Interleukin-6 concentrations in the urine and dipstick analyses were related to bacteriuria but not symptoms in the elderly: a cross sectional study of 421 nursing home residents.

BACKGROUND: Up to half the residents of nursing homes for the elderly have asymptomatic bacteriuria (ABU), which should not be treated with antibiotics. A complementary test to discriminate between symptomatic urinary tract infections (UTI) and ABU is needed, as diagnostic uncertainty is likely to generate significant antibiotic overtreatment. Previous studies indicate that Interleukin-6 (IL-6) in the urine might be suitable as such a test. The aim of this study was to investigate the association between laboratory findings of bacteriuria, IL-6 in the urine, dipstick urinalysis and newly onset symptoms among residents of nursing homes. METHODS: In this cross sectional study, voided urine specimens for culture, urine dipstick and IL-6 analyses were collected from all residents capable of providing a voided urine sample, regardless of the presence of symptoms. Urine specimens and symptom forms were provided from 421 residents of 22 nursing homes. The following new or increased nonspecific symptoms occurring during the previous month were registered; fatigue, restlessness, confusion, aggressiveness, loss of appetite, frequent falls and not being herself/himself, as well as symptoms from the urinary tract; dysuria, urinary urgency and frequency. RESULTS: Recent onset of nonspecific symptoms was common among elderly residents of nursing homes (85/421). Urine cultures were positive in 32% (135/421), Escherichia coli was by far the most common bacterial finding. Residents without nonspecific symptoms had positive urine cultures as often as those with nonspecific symptoms with a duration of up to one month. Residents with positive urine cultures had higher concentrations of IL-6 in the urine (p < 0.001). However, among residents with positive urine cultures there were no differences in IL-6 concentrations or dipstick findings between those with or without nonspecific symptoms. CONCLUSIONS: Nonspecific symptoms among elderly residents of nursing homes are unlikely to be caused by bacteria in the urine. This study could not establish any clinical value of using dipstick urinalysis or IL-6 in the urine to verify if bacteriuria was linked to nonspecific symptoms.

Genetic variation in the transforming growth factor-beta1 gene is associated with susceptibility to IgA nephropathy.

BACKGROUND: There is growing evidence of genetic risk for susceptibility to IgA nephropathy. Among several candidate genes related to immunological regulation in renal tissue, TGFB1 is known to be a contributor to proliferation and the development of fibrosis. METHODS: We analysed several SNPs in a region of this gene using 212 DNA samples from biopsy-proven IgA nephropathy patients, 146 men and 66 women and 477 healthy age-matched controls (321 men and 156 women) from the same population in Sweden. RESULTS: Frequencies of four out of five selected SNPs (rs6957, rs2241715, rs1800471, rs1982073 and rs1800469) were found to significantly differ between male patients and male controls in a co-dominant model (corrected P

Long-term treatment results and the immunoglobulin G subclass distribution patterns of proteinase-3-antineutrophil cytoplasm antibody (ANCA) and myeloperoxidase-ANCA in ANCA-associated vasculitis.

OBJECTIVE: Small vessel vasculitis associated with antibodies to neutrophil cytoplasm antigens has been denominated antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). MATERIAL AND METHODS: Ninety-eight patients with various forms of AAV with renal involvement were studied retrospectively with regard to treatment, side-effects and outcome. The immunoglobulin G (IgG) subclass distribution patterns in serum were determined in 51 patients with nephelometry and those of anti-proteinase-3 (PR3) and anti-myeloperoxidase (MPO) in 44 patients by enzyme-linked immunosorbent assay. RESULTS: Fifty-nine patients with a mean age of 63 years were given treatment with intermittent intravenous regimens of cyclophosphamide and continuous corticosteroids, whereas 39 patients with a mean age of 58 years were given continuous oral treatment. Malignancy, mainly due to skin tumours, was more common in AAV than in the general population. The total IgG subclass distribution pattern was asymmetric. The response to PR3 was of IgG(1), IgG(3) and IgG(4) isotypes, while IgG(1) and IgG(3) predominated in the response to MPO. CONCLUSION: The aberrant IgG subclass distribution pattern detected in the autoantibodies may be of importance in the pathogenesis of AAV.

