS registers in Denmark, Norway and Sweden 1977-95 among homosexual men: estimation of absolute rates, incidence rates and prevalence of HIV.

BACKGROUND: The Scandinavian countries, Denmark, Norway and Sweden, have established both HIV and AIDS registers to monitor the HIV epidemic. Information in such registers can be used to estimate the number of new HIV infections over time, incidence rates and prevalence. Information from the HIV registers made it possible to study what kind of effects such information had in the estimation process, compared with using information about new AIDS cases only. METHODS: A Markov model back-calculation approach was used. One model incorporated data on cases of both HIV and AIDS. Another model incorporated data on cases of AIDS only. Death or emigration prior to the onset of AIDS and effects of treatment were included in both models. RESULTS: Estimates of absolute rates of HIV for men who have sex with men (MSM) showed a distinct development in each country. Significant differences in incidence rates and prevalence of HIV among MSM were found between Scandinavian countries when information on diagnosed HIV was incorporated. Precision was improved when using both HIV and AIDS diagnosed cases compared with using AIDS cases only. The epidemic in Denmark was more extensive than in the two other countries for the whole study period. DISCUSSION: The results were fairly robust against reasonable variation in the model parameters. The more extensive epidemic in Denmark may have been caused by the homosexual culture denying that HIV was a disease more relevant to them than to others, until the HIV test was publicly available in 1985.

Individuation, ego development and the quality of conflict negotiation in the family of adolescent girls.

Individuation, ego development and family negotiation of conflict were studied in 27 Norwegian families with an adolescent daughter, 16-19 years, drawn from a larger sample to represent a rectangular distribution of ego development. Individuality and Connectedness (individuation) as conceptualized and scored by Condon et al. (1984) was modified and adapted to a Norwegian material. Four factors were extracted, one related to individuality (self-assertion and separateness) and two to connectedness (clarification and acceptance). Ego development, measured by the Washington University Sentence Completion Test (Loevinger & Wessler, 1970) was related to connectedness between mother and daughter and between father and daughter, but not to individuality. Maturity of conflict negotiation was positively related to connectedness between mother and daughter and negatively to individuality between father and daughter. It was argued that for women, individuality may not be a singular goal in ego development or in individuation and that self-other differentiation of identity and interests may develop within a close relationship and not only through separation.

Different activation patterns in the plasma kallikrein-kinin and complement systems during coronary bypass surgery.

Components of the plasma kallikrein-kinin and complement systems were determined in patients undergoing open heart surgery with cardiopulmonary bypass. Spontaneous kallikrein activity (KK), plasma prekallikrein (PKK), functional kallikrein inhibition capacity (KKI), C3 activation products (C3-act), and the terminal complement complex (TCC) were measured. A marked, transitory increase in KK and a decrease in PKK were found prior to cardiopulmonary bypass just after heparin injection. An additional decline in PKK and KKI during bypass with a return to near control levels in the postoperative period was observed. C3-act increased in all patients during bypass, reaching a peak value at wound closure. The TCC concentration also increased significantly during cardiopulmonary bypass, returned to control levels in the early postoperative period, and then increased again in the late postoperative period. It is concluded that activation of the kallikrein-kinin system started after injection of heparin, prior to cardiopulmonary bypass. Activation of both the initial and the terminal complement cascade, however, started only after onset of cardiopulmonary bypass.

Cytotoxicity and effects of T2-toxin on plasma proteins involved in coagulation, fibrinolysis and kallikrein-kinin system.

The activity of both the coagulation and fibrinolytic systems was markedly depressed 24 h after a sublethal dose of T-2 toxin. T-2 toxin was active as an anticoagulant at low doses, which did not affect the basal state of the animals. The kallikrein-kinin system was also affected by depletion of the prekallikrein, which indicates increased bradykinin levels in plasma. At the same time there was an increased activity of some clinically relevant enzymes in serum, indicating tissue injuries caused by T-2 toxin. All effects observed in this study reached their maximum within 24 h after administration, which corresponds to the time animals usually die when receiving a lethal dose. T-2 toxin does not, however, seem to affect the protease enzymes by reduced protein synthesis, because of early onset of the effects, nor does it act as a trigger itself. The effect of T-2 toxin on plasma protease enzymes is probably secondary to cytotoxic effects in the vascular endothelium.

Uncontrolled plasma proteolysis: a major threat to the septicemic patient.

