Stability and relative validity of the Multiple Sclerosis Impact Profile (MSIP).

OBJECTIVE: To examine the stability and relative validity of the Multiple Sclerosis Impact Profile (MSIP) in criterion-related groups. The MSIP is a disease-targeted health impact measure based on a selection of International Classification of Functioning, Disability and Health (ICF) aspects selected by 98 patients and medical and non-medical health professionals. METHOD: Data were obtained from a postal survey of 377 individuals with Multiple Sclerosis (MS) attending the MS centre of the University Medical Center Groningen (UH) and 153 subjects from the MS patients' association. Stability was tested with t-tests for paired samples and intraclass correlation coefficients for repeated measures in a sample of 251 individuals from the UH sample. The Relative Validity (RV) was estimated using the Short Form Questionnaire (SF-36), the World Health Organization Quality of Life-BREF (WHOQOL-BREF), the Disability and Impact Profile (DIP), the Impact on Autonomy Questionnaire (IPAQ) and the Groningen Activity Restriction Scale (GARS). RESULTS: These indicate that the MSIP is a stable measure in time. MSIP scales showed satisfactory and strong RV. In general, the domain-specific activities and participation measures (GARS and IPAQ) performed equally or slightly better than the comparable MSIP-scales, while the MSIP performed better than the multidimensional health impact measures (SF-36, DIP and WHOQOL-BREF). CONCLUSION: The MSIP demonstrated good stability and RV compared to generic health impact and domain-specific measures.

Host genetics of Bordetella pertussis infection in mice: significance of Toll-like receptor 4 in genetic susceptibility and pathobiology.

The susceptibility to and the severity of Bordetella pertussis infections in infants and children varies widely, suggesting that genetic differences between individuals influence the course of infection. We have previously identified three novel loci that influence the severity of whooping cough by using recombinant congenic strains of mice: Bordetella pertussis susceptibility loci 1, 2, and 3 (Bps1, -2, and -3). Because these loci could not account for all genetic differences between mice, we extended our search for additional susceptibility loci. We therefore screened 11 inbred strains of mice for susceptibility to a pertussis infection after intranasal infection. Susceptibility was defined by the number of bacteria in the lungs, being indicative of the effect between the clearance and replication of bacteria. The most resistant (A/J) and the most susceptible (C3H/HeJ) strains were selected for further genetic and phenotypic characterization. The link between bacterial clearance and chromosomal location was investigated with 300 F2 mice, generated by crossing A/J and C3H/HeJ mice. We found a link between the delayed clearance of bacteria from the lung and a large part of chromosome 4 in F2 mice with a maximum log of the odds score of 33.6 at 65.4 Mb, which is the location of Tlr4. C3H/HeJ mice carry a functional mutation in the intracellular domain of Tlr4. This locus accounted for all detectable genetic differences between these strains. Compared to A/J mice, C3H/HeJ mice showed a delayed clearance of bacteria from the lung, a higher relative lung weight, and increased body weight loss. Splenocytes from infected C3H/HeJ mice produced almost no interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) upon ex vivo restimulation with B. pertussis compared to A/J mice and also showed a delayed gamma interferon (IFN-gamma) production. TNF-alpha expression in the lungs 3 days after infection was increased fivefold compared to uninfected controls in A/J mice and was not affected in C3H/HeJ mice. In conclusion, Tlr4 is a major host factor explaining the differences in the course of infection between these inbred strains of mice. Functional Tlr4 is essential for an efficient IL-1-beta, TNF-alpha, and IFN-gamma response; efficient clearance of bacteria from the lung; and reduced lung pathology.

Suppression of antigraft immunity by preimmunization. V. Characterization of suppressor T memory cells.

We have previously shown that after intravenous (i.v.) immunization of mice with allogeneic spleen cells, two populations of suppressor T (Ts) cells may occur that can suppress delayed-type hypersensitivity (DTH) to alloantigens: Ts effector cells that transiently occur in the spleen, and long-lived, recirculating Ts cells that occur in thoracic duct lymph and can be transferred by parabiosis. In this study, we investigated whether the latter Ts cells fulfill the criteria for memory T lymphocytes, such as induction by doses of antigen lower than required for T effector cell induction, accelerated onset of activity after reactivation and an increased activity as compared with virgin T cells. The Ts cells accounting for the long-lasting state of suppression of DTH to alloantigens indeed fulfilled these criteria. These Ts memory cells displayed the Thy-1+, L3T4-, Lyt-1+2+ phenotype.

