[Renal replacement or conservative treatment in end-stage renal disease in elder patients?] / Nierenersatz oder konservative Therapie bei chronischem Nierenversagen im Alter?

When elder individuals develop chronic kidney failure, doctors, patients, and family members are faced with the decision: Should dialysis (still) be initiated, or should a conservative-palliative therapy strategy be chosen? A prerequisite for shared decision-making is structured education about the various options, ensuring all necessary information and consequences are communicated. This article outlines the advantages and disadvantages of haemodialysis and peritoneal dialysis, as well as conservative-palliative therapy. Additionally, it discusses the option of a trial dialysis and the choice to discontinue ongoing dialysis.

[Management of polypharmacy in older people with multimorbidity]. / Management der Polypharmazie bei älteren Menschen mit Multimorbidität.

If the individual diagnoses of older people with multimorbidity are treated according to guidelines and by different specialists, confusing medication plans are sometimes the consequence. Therefore, a regular and structured drug evaluation is essential. As the life goals of patients can be very different, especially in older age, certain preliminary considerations should be made when starting, prescribing or discontinuing medication, taking into account the individual situation, including geriatric aspects. Updated so-called positive and negative lists provide assistance as to which medications are suitable or unsuitable for older people. Discontinuing certain medications when the life expectancy is reduced certainly makes sense but undertreatment of symptoms that cause distress to people, such as pain, should definitely be avoided.

A ubiquitous bone marrow reservoir of preexisting SARS-CoV-2-reactive memory CD4+ T lymphocytes in unexposed individuals.

Circulating, blood-borne SARS-CoV-2-reactive memory T cells in persons so far unexposed to SARS-CoV-2 or the vaccines have been described in 20-100% of the adult population. They are credited with determining the efficacy of the immune response in COVID-19. Here, we demonstrate the presence of preexisting memory CD4+ T cells reacting to peptides of the spike, membrane, or nucleocapsid proteins of SARS-CoV-2 in the bone marrow of all 17 persons investigated that had previously not been exposed to SARS-CoV-2 or one of the vaccines targeting it, with only 15 of these persons also having such cells detectable circulating in the blood. The preexisting SARS-CoV-2-reactive memory CD4+ T cells of the bone marrow are abundant and polyfunctional, with the phenotype of central memory T cells. They are tissue-resident, at least in those persons who do not have such cells in the blood, and about 30% of them express CD69. Bone marrow resident SARS-CoV-2-reactive memory CD4+ memory T cells are also abundant in vaccinated persons analyzed 10-168 days after 1°-4° vaccination. Apart from securing the bone marrow, preexisting cross-reactive memory CD4+ T cells may play an important role in shaping the systemic immune response to SARS-CoV-2 and the vaccines, and contribute essentially to the rapid establishment of long-lasting immunity provided by memory plasma cells, already upon primary infection.

[Treatment of geriatric patients with end-stage renal failure : Dialysis or conservative procedure?] / Versorgung des geriatrischen Patienten mit terminaler Niereninsuffizienz : Dialyse oder eher konservatives Prozedere?

Compared to younger patients, an acceptable state of health in older patients with various comorbidities is rarely achieved by the initiation of dialysis. Despite dialysis treatment, further functional and cognitive impairments often rapidly occur in geriatric patients. Thus, newer studies are concerned with the quality of life of this patient group after initiation of dialysis as well as with palliative treatment strategies as alternatives. A structured clarification for the patients on all possibilities with mediation of all necessary information is a prerequisite for a shared decision-making. To assess life expectancy after dialysis initiation, various scores have been developed but the sensitivity could not fulfil the expectations. In the case of renal replacement, chronic intermittent hemodialysis is the treatment form most frequently performed in geriatric patients. The main concern of conservative palliative treatment is the quality of life and the management of uremic symptoms, which have to be addressed by a multidisciplinary team.

Tolerogenic Immunomodulation by PEGylated Antigenic Peptides.

