Agreement between health utility instruments in cochlear implantation.

OBJECTIVES: The objectives of our study were threefold: to compare health utility scores measured with different health utility instruments in adult patients with bilateral deafness, to compare the change in health utility scores after unilateral or bilateral cochlear implantation using the different health utility instruments and to assess which health utility instrument would be the most appropriate for future studies on cochlear implantation. DESIGN: A prospective study. SETTING: The data for this article were collected as part of a multicentre randomised controlled trial in the Netherlands on the benefits of simultaneous bilateral cochlear implantation compared to unilateral cochlear implantation. PARTICIPANTS: The study included 38 adult patients with severe to profound bilateral post-lingual sensorineural hearing loss. MAIN OUTCOME MEASURES: Participants completed various quality of life questionnaires (the EuroQol five-dimensional questionnaire (EQ-5D), the Health Utilities Index mark 3 (HUI3), a visual analogue scale (VAS) for general quality of life and a VAS for hearing) preoperatively, and one and two years postoperatively. The general health utility instruments (EQ-5D, HUI3 and VAS general) were compared. RESULTS: The EQ-5D, HUI3 and VAS general utility scores differed significantly. The intraclass correlation coefficients showed poor to no agreement between these instruments. A gain in health utility after cochlear implantation was found with the HUI3 and VAS general. The highest gain in health utility was found with the HUI3. CONCLUSIONS: A health utility score depends on the health utility instrument that is used in a specific patient population. We recommend using the HUI3 in future studies on cochlear implantation.

The vault complex.

Vaults are large ribonucleoprotein particles found in eukaryotic cells. They are composed of multiple copies of a Mr 100,000 major vault protein and two minor vault proteins of Mr 193,000 and 240,000, as well as small untranslated RNAs of 86-141 bases. The vault components are arranged into a highly characteristic hollow barrel-like structure of 35 x 65 nm in size. Vaults are predominantly localized in the cytoplasm where they may associate with cytoskeletal elements. A small fraction of vaults are found to be associated with the nucleus. As of yet, the precise cellular function of the vault complex is unknown. However, their distinct morphology and intracellular distribution suggest a role in intracellular transport processes. Here we review the current knowledge on the vault complex, its structure, components and possible functions.

Multiple human vault RNAs. Expression and association with the vault complex.

Human vaults are intracellular ribonucleoprotein particles believed to be involved in multidrug resistance. The complex consists of a major vault protein (MVP), two minor vault proteins (VPARP and TEP1), and several small untranslated RNA molecules. Three human vault RNA genes (HVG1-3) have been described, and a fourth was found in a homology search (HVG4). In the literature only the association of hvg1 with vaults was shown in vivo. However, in a yeast three-hybrid screen the association of hvg1, hvg2, and hvg4 with TEP1 was demonstrated. In this study we investigated the expression and vault association of different vault RNAs in a variety of cell lines, including pairs of drug-sensitive and drug-resistant cells. HVG1-3 are expressed in all cell lines examined, however, none of the cell lines expressed HVG4. This probably is a consequence of the absence of essential external polymerase III promoter elements. The bulk of the vault RNA associated with vaults was hvg1. Interestingly, an increased amount of hvg3 was bound to vaults isolated from multidrug-resistant cell lines. Our findings suggest that vaults bind the RNA molecules with different affinities in different situations. The ratio in which the vault RNAs are associated with vaults might be of functional importance.

Health and endogenous growth.

The focus of endogenous growth theory on human capital formation and the physical embodiment of knowledge in people, suggests the integration of the growth supporting character of health production and the growth generating services of human capital accumulation in an endogenous growth framework. We show that a slow down in growth may be explained by a preference for health that is positively influenced by a growing income per head, or by an ageing population. Growth may virtually disappear for countries with high rates of decay of health, low productivity of the health-sector, or high rates of discount.

Self-motion in glass-forming polymers: a molecular dynamics study.