In order to further elucidate the pathophysiological significance of plasma proteolysis during septicemia, surgical patients with septicemia were studied by means of chromogenic peptide substrate assays. In fatal cases continuous low values for prekallikrein, plasminogen and antithrombin III were found until death. At autopsy a persistent septic focus was found in all but one of the fatal cases. Very low levels of prekallikrein during sepsis and reduced functional inhibition of plasma kallikrein in septic shock indicated a poor prognosis. In the survivors the parameters returned towards the normal range upon successful therapy. Furthermore the paper demonstrates the application of a new parameter, the proenzyme functional inhibition index (PFI-index) in patients with septicemia. The data reveal that by means of this parameter patients at high risk can be identified at an early stage of the disease.

Side effects of cyclosporin A treatment in patients with rheumatoid arthritis.

Cyclosporin A (CyA) and azathioprine (Aza) were compared with respect to renal side effects in an open controlled, randomized study of patients with rheumatoid arthritis. Twelve patients were treated with CyA (mean dose 7.8 +/- 1.2 mg/kg/day) and 12 with azathioprine for 26 weeks. All patients also received prednisolone 5 mg/day. The patients had normal serum creatinine (less than 120 mumoles/liter) and protein-free urine before the trial. CyA increased serum creatinine in nine out of the 11 patients followed for 26 weeks, the mean increase was approximately 50%. Creatinine clearance was reduced by 31%. Mean arterial pressure (MAP) and serum potassium were significantly increased by CyA. Urinary beta 2-microglobulin excretion was significantly increased by CyA, in five of the patients more than ten times. Urinary kallikrein excretion was reduced by more than 50% and urinary albumin excretion was doubled. All these parameters remained normal and unchanged in the azathioprine group. CyA was withdrawn in seven patients after 26 weeks. Urinary beta 2-microglobulin was still increased by 85% nine months after CyA treatment. The other parameters were gradually normalized after three to nine months except for one patient who developed renal failure. Urinary beta 2-microglobulin excretion was a very sensitive parameter for renal tubular damage in this study.

Studies on pathological plasma proteolysis in patients with septicemia.

Plasma proteolysis was studied in surgical patients with septicemia by means of chromogenic peptide substrate assays. Using these methods both levels of proenzyme, functional inhibition capacity and enzyme activities indicating alpha 2-macroglobulin protease complexes were determined. In fatal cases continuous low values for prekallikrein, plasminogen and antithrombin III were found until death. At autopsy a persistent septic focus was found in all but one of the fatal cases. Very low levels of prekallikrein during sepsis and reduced functional inhibition of plasma kallikrein in septic shock indicated a poor prognosis. In the survivors the parameters returned towards the normal range upon successful therapy. Furthermore, the paper demonstrates the application of a new parameter, the Proenzymes functional inhibition index (PFI-index) in patients with septicemia. The data reveal that by means of this parameter, patients at high risks can be identified at an earlier stage of the disease than previously done.

Plasma kallikrein-kinin system in septicemia.

Plasma prekallikrein and functional kallikrein inhibition were studied in 18 surgical patients with complicating septicemia using chromogenic peptide substrate assays. Nine patients died and nine survived. In all 18 patients plasma prekallikrein values were reduced markedly when septicemia was diagnosed. During treatment gradually increasing values were found in the survivors, whereas values remained low in the fatal cases. Significantly reduced functional plasma kallikrein inhibition was associated with the development of fatal septic shock. The findings show that determination of these components of the plasma kallikrein-kinin system gives valuable information of prognostic value in patients with septicemia. Furthermore, the chromogenic peptide substrate assays used are fast and easy to perform and therefore suitable for intensive care medicine.

The functional inhibition of plasma kallikrein. A critical factor in septic shock.

Functional kallikrein inhibition and prekallikrein levels have been studied during septic shock and septicemia in 13 patients using chromogenic peptide substrate assays. Eleven septic shock episodes were studied of which 5 were fatal. Marked reductions in functional kallikrein inhibition and prekallikrein values occurred during fatal septic shock. In patients who could be resuscitated from septic shock, functional kallikrein inhibition was in the normal range, but significantly lower than in patients with septicemia only. Also in these two groups of patients decreased prekallikrein values were found. During treatment a gradual increase in prekallikrein was observed in the survivors and functional kallikrein inhibition values remained in the normal range during the whole course. Our results indicate that the functional inhibition of plasma kallikrein plays a major role in determining the outcome of septic shock.