Current treatments for autoimmune disorders rely on non-specific immunomodulatory and global immunosuppressive drugs, which show a variable degree of efficiency and are often accompanied by side effects. In contrast, strategies aiming at inducing antigen-specific tolerance promise an exclusive specificity of the immunomodulation. However, although successful in experimental models, peptide-based tolerogenic "inverse" vaccines have largely failed to show efficacy in clinical trials. Recent studies showed that repetitive T cell epitopes, coupling of peptides to autologous cells, or peptides coupled to nanoparticles can improve the tolerogenic efficacy of peptides, suggesting that size and biophysical properties of antigen constructs affect the induction of tolerance. As these materials bear hurdles with respect to preparation or regulatory aspects, we wondered whether conjugation of peptides to the well-established and clinically proven synthetic material polyethylene glycol (PEG) might also work. We here coupled the T cell epitope OVA323-339 to polyethylene glycols of different size and structure and tested the impact of these nano-sized constructs on regulatory (Treg) and effector T cells in the DO11.10 adoptive transfer mouse model. Systemic vaccination with PEGylated peptides resulted in highly increased frequencies of Foxp3+ Tregs and reduced frequencies of antigen-specific T cells producing pro-inflammatory TNF compared to vaccination with the native peptide. PEGylation was found to extend the bioavailability of the model peptide. Both tolerogenicity and bioavailability were dependent on PEG size and structure. In conclusion, PEGylation of antigenic peptides is an effective and feasible strategy to improve Treg-inducing, peptide-based vaccines with potential use for the treatment of autoimmune diseases, allergies, and transplant rejection.

Impact of iron oxide nanoparticles on xenobiotic metabolism in HepaRG cells.

Iron oxide nanoparticles are used in various industrial fields, as a tool in biomedicine as well as in food colorants, and can therefore reach human metabolism via oral uptake or injection. However, their effects on the human body, especially the liver as one of the first target organs is still under elucidation. Here, we studied the influence of different representative iron oxide materials on xenobiotic metabolism of HepaRG cells. These included four iron oxide nanoparticles, one commercially available yellow food pigment (E172), and non-particulate ionic control FeSO4. The nanoparticles had different chemical and crystalline structures and differed in size and shape and were used at a concentration of 50 µg Fe/mL. We found that various CYP enzymes were downregulated by some but not all iron oxide nanoparticles, with the Fe3O4-particle, both γ-Fe2O3-particles, and FeSO4 exhibiting the strongest effects, the yellow food pigment E172 showing a minor effect and an α-Fe2O3 nanoparticle leading to almost no inhibition of phase I machinery. The downregulation was seen at the mRNA, protein expression, and activity levels. Thereby, no dependency on the size or chemical structure was found. This underlines the difficulty of the grouping of nanomaterials regarding their physiological impact, suggesting that every iron oxide nanoparticle species needs to be evaluated in a case-by-case approach.

The relevant psychological burden of having a benign brain tumor: a prospective study of patients undergoing surgical treatment of cranial meningiomas.

OBJECTIVE: Meningiomas are the most common intracranial neoplasm. Evidence concerning surgical management and outcome is abundant, while the implications for the quality of life (QOL) of a patient confronted with the diagnosis and undergoing surgery are unclear. The authors conducted a prospective study to evaluate QOL in relation to psychological comorbidities comorbidities. METHODS: A prospective study of patients undergoing elective surgery for the removal of an intracranial meningioma was performed. The authors evaluated depression (Allgemeine Depressionsskala K score) and anxiety (Post-Traumatic Stress Scale-10 [PTSS-10]; State Trait Anxiety Inventory-State Anxiety and -Trait Anxiety [STAI-S and STAI-T]; and Anxiety Sensitivity Index-3 [ASI-3]) scores before surgery and at 3 and 12 months after surgery. The correlation between preoperative psychological burden and postoperative QOL as measured by the 36-Item Short Form Health Survey and EQ-5L questionnaires was analyzed. Incidence and influence of these psychiatric comorbidities on clinical outcome were examined. RESULTS: A total of 78 patients undergoing resection of a meningioma between January 2013 and September 2017 participated in the preoperative psychological screening and 71 patients fully completed postoperative follow-up examination after 1 year of follow-up. At presentation, 48 patients (67.7%) had abnormal anxiety scores, which decreased to 29.6% (p = 0.003). On follow-up at 12 months, mean EQ-5L visual analog scale scores were significantly lower in patients with pathological scores on the PTSS-10 (0.84 vs 0.69; p = 0.004), STAI-S (0.86 vs 0.68; p = 0.001), and STAI-T (0.85 vs 0.71; p = 0.011). Neurological status (modified Rankin Scale) improved slightly and showed some correlation with psychological comorbidities QOL scores (p = 0.167). There was a nonsignificant increase of EQ-5L scores over the period of follow-up (p = 0.174) in the repeated-measures analysis. In the regression analysis, impaired QOL and physical disability on follow-up correlated with elevated preoperative anxiety and depression levels. CONCLUSIONS: The QOL and physical disability of patients undergoing resection of an intracranial meningioma highly depend on preoperative anxiety and depression levels. Stress and anxiety scores generally decrease after the resection, which leads us to conclude that there is a tremendous emotional burden caused by an upcoming surgery, necessitating close psychooncological support in order to uphold functional outcome and health-related QOL in the postoperative course.