Interferon-gamma dose-dependently inhibits prostaglandin E2-mediated dendritic-cell-migration towards secondary lymphoid organ chemokines.

Monocyte-derived human dendritic cells (MoDCs) are increasingly applied as cellular vaccines for cancer patients. Important features for their efficacy include high migratory responsiveness to lymph node-chemokines and most likely their ability to produce bioactive IL-12 p70 upon subsequent contact with CD40 ligand-expressing T-cells. The current standard DC-maturation cocktail for clinical trials is inflammatory cytokines (TNF-alpha, IL-1beta and IL-6) combined with prostaglandin E(2) (PGE(2)), inducing phenotypically mature MoDCs with high migratory responsiveness to CCR7 ligands. This cocktail does not, however, induce or prime for production of IL-12 p70. Addition of IFN-gamma to PGE(2)-containing maturation cocktails has been shown to prime for substantial production of IL-12 p70 by subsequent CD40 ligation, but the impact of IFN-gamma on phenotypic maturation and migratory responsiveness induced by PGE(2)-containing inflammatory stimuli still remains elusive. Here, we demonstrate that addition of IFN-gamma to the standard maturation cocktail decreased CCR7 mRNA and down-regulated CCR7 expression on MoDCs in a dose-dependent manner. Moreover, addition of IFN-gamma was found to suppress MoDC-migration towards the CCR7-ligands CCL19 and CCL21. These novel findings indicate that addition of IFN-gamma to DC-maturation stimuli may have no beneficial impact on MoDC-vaccine efficiency and further implicate IFN-gamma as a negative feedback factor in DC migration towards draining lymph nodes when full-blown Th1-type responses are established. Such mechanism may restrict an uncontrolled and potentially harmful amplification of the adaptive Th1 response.

Avidity of tetanus and Hib antibodies after childhood acute lymphoblastic leukaemia - implications for vaccination strategies.

AIM: To investigate the possible relationship between serum levels and avidities of antibodies against tetanus toxoid (TT) and Haemophilus influenzae type b (Hib) in children that were vaccinated after treatment for childhood acute lymphoblastic leukaemia (ALL). METHODS: The study groups were 31 paediatric patients with ALL and 18 healthy controls. All subjects were vaccinated with TT and a protein conjugated Hib vaccine. Antibody levels were analysed at three time points: At diagnosis of ALL, after cessation of treatment before vaccination and three weeks after vaccination. Avidity was measured twice, with a thiocyanate elution assay, at diagnosis of ALL and three weeks after vaccination. RESULTS: There was a correlation between level and avidity of tetanus antibodies after vaccination (r(s) = 0.59, P < 0.001). In the standard-risk and intermediate-risk ALL groups, all patients responded with protective levels of tetanus antibodies with normal avidity. In the high-risk ALL group 7/9 patients had subprotective levels of tetanus antibodies after vaccination and concomitantly the lowest avidity, implying poor protection against tetanus. No patients were found with low levels and low avidity of anti-Hib IgG, and 29/31 patients had full protection after a single dose of conjugated Hib-vaccine. CONCLUSION: The vaccination strategy after childhood ALL must be different for low-risk and high-risk ALL groups, since the high-risk group fail to elicit a recall response to tetanus.

Association of the -159 CD14 gene polymorphism and lack of association of the -308 TNFA and Q551R IL-4RA polymorphisms with severe chronic periodontitis in Swedish Caucasians.

BACKGROUND: Severe forms of periodontitis are suggested to have a genetic basis. OBJECTIVE: The aim of the present investigation was to study the association of gene polymorphisms related to some immune regulation components (G-308A TNFA, Q551R IL-4RA and C-159T CD14) with severe chronic periodontitis. MATERIALS AND METHODS: Sixty patients (aged 36-74 years; mean 54.5+/-8.5) with severe and generalized chronic periodontitis were included. The patients exhibited bone loss >50% at all teeth. Thirty-nine periodontally healthy subjects between 35 and 78 years of age (mean 51.0+/-10.9) were recruited as controls. DNA was isolated from peripheral blood cells and genotyping was performed by combination of PCR and restriction endonuclease mapping. RESULTS: While gene polymorphisms for TNFA and IL-4RA did not show any association with severe chronic periodontitis, the analysis of the -159 CD14 gene polymorphism revealed significant differences between test and control groups. The proportion of subjects that exhibited the TT genotype was significantly smaller in the group with severe periodontitis than in periodontal healthy group (p=0.028; Fisher's exact test). The C allele carriage was 90% in the periodontitis group and significantly higher than in the healthy control group (72%). CONCLUSION: It is suggested that the -159 CD14 gene polymorphism is associated with chronic periodontitis in Caucasian subjects of a north European origin.