Degradation of amyloid proteins with protease I from Aspergillus oryzae. In vivo increase in SAA clearance rate after enzyme infusion.

The effect of the thrombolytic enzyme protease I from Aspergillus oryzae (brinase) on the amyloid protein AA was investigated. The effect of the enzyme on purified, low molecular weight protein AA was very high. Protein AA in intact amyloid fibrils suspended in neutral buffer was also degraded by the enzyme, although at a much lower rate. Amyloid fibrils in tissue sections could also be attacked and removed, leaving the tissue structure fairly intact. The in vivo effect of brinase on protein SAA was demonstrated in rabbits by an increase in the clearance rate of SAA after enzyme infusion.

Experimental post-traumatic lung insufficiency in dogs: ultrastructure of lung lesions.

The ultrastructure of developing lung lesions in two groups of dogs exposed to a combination of haemorrhagic hypotension and liver trauma was studied with particular attention to changes at the alveolar level and lung micro-vessels. Lung samples were obtained every four hours and at collapse in one group and 12 hrs after initiation of the trauma in the other. An interstitial oedema was recognized in biopsies obtained 4 hrs after initiation of the trauma, and before marked lesions were observed at the ultrastructural level in endothelial cells. Endothelial damage was, however, evident in biopsies obtained at 8 hrs and at collapse. Aggregates of degranulated and degenerated leucocytes and platelets were occasionally found to obstruct respiratory capillaries together with erythrocytes, some of which seemed to be haemolysing. A considerable amount of protein-rich oedema, cellular debris and fibrinoid material was found in alveolar lumina at collapse. The present experiments indicate that increased vascular permeability in lung micro-vessels is of importance for the development of the characteristic lesions seen in shock lung. Possible pathogenetic mechanisms, initiating the lung lesions, are discussed with special emphasis on the significance of kinin activation and the presence of polymorphonuclear leucocytes and microthrombi.

Treatment of sepsis in the surgical patient evaluated by means of chromogenic peptide substrate assays.

In the present study treatment of sepsis in 18 surgical patients, 9 survivors and 9 fatal cases, were evaluated by determining components of the plasma proteolytic enzyme systems using chromogenic peptide substrate assays. During persistent sepsis, continuous low values for prekallikrein, plasminogen and antithrombin III were found until death. At autopsy a septic focus was found in all but one of the fatal cases. Very low levels of prekallikrein during sepsis and reduced functional inhibition of plasma kallikrein in septic shock indicated a poor prognosis. In the survivors all parameters returned towards normal range upon successful therapy. Plasminogen and antithrombin III were most rapidly normalized. It is concluded that determination of components of the plasma protease systems using chromogenic peptide substrate assays, gives valuable information about course and prognosis in surgical sepsis, and that they are suitable for practical clinical use.

Studies of components of the coagulation systems in normal individuals and septic shock patients.

Components of the coagulation system were determined in plasma samples from normal individuals and septic shock patients. The parameters measured included Hageman factor (HF), prekallikrein (PKK), high molecular weight kininogen (HMwK), antithrombin III (AT III), fibrinogen (Fg) and fibrin(ogen) degradation products (FDP's). The combined effects of factors II, VII & X were estimated using Normotest (NT). Plasma levels of HF, PKK, and HMwK and both immunochemical levels and functional activities of AT III were significantly lower in the septic shock patients. NT values were also significantly reduced. Fibrinogen levels varied from very low to very high indicating both Fg consumption and acute-phase synthesis. Elevated FDP levels were seen during septic shock, but no difference between survivors and fatal cases was found. Prekallikrein levels and functional AT III activities were significantly higher in the samples from patients who recovered following septic shock than in the samples from subjects who died. During treatment all the parameters gradually returned toward normal in the survivors, whereas continuous low values for HF, AT III, PKK, and NT were observed in the fatal cases.

Aspects of plasma proteolysis in lethal canine endotoxin shock.

Endotoxin shock was induced in dogs by infusing 6 mg/kg body weight E-coli endotoxin intravenously over a three hours period. Circulatory collapse and death occurred within 7 1/2 to 15 hours. The involvement of plasma proteases in this lethal canine endotoxin shock model was studied using chromogenic peptide substrate assays. Also other techniques including immunochemical methods, clotting assays and hemolytic assay were used. The present paper summarizes our findings.