Peritraumatic distress fully mediates the relationship between posttraumatic stress symptoms preoperative and three months postoperative in patients undergoing spine surgery.

Background: Growing evidence shows the significance of illness and surgical procedures as traumatizing stressors. Risk factors are widely investigated in various settings and samples, using numerous measures of posttraumatic stress and posttraumatic stress disorder (PTSD). While pretrauma psychological distress is acknowledged as an influential factor, peritraumatic experiences are controversially still being discussed as relevant to the development of PTSD. Objective: In a group of patients consecutively undergoing elective spine surgery (N = 89) in a German hospital, this longitudinal study addressed the question of how pretrauma PTSD symptoms and peritrauma distress interact with one another in regard to the amount of posttrauma symptoms of PTSD. Methods: Pre- and posttrauma symptoms of PTSD as well as peritrauma distress were assessed through questionnaires one week before, one week after or three months after surgery. Results: Even though all three variables showed significant correlations with one another, mediation analysis revealed that peritrauma distress fully mediated the relationship between pre- and posttrauma PTSD symptoms. Conclusions: These results add new insights to the controversial discussion on the role peritraumatic experiences play in the development of PTSD, especially in medical settings.

Contexto: Evidencias crecientes muestran el significado de la enfermedad y de los procedimientos quirúrgicos como estresores traumatizantes en si mismos. Los factores de riesgo son ampliamente investigados en varios contextos y muestras, usando numerosas medidas de estrés postraumático y del trastorno de estrés postraumático (TEPT). Mientras que el estrés psíquico pretraumático es reconocido como un factor influyente, las experiencias peritraumáticas están siendo aun objeto de controversia como elementos relevantes para el desarrollo de un TEPT. Objetivo: En un grupo de pacientes sometidos a cirugía selectiva espinal (N=89) en un hospital alemán, este estudio longitudinal iba dirigido a estudiar la cuestión de en qué medida tanto los síntomas de TEPT pretraumáticos como el estrés pretraumático, interactúan uno con el otro en relación con la aparición de síntomas postraumáticos de un TEPT. Métodos: Los síntomas pre y postraumáticos de TEPT así como el estrés pretraumático fueron evaluados y determinados a través de cuestionarios, una semana antes, una después y tres meses después de la intervención quirúrgica. Resultados: Aunque las tres variables mostraron correlaciones significativas entre sí, el análisis de la mediación revela que el estrés peritraumático es el mayor mediador de la relación entre síntomas de TEPT, pre y postraumáticos. Conclusiones: estos resultados añaden nuevas perspectivas a la controvertida discusión sobre el papel que juegan las experiencias peritraumáticas en el desarrollo del TEPT, especialmente en contextos médicos.

Multivalent Peptide-Nanoparticle Conjugates for Influenza-Virus Inhibition.

To inhibit binding of the influenza A virus to the host cell glycocalyx, we generate multivalent peptide-polymer nanoparticles binding with nanomolar affinity to the virus via its spike protein hemagglutinin. The chosen dendritic polyglycerol scaffolds are highly biocompatible and well suited for a multivalent presentation. We could demonstrate in vitro that by increasing the size of the polymer scaffold and adjusting the peptide density, viral infection is drastically reduced. Such a peptide-polymer conjugate qualified also in an in vivo infection scenario. With this study we introduce the first non-carbohydrate-based, covalently linked, multivalent virus inhibitor in the nano- to picomolar range by ensuring low peptide-ligand density on a larger dendritic scaffold.

Identification of Targeting Peptides for Mucosal Delivery in Sheep and Mice.