We present results of molecular dynamics simulations of an undercooled polymer melt, performed to study the validity of mode-coupling theory (MCT) for realistic polymer melts in general. The mean square displacements of the chain segments are computed to study the diffusion constant of the Rouse-like motion. It is shown that this diffusion constant follows a power law behavior as a function of the temperature, as predicted by the MCT. In addition, we studied the incoherent part of the intermediate scattering function and show that these functions obey the second scaling law of the MCT. We also calculated the relaxation times of the alpha-relaxation and found that they follow the same power law (gamma=2.9) as the diffusion constant. Using gamma, and the relationships given by MCT, we obtain values for a (0.27) and b (0.46) and use these exponents to describe the beta-relaxation regime. We find that the long time part of the beta-relaxation can be described accurately by the Von Schweidler relaxation over a wide range of wave numbers. In the short time regime of the beta-relaxation, no critical decay is observed.

Patient flows and optimal health-care resource allocation at the macro-level: a dynamic linear programming approach.

In this paper we present a deterministic allocation model in which a patient's health-state changes due to health-care interventions. This change in a patient's health-state has a direct effect on the patient's expected future need for health-care. Hence, current allocation decisions determine to some extent the set of possible allocation decisions in the future. In order to take this into account we have formulated a dynamic linear programming version of a patient-flow system. This enables us to describe the effects of using different objective functions on the optimum level and composition of the provision of health services within given resource constraints. The linear programming approach enables the quantification of the health effects and therefore the desirability of the (re-)allocation of health-care resources. We provide some simulation results in order to illustrate the working of the model.

Cerebral lesions in mice infected with Plasmodium berghei are the result of an immunopathological reaction.

Cerebral lesions in mice with Plasmodium berghei infections can be prevented by timely treatment with immune serum, by splenectomy, and by administration of dexamethasone. T cell deficient mice do not develop cerebral lesions. The results of these studies are compatible with the hypothesis that a pathological reaction is responsible for development of cerebral lesions in mice infected with P. berghei.

Immunological aspects of cerebral lesions in murine malaria.

The majority of male C57Bl/Rij mice died infected with Plasmodium berghei early in the second week. Death was closely correlated to collapse of the thermoregulation of the body, with perivascular oedema and petechial haemorrhages in the brain. Mice that did not show a collapse of thermoregulation (temperature drop below 30 degrees C) and survived for more than 2 weeks after infection did not show haemorrhages. Development of this syndrome (temperature below 30 degrees C; early death; haemorrhages) during infection depended on the presence of the spleen and was prevented by irradiation of the spleen or a timely treatment with dexamethasone, anti-T-cell serum or immune serum.

Selective depletion of immunoglobulin isotypes after decomplementation of mouse sera by heat treatment.

Inactivation of mouse serum by heat treatment (30 min at 56 degrees C) decreased antibody reactivity as shown by haemagglutination assays. This appeared to be due to loss of antibody since Ouchterlony analysis showed disappearance of antibody after heat treatment. By both isotype-specific ELISA and Ouchterlony analysis it was shown that mouse IgM, IgG2b and IgG3 are sensitive to heat treatment whereas IgG2a is relatively resistant. IgG1 is not sensitive to heat treatment. To avoid complement-dependent lysis in haemagglutination assays EDTA should be added to the serum samples.

Stage-specific proteins of Plasmodium berghei-infected red blood cells detected by antibodies of immune mouse serum.

The asynchronously developing malaria parasite Plasmodium berghei was synchronized using in vitro cultivation techniques (Mons et al. 1985). After the infection of naive mice, preparations of parasitized erythrocytes with a high level of synchronism could be obtained. Immunofluorescence and immunoblotting techniques using serum from immunized mice were applied to determine stage-specific immunogenic molecules in the parasitized erythrocyte preparations. These techniques allowed the detection of not only parasite-derived but also altered-self molecules. Membrane fluorescence of infected erythrocytes was detected only in preparations containing late trophozoites and schizonts. The appearance of this fluorescence pattern coincided with the presence of immunogenic polypeptides of mol. wt. greater than 200 kD, 86 kD, and 56 kD especially, among some other polypeptides. Preliminary experiments using lactoperoxidase-catalyzed radioiodination suggested that the greater than 200 kD and 56 kD molecules were present at the erythrocyte surface. One molecule with mol. wt. 153 kD was associated with the presence of ring-infected erythrocytes. However, membrane fluorescence of ring-stage-infected erythrocytes was not found. Noninfected erythrocytes sometimes showed membrane fluorescence.