Intensive treatment for childhood acute lymphoblastic leukemia reduces immune responses to diphtheria, tetanus, and Haemophilus influenzae type b.

OBJECTIVES: Immunity to diphtheria toxoid (D), tetanus toxoid (T), and Haemophilus influenzae type b (Hib) is affected in children with acute lymphoblastic leukemia (ALL). The aims were to examine immunity and to compare the response to immunization at 1 or 6 months after treatment. METHODS: Thirty-one patients were immunized with DT and conjugated Hib vaccine (ActHib) at 1 month or 6 months after treatment of ALL with the NOPHO 92 protocol. Antibody levels were determined before and 3 weeks after vaccination. Specific T and Hib antibody-secreting cells of IgG/IgA/IgM isotypes were analyzed in peripheral blood using an ELISPOT technique. RESULTS: All specific antibody levels decreased during ALL treatment, and protective levels after treatment were noted for 17% against D, 33% against T, and 100% against Hib. No high-risk patient had full D or T protection after treatment. After vaccination all the standard- and intermediate-risk patients achieved full protection against D, T, and Hib. The high-risk group showed insufficient immune response (full protection after vaccination: D 56%, T 22%, Hib 78%). No difference was found between vaccination at 1 month or 6 months after treatment. The poor antibody production in the high-risk group correlated to low numbers of antibody-secreting cells. CONCLUSIONS: Nonprotective antibody levels against D, T, and Hib after childhood ALL are more common than previously thought. Insufficient immune response was restricted to the high-risk group and was related to a low number of memory B cells in this study. Immunizations should be included in follow-up after childhood ALL, and the policy should be adapted to treatment intensity.

Impaired kidney graft survival is associated with the TNF-alpha genotype.

BACKGROUND: The TNF2 allele at position -308 of the tumor necrosis factor (TNF)-alpha gene is associated with high TNF production. The purpose was to study the association of this gene polymorphism with rejection episodes and graft survival after kidney transplantation. METHODS: A retrospective analysis of transplant outcomes of patients who only had been treated with one single form of immunosuppression consisting of cyclosporine, azathioprine, and prednisolon was performed. RESULTS: We found that 115 (73%) patients had the TNF1/TNF1 genotype, whereas 42 (27%) were TNF2 positive. There was no difference in the overall acute rejection frequency between these two groups (50% in each), but our data showed a non-significant tendency towards a higher frequency of steroid resistant rejections in the TNF2 positive group (57% vs. 40%). There was no significant difference in graft survival between the two genotype groups, although an early tendency towards worse survival was seen in TNF2 recipients. However, the TNF2 positive recipients with rejection episodes had far worse graft survival compared with the TNF1/TNF1 recipients with rejection episodes (P<0.02). No difference was seen between the two genotype groups in patients without rejection episodes. CONCLUSION: Our data propose that potentially high TNF producers with the TNF2 allele do not have an increased risk for rejection episodes, but if rejection episodes occur, they have a significantly increased risk for early graft loss. TNF production may intensify rejection, but is not a primary factor for the induction of such acute immune activation.

Polymorphism in promoter region of IL10 gene is associated with rheumatoid arthritis in women.