In this study we identified and characterized a novel cyclic peptide that facilitates the rapid transportation of conjugated molecules across the epithelial layer of the small intestine. The peptide was initially selected from phage display libraries using a large animal experimental model, which employed consecutive in vitro and in vivo panning. The procedure was designed to enrich for peptides that facilitated transcytosis across the intestinal epithelium into the intestinal afferent lymphatic system. A small set of peptides was repeatedly isolated using this selection method; however, the cyclic nonamer CTANSSAQC, 13C, dominated. The activity of the putative targeting peptide 13C was then verified using a mouse model. These experiments showed that the 13C peptide as well as macromolecules conjugated to it were rapidly transported across the intestinal mucosa into distinct subsets of epithelial cells and CD11c+ cells located in the lamina propria and Peyer's Patches. Significant amounts of intact protein could be delivered into the systemic circulation after rectal and nasal application. Thus, peptide 13C is regarded as an attractive carrier candidate for mucosal delivery of large molecules. The preferential targeting to distinct intestinal cells may be utilized to deliver active biological drugs for the effective control of diseases of the gut.

Tolerogenic modulation of the immune response by oligoglycerol- and polyglycerol-peptide conjugates.

Peptide-based therapy is a promising strategy for antigen-specific immunosuppression to treat or even heal autoimmune diseases with significantly reduced adverse effects compared to conventional therapies. However, there has been no major success due to the drawbacks of native peptides, i.e., limited bioavailability. Considering the importance and limitations of peptide-based therapies for treatment of autoimmune diseases, we designed and constructed oligoglycerol (OG)- and polyglycerol (PG)-based peptide conjugates. They were evaluated for their biological activity (in vitro and in vivo), bioavailability, and tolerogenic potential. Among the OG- and PG-peptide constructs, PG-peptide constructs exhibited an extended bioavailability compared to OG-peptide constructs and unconjugated peptide. Interestingly, size, structure, and linker chemistry played a critical role for the tolerogenic capacity of the constructs. The PG-peptide construct bound via an ester linkage was the most tolerogenic conjugate, while the PG-peptide construct bound via an amide induced stronger proliferation, but also higher TNF production and lower frequencies of Foxp3(+) regulatory T-cells. Therefore, we conclude that PG-peptide conjugates bound via an ester linkage are not only promising candidates for tolerogenic vaccination, but also open a new avenue toward the application of peptides for the treatment of autoimmune diseases.

miR-148a is upregulated by Twist1 and T-bet and promotes Th1-cell survival by regulating the proapoptotic gene Bim.

Repeatedly activated T helper 1 (Th1) cells present during chronic inflammation can efficiently adapt to the inflammatory milieu, for example, by expressing the transcription factor Twist1, which limits the immunopathology caused by Th1 cells. Here, we show that in repeatedly activated murine Th1 cells, Twist1 and T-bet induce expression of microRNA-148a (miR-148a). miR-148a regulates expression of the proapoptotic gene Bim, resulting in a decreased Bim/Bcl2 ratio. Inhibition of miR-148a by antagomirs in repeatedly activated Th1 cells increases the expression of Bim, leading to enhanced apoptosis. Knockdown of Bim expression by siRNA in miR-148a antagomir-treated cells restores viability of the Th1 cells, demonstrating that miR-148a controls survival by regulating Bim expression. Thus, Twist1 and T-bet not only control the differentiation and function of Th1 cells, but also their persistence in chronic inflammation.

Respiratory diseases are associated with molar-incisor hypomineralizations.

The objective of our study was to evaluate the association of molar-incisor hypomineralizations (MIHs) with prospectively collected potential causative factors from the first 4 years of life, e.g. respiratory diseases, breastfeeding, maternal smoking and parental education. A total of 692 children (10 years old) from the GINI birth cohort study participated. The dental examination included the registration of enamel hypomineralizations (EHs) according to the EAPD criteria. Children with EH were sub-categorized into those with at least one EH (MIH/1), those with a minimum of one EH on at least one first permanent molar (MIH/2) and those with EH on at least one first permanent molar and a permanent incisor (MIH/3). All relationships between causative factors and caries or MIH were evaluated using simple and multiple logistic regression analyses. EHs were observed in 37.9% (MIH/1), 14.7% (MIH/2) and 9.2% (MIH/3) of all subjects. After adjustment for confounding factors, 10-year-old children with at least one episode of respiratory disease had a significantly higher risk (2.48 times, adjusted OR) for the development of MIH/3. In case of breastfeeding, a non-significant association was observed. None of the tested factors was associated with either MIH/1 or MIH/2. Early respiratory diseases seem to be directly or indirectly related to MIH/3 only. The role of (systemic) medications used for treatment of these diseases needs to be investigated in future studies.

Early-life determinants of asthma from birth to age 20 years: a German birth cohort study.