Plasmodium berghei: relative immunogenicity of infected reticulocytes and infected oxyphilic red blood cells.

Hyperbleeding of mice 1 day before and 1 day after infection with Plasmodium berghei resulted in a more aggravated infection. Parasitemia rose significantly faster, but the mean survival time of these mice was not significantly different from control mice. At Day 5 of infection, parasites were almost exclusively in reticulocytes in contrast to control infections in which parasites were found in oxyphilic erythrocytes at Day 5 after infection. Purified parasitized reticulocytes taken from hyperbled mice at Day 5 after infection contained more young developmental parasite stages than purified parasitized oxyphilic erythrocytes taken from normal mice at Day 5 to 7 after infection. Parasitized reticulocytes were more readily opsonized by antibodies from immune serum when compared to parasitized oxyphilic red blood cells and when used to stimulate immune spleen cells the former were better stimulator cells than the latter. Results suggest either that parasitized reticulocytes are more immunogenic then parasitized oxyphilic red blood cells or that suspensions of parasitized reticulocytes contain more immunogenic parasite stages than suspensions of parasitized oxyphilic red blood cells.

Plasmodium berghei: reduction of the mouse's specific lymphoproliferative response in relation to corticosterone and pregnancy.

Spleen cells from mice immune to Plasmodium berghei exhibited a significantly increased in vitro proliferative response to parasitized reticulocytes compared to spleen cells from normal mice. The specific response to malaria antigen was decreased in spleen cells from pregnant immune mice in contrast to the nonspecific response to the mitogen phytohemagglutinin. Addition of mouse serum to spleen cell cultures of immune mice depressed both the phytohemagglutinin and the specific proliferative response, whereas serum of pregnant mice exerted an even stronger inhibition than serum of nonpregnant mice. Charcoal adsorption of mouse sera for the elimination of steroid hormones removed the serum dependent immunosuppression from normal as well as pregnant serum. Corticosterone added to the spleen cell cultures depressed also the proliferative response. These findings demonstrate that the response to malaria antigen is decreased in immune mice during pregnancy. The possible effect of serum corticosterone on the depression of the immune response is discussed.

Pregnancy-induced recrudescences strengthen malarial immunity in mice infected with Plasmodium berghei.

A considerable proportion of mice lose acquired immunity to Plasmodium berghei during the first pregnancy. Immune parous mice, however, have a better immune status than virgin mice, the risk of loss of immunity during a subsequent pregnancy is greatly reduced, the capacity to clear parasites is enhanced, and the maintenance of immunity is less dependent on certain splenic functions. The establishment of improved immunity is dependent on the presence of proliferating parasites during the second half of pregnancy when immunosuppression results in recrudescence. Immune reactivity is also improved after a (chemotherapeutically controlled) recrudescent infection provoked by immunosuppressive treatment of immune mice with corticoids or anti-T cell serum. This mimics the situation encountered during pregnancy. Hence, improved immunity after pregnancy is a consequence of a reconfrontation of a suppressed and/or convalescent immune system with proliferating parasites.

Interactions of Plasmodium berghei-infected erythrocytes with complement.

Incubation of radioactively labeled parasitized (Plasmodium berghei) erythrocytes (PE) with adherent peritoneal exudate cells in the presence of 10% (v/v) fresh mouse serum (NMS) resulted in the uptake of a proportion of radioactive material (PE). Inactivation of the added serum by heat or zymosan treatment resulted in diminished uptake of radioactivity. These results suggest that PE activated complement. Incubation of fresh NMS with PE reduced the hemolytic complement level of the serum as shown by its subsequent decreased ability to lyse antibody-coated rabbit red blood cells. No such effect was found when uninfected erythrocytes from either infected or uninfected blood were preincubated with fresh NMS. Thus, PE or PE-derived material activated complement. Addition of EGTA during incubation of fresh NMS with PE did not inhibit the decrease in complement level. This indicated that complement was activated by the alternative pathway. Complement levels decreased even when fresh NMS and PE were incubated in the presence of EDTA (which inhibits both classical and alternative pathway activation), suggesting that a complement activating factor (or a complement inhibitor) was released from the PE. However, lysis of PE after incubation with either fresh rabbit or guinea pig serum did not occur unless anti-mouse erythrocyte antibody was added. The production of a complement-activating factor by PE might explain part of the decreasing complement levels during infection and might enable the parasite to escape from a complement-mediated defense mechanism of the host.