OBJECTIVE: Rheumatoid arthritis (RA) is a genetically complex disease with many possible phenotypes. We investigated IL10 and TNFA gene polymorphisms in a group of Swedish women and men with RA compared with healthy individuals to estimate combinations of alleles specific for the disease. METHODS: We analyzed 264 patients with RA and 286 healthy controls for biallelic single-nucleotide polymorphisms in the -308 position of the TNFA and in the -1087 position of the IL10 gene by polymerase chain reaction with restriction endonuclease mapping. RESULTS: The frequencies of the -308 TNFA genotypes were not different in women and men with RA in comparison to the controls. In contrast, frequencies of the GG, AG, and AA -1087 IL10 genotypes were significantly different in women in the investigated groups: 26%, 58%, and 15% for RA patients and 24%, 54%, and 28% for the controls (chi-square = 8.18, p < 0.02). We confirmed this finding in a separate dataset of female patients and controls. The frequencies of the IL10 genotypes in men were similar in the patients and controls. We found no differences in the distribution of the TNFA or IL10 genotypes in relation to rheumatoid factor in the patients. CONCLUSION: On the basis of IL10 polymorphism, female patients with RA seem to represent a separate disease subgroup.

Association of the -1087 IL 10 gene polymorphism with severe chronic periodontitis in Swedish Caucasians.

BACKGROUND: Severe forms of periodontitis are suggested to have a genetic basis. OBJECTIVE: The aim of the present investigation was to study association of an IL10 gene polymorphism (G to A transition at the -1087 position) with severe chronic periodontitis. MATERIALS AND METHODS: Two groups of Swedish Caucasian subjects were included. One group consisted of 60 patients (aged 36-74 years; mean 54.5+/-8.5) with severe and generalized chronic periodontitis. The patients exhibited bone loss >50% at all teeth. Thirty-nine periodontally healthy subjects between 35-78 years of age (mean 51.0+/-10.9) were also recruited. DNA was isolated from peripheral blood cells and genotyping was performed by combination of PCR with restriction endonuclease mapping. RESULTS: The proportion of subjects that exhibited the GG genotype was significantly larger in the group with severe periodontitis than in the periodontally healthy group. The difference regarding the occurrence of the GG genotype between the two groups was more conspicuous in non-smokers and yielded an odds ratio of 6.1. The G allele carriage in non-smokers was >90 % in the periodontitis group and was significantly higher than in the healthy controls. CONCLUSION: It is suggested that the -1087 IL10 polymorphism in Caucasian subjects of a north European origin is associated with severe chronic periodontitis.

Long term enhancement of the IgG2 antibody response to Haemophilus influenzae type b by breast-feeding.

SUBJECTS: Sets of sera were obtained from 30 children <6 years of age with invasive type b (Hib) infection and their mothers. Duration and mode of breast-feeding were monitored. Titers of IgG1, IgG2, IgA and IgM antibodies against Hib capsular polysaccharide were determined in sera taken during the acute illness and during early and late convalescence. RESULTS: Children 18 months or older with longer durations of exclusive breast-feeding (13 weeks or more; mean, 19.3 weeks) had higher Hib antibody concentrations of the IgG1, IgG2, IgA and IgM isotypes than those with a shorter duration of exclusive breast-feeding (<13 weeks; mean, 5.4 weeks). The difference was greatest for the IgG2 isotype. In regression analyses the association between the duration of exclusive breast-feeding and the anti-Hib IgG2 concentration was significant when breast-feeding, type of Hib infection, maternal Hib antibody titer and age were used as explanatory factors. In the group of 14 children <18 months of age no significant differences were noted. DISCUSSION: This study indicates the presence of a long lasting enhancing effect of breast-feeding on the antibody response to Hib in children, in particular on IgG2 Hib antibody production. This may result from the content in the milk of IFN-gamma and IFN-gamma-producing cells and possibly other factors, which can support IgG2 antibody production.

Aberrations in placental cytokine mRNA related to intrauterine growth retardation.

During normal pregnancy, a predominance of Th2 type cytokines prevails and is considered to protect the fetus. Animal experiments suggest that an increase of Th1 type cytokines may instead have deleterious effects. We have studied with the reverse transcription PCR technique mRNA for IL-1alpha, IL-1beta, IL-6, IL-8, IL-10, transforming growth factor-beta, tumor necrosis factor-alpha, and interferon-gamma in placentas from full-term appropriately grown newborns, newborns with intrauterine growth retardation (IUGR) and newborns who were only small for gestational age. The mRNA for IL-10 was significantly reduced in the IUGR placentas (p < 0.05), whereas the mRNA for IL-8 was significantly higher (p < 0.05) for the IUGR cases compared with the full-term neonates. It might be that reduced IL-10 in the placenta is involved in the pathogenesis of IUGR.