Defective support of S1/S1d splenic stroma for humoral regulation of stem cell proliferation.

Humoral regulation of CFUs proliferation was investigated in S1/S1d mice characterized by a stromal defect, which severely limits in situ proliferation of in vivo colony-forming cells (CFUs). Injection of LPS-W evoked a large enhancement of CFUs numbers in the spleen of normal +/+ mice. S1/S1d mice were found to be refractory to low doses of LPS-W (up to 15 micrograms/mouse) and to have a diminished response to high doses (up to 150 micrograms). Serum transfer experiments showed that S1/S1d mice are not defective in the early elaboration (6 h) of a humoral factor (SHSF), which mediates the LPS-induced splenic stem-cell accumulation. In a serum-free in vitro system post-LPS S1/S1d and +/+ sera induced a similar degree of CFUs proliferation, indicating the ability of S1/S1d mice to produce normal levels of stem-cell-activating factor (SAF). Transfer of potent post-LPS serum from normal mice evoked a poorer splenic CFUs accumulation in S1/S1d mice as compared to normal +/+ littermates. The population size of splenic stem cells in S1/S1d mice parabiosed with normal +/+ mice also showed a limited increase in response to LPS-W injection. This diminished in vivo response of S1/S1d mice was not due to a decreased sensitivity of their CFUs for SAF, since S1/S1d and +/+ CFUs showed similar survival rates in vitro in the presence of SAF. We propose that the defective response of S1/S1d mice to LPS-induced humoral regulators is due to a nonmigratory component of the S1/S1d splenic stroma, which limits splenic CFUs proliferation either by a short-range inhibitory activity or by a deficiency of a local stimulatory activity or nutrient unlike SAF or SHSF, which might act in synergy with SAF.

Suppression of antigraft immunity by preimmunization. IV. Persistence by long-lived recirculating suppressor T cells.

Delayed-type hypersensitivity (DTH) against histocompatibility (H) antigens in mice, which normally arises after s.c. immunization, can be prevented by i.v. preimmunization with irradiated spleen cells carrying the relevant H antigens. We have previously shown that during the first week after i.v. preimmunization the nonresponsiveness is due to suppressor T lymphocytes. The induced state of nonresponsiveness, however, is long-lasting. In this study we investigated whether this long-lasting state of nonresponsiveness of DTH is associated with suppressor T lymphocytes or is caused by inactivation of the relevant clones of alloreactive T cells. This was done by parabiosis of nonresponsive and naive mice and by transfer of thoracic duct lymphocytes from nonresponsive mice, harvested at various intervals after the i.v. immunization. At a long interval after the i.v. immunization, the state of nonresponsiveness could still be transferred to syngeneic naive mice by parabiosis, as well as by transfer of thoracic duct lymphocytes. Selective elimination of the T cells from the latter by treatment with anti-Thy-1.2 plus complement prevented the transfer of the state of nonresponsiveness, indicating that suppressor T cells were involved.

Properties of Ornithine Carbamoyltransferase from Pisum sativum L.

Some properties of ornithine carbamoyltransferase from chloroplasts isolated from leaves of Pisum sativum L. (cv Marzia) were compared with those of the enzyme partially purified (316-fold) from shoots of seedlings after 3 weeks of cultivation.Both preparations showed a pH optimum at pH 8.3 and had the same affinity to ornithine (K(m) = 1.2 millimolar) as well as to carbamoyl phosphate (K(m) = 0.2 millimolar). The approximate molecular weight determined by gel sieving was 77,600.A desalted ammonium sulfate precipitate from 14-day seedlings (inclusive roots and senescing cotyledons) was applied on a column of anion exchanger. The elution pattern showed one peak of ornithine carbamoyl-transferase activity. This elution pattern was the same as observed for the enzyme from chloroplasts.The results suggest the presence of one form of ornithine carbamoyl-transferase in pea seedlings.

The long-lasting state of specific nonresponsiveness induced by intravenous immunization with alloantigens is due to the generation of recirculating suppressor T cells.

We investigated whether the long-lasting state of nonresponsiveness that is induced by intravenous immunization with alloantigens is mediated by suppressor T cells, or is caused by inactivation or deletion of the relevant alloreactive T cell clones. The data from parabiosis and thoracic duct drainage experiments suggest that the state of nonresponsiveness depends on recirculating non-proliferating Ts memory cells.