ACTH-dependent modulation of malaria immunity in mice.

Tetracosactrin, a synthetic adrenocorticotrophic hormone (ACTH) analogue delivered by osmotic minipumps implanted s.c. in mice induced a dose-dependent increase of plasma corticosterone levels. In mice with an established immunity to Plasmodium berghei the increase of the plasma corticosterone level due to tetracosactrin treatment correlated with loss of immunity against this malaria parasite. The observed plasma corticosterone levels associated with loss of malaria immunity were of the same order as those in mice that lost their immunity during pregnancy. Adrenalectomy before administration of the ACTH analogue prevented both the increase of plasma corticosterone and loss of malaria immunity. Adrenalectomized mice still lost their malaria immunity when treated with the synthetic corticoid dexamethasone. The effector function of malaria immunity is sensitive to corticoids, and, at least during pregnancy, the naturally occurring serum corticosterone level appears to be an important regulator of malaria immunity.

Malarial immunity in pregnant mice, in relation to total and unbound plasma corticosterone.

A pregnancy dependent loss of malarial immunity is accompanied by an (excessive) increase of total as well as free plasma corticosterone. This loss of immunity was largely prevented by adrenalectomy. Moreover, malarial immunity was more sensitive to dexamethasone immunosuppression during pregnancy. Primary infections are more virulent during pregnancy and like in recrudescent mice, cause excessive total and free plasma corticosterone levels. Corticosterone may be considered an immuno-regulatory serum factor during pregnancy, the endocrine regulation of which is disturbed in pregnant, infected mice.

Corticosterone regulation of the effector function of malarial immunity during pregnancy.

In the experimental Plasmodium berghei mouse model, as in human malaria, reduced maternal responsiveness and even loss of immunity were observed during pregnancy. Loss of immunity in the second half of pregnancy occurred during a period of elevated plasma corticoid levels. Further analysis showed that plasma corticoid levels were significantly higher in immunodepressed mice than in mice that remained immune throughout pregnancy. Plasma corticosterone levels differed increasingly from those in mice with persistent immunity towards recrudescence. In nonimmune infected controls, however, only a slight increase in plasma corticosterone, already present during the subpatent period, was measured. Blocking the maternal corticoid production by adrenalectomy delayed the increase of plasma corticosterone (fetoplacental origin) and reduced the number of mice that lost immunity during pregnancy considerably. The role of various plasma corticoid levels in the regulation of effector function of immunity during pregnancy is discussed.

Carotenoids function in photoperiodic induction of diapause in a predacious mite.

Predacious mites fed for two generations solely on the eggs of wild-type spider mites responded normally to short day lengths by entering diapause. However, predacious mites fedfor two generations on eggs of albino spider mites, which are completely devoid of carotenoids, did not respond to short-day photoperiods. Apparently carotenoids are essential for photoperiodic induction; possibly a carotenoid or carotenoid derivative functions as the photopigment concerned in photoperiodic light reception in these mites.

Pregnancy associated recrudescence in murine malaria (Plasmodium berghei).

Depending on the strain, a variable proportion of mice solidly immune to the rodent malaria parasite Plasmodium berghei developed a recrudescence during pregnancy that was either transient or lethal. Recrudescence was not observed in all mice, and the rate was lower in gravida II as compared to gravida I mice. On the other hand a proportion of the mice that did not develop recrudescence exhibited a pregnancy associated clearance of persisting parasites in immune mice (premunition-sterile immunity), being more pronounced in gravida II than gravida I mice. Development of the mechanism of enhanced clearance is apparently parasite dependent. Enhanced clearance was manifest until day 4 of pregnancy. Pregnancy associated immunodepression was observed most strongly between day 4 and 16 of pregnancy, when the highest rates of recrudescence and associated mortality were found. Immunodepression apparently disappears at the end of pregnancy or shortly after parturition.

Depressed malarial immunity in pregnant mice.

A proportion of mice solidly immune to the rodent malaria parasite Plasmodium berghei exhibited a pregnancy-associated depressed immunity with a transient or even lethal recrudescence.