Amino Acid leakage from cotyledons of developing and germinating pea seeds.

The leakage of amino acids from cotyledons of developing pea seeds into a bathing medium was relatively high at an early stage of development but low at later stages. Depending on the stage of development, the leakage was influenced differently by the sulfhydrylgroup modifier, PCMBS, and the metabolic uncoupler, CCCP. No prolonged leakage was measured from detached cotyledons and cotyledon discs after five days of germination. The composition of the amino acid fraction released by developing cotyledons differed from the amino acid pool of the cotyledons. Particularly alanine and also serine, glycine and γ-aminobutyric acid were released whereas glutamine and arginine showed a relatively low leakage. The amino acid fraction which normally enters the free space between the seedcoat and the embryo contained relatively large amounts of both alanine and glutamine. Results of the leakage experiments are discussed in relation to the sink-source transition of the storage parenchyma cells.

Arginine catabolism in the cotyledons of developing and germinating pea seeds.

Arginine is the predominant free amino acid in the cotyledons of developing seeds of Pisum sativum L. cv Marzia. Breakdown of arginine was measured by injecting l-[guanido-(14)C]arginine into detached cotyledons. Cotyledons of developing seeds showed a low rate of (14)CO(2) evolution whereas a much higher rate of (14)CO(2) evolution was measured from cotyledons of seeds 4 days after the onset of germination. The activities of the catabolic enzymes arginase, urease, and ornithine aminotransferase were measured throughout development and germination. Arginase and ornithine aminotransferase were present at an early stage of development. Urease activity appeared later as the seeds started to desiccate. During germination, all three enzymes were present. The different course of activity of these enzymes indicates that they are controlled separately.To explain the simultaneous presence of arginine and arginase without arginine degradation in the cotyledons of developing seeds, we propose a different intracellular localization of substrate and enzyme. In cotyledons of germinating pea seeds, urease has an enzymic function in arginine degradation.

Secondary delayed-type hypersensitivity to sheep red blood cells and minor histocompatibility antigens in mice: transfer of memory by recirculating thoracic duct lymphocytes.

Secondary delayed-type hypersensitivity (DTH) in mice to sheep red blood cells (SRBC) and minor histocompatibility (H) antigens is dependent on long-lived memory T cells. In this paper we investigated whether these memory T cells recirculate. It was shown that late phase "immune' thoracic duct lymphocytes (TDL) from mice which were immunized with SRBC or non-H-2-incompatible spleen cells several weeks previously could adoptively transfer secondary DTH to these antigens. Passing the immune TDL through intermediate recipients demonstrated that these SRBC- or minor H-antigen-reactive memory T cells recirculate from blood to lymph. In contrast to mice immunized with minor H antigens, no secondary type DTH reactivity could be demonstrated in mice immunized with H-2-incompatible spleen cells. Also, after adoptive transfer of TDL from mice immunized with H-2-alloantigens, it was impossible to demonstrate an accelerated DTH reactivity.

Activity of enzymes of arginine metabolism in the cotyledons of developing and germinating pea seeds.

Ornithine carbamoyltransferase, argininosuccinate synthetase, argininosuccinate lyase, and arginase activity were measured in extracts from cotyledons of developing and germinating seeds of Pisum sativum L. The course of activity of these four urea cycle enzymes showed a similar pattern during seed development. The activity per cotyledon increased sharply initially and reached a maximum about 5 weeks after anthesis, when the relative water content of the seeds was about 60%. About 8 weeks after anthesis, the seeds were mature (air-dry) and had enzyme activities which were much lower. The activities of the enzymes differed considerably. Ornithine carbamoyltransferase showed the highest activity, followed in order of decreasing activity by arginase, argininosuccinate lyase, and finally argininosuccinate synthetase.The course of the activity of the four enzymes was different during germination. Arginase activity increased sharply 7 hours after the onset of germination and remained at a constant level during the following days. Argininosuccinate synthetase activity decreased; the other enzymes showed a small increase in activity and a subsequent decrease. Results are discussed in relation to the regulation of the arginine metabolism during pea seed development and germination.

Carcinoma of the renal pelvis following the abuse of phenacetin-containing analgesic drugs.

Five cases of renal pelvic carcinoma are reported in female patients who abused phenacetin-containing analgesics. The mechanism of carcinogenesis in analgesic abuse is discussed and epidemiological factors are considered. The possibility of development of a renal pelvic tumour in patients with analgesic nephropathy is emphasised.