BACKGROUND: The lack of longitudinal data analyses from birth to adulthood is hampering long-term asthma prevention strategies. OBJECTIVE: We aimed to determine early-life predictors of asthma incidence up to age 20 years in a birth cohort study by applying time-to-event analysis. METHODS: In 1990, the Multicenter Allergy Study included 1314 newborns in 5 German cities. Children were evaluated from birth to age 20 years at 19 time points. Using a Cox regression model, we examined the associations between 36 early-life factors and onset of asthma based on a doctor's diagnosis or asthma medication (primary outcome), typical asthma symptoms, or allergic asthma (including positive IgE measurements). RESULTS: Response at 20 years was 71.6%. Two hundred eighteen subjects met the primary outcome criteria within 16,257 person years observed. Asthma incidence was lower in participants who were vaccinated (measles, mumps, and rubella vaccine/tick-borne encephalitis vaccine/BCG vaccine: adjusted hazard ratio [HR], 0.66 [95% CI, 0.47-0.93]). Up to age 20 years, asthma incidence was higher in subjects who had parents with allergic rhinitis (adjusted HR, 2.24 [95% CI, 1.67-3.02]), started day care early or late (before 18 months: adjusted HR, 1.79 [95% CI, 1.03-3.10]; after 3 years: adjusted HR, 1.64 [95% CI, 0.96-2.79]), had mothers who smoked during pregnancy (adjusted HR, 1.79 [95% CI, 1.20-2.67]), had poor parents (adjusted HR, 1.55 [95% CI, 1.09-2.22]), and had parents with asthma (adjusted HR, 1.65 [95% CI, 1.17-2.31]). Not associated with asthma were aspects of diet and breast-feeding, pet ownership, presence of older siblings, and passive smoking. CONCLUSION: Parental asthma and nasal allergy increase asthma incidence in offspring up to adulthood. Avoiding tobacco smoke exposure during pregnancy, receiving vaccinations in early childhood, and starting day care between 1.5 and 3 years of age might prevent or delay the development of asthma.

Exposure to second-hand smoke and direct healthcare costs in children - results from two German birth cohorts, GINIplus and LISAplus.

BACKGROUND: Although the negative health consequences of the exposure to second hand tobacco smoke during childhood are already known, evidence on the economic consequences is still rare. The aim of this study was to estimate excess healthcare costs of exposure to tobacco smoke in German children. METHODS: The study is based on data from two birth cohort studies of 3,518 children aged 9-11 years with information on healthcare utilisation and tobacco smoke exposure: the GINIplus study (German Infant Study On The Influence Of Nutrition Intervention Plus Environmental And Genetic Influences On Allergy Development) and the LISAplus study (Influence of Life-Style Factors On The Development Of The Immune System And Allergies In East And West Germany Plus The Influence Of Traffic Emissions And Genetics). Direct medical costs were estimated using a bottom-up approach (base year 2007). We investigated the impact of tobacco smoke exposure in different environments on the main components of direct healthcare costs using descriptive analysis and a multivariate two-step regression analysis. RESULTS: Descriptive analysis showed that average annual medical costs (physician visits, physical therapy and hospital treatment) were considerably higher for children exposed to second-hand tobacco smoke at home (indoors or on patio/balcony) compared with those who were not exposed. Regression analysis confirmed these descriptive trends: the odds of positive costs and the amount of total costs are significantly elevated for children exposed to tobacco smoke at home after adjusting for confounding variables. Combining the two steps of the regression model shows smoking attributable total costs per child exposed at home of €87 [10-165] (patio/balcony) and €144 [6-305] (indoors) compared to those with no exposure. Children not exposed at home but in other places showed only a small, but not significant, difference in total costs compared to those with no exposure. CONCLUSIONS: This study shows adverse economic consequences of second-hand smoke in children depending on proximity of exposure. Tobacco smoke exposure seems to affect healthcare utilisation in children who are not only exposed to smoke indoors but also if parents reported exclusively smoking on patio or balcony. Preventing children from exposure to second-hand tobacco smoke might thus be desirable not only from a health but also from an economic perspective.

Renal function during rofecoxib therapy in patients with metastatic cancer: retrospective analysis of a prospective phase II trial.

BACKGROUND: Angiostatic/antiinflammatory therapy with COX-II inhibitors and pioglitazone seems to be a well tolerated and promising regimen in patients with metastatic cancer. COX-II inhibitors may have less gastrointestinal side effects than conventional non-steroidal antiinflammatory drugs, but their impact on renal function seems to be similar. METHODS: 87 patients with metastatic/advanced cancer were treated up to 12 months (mean 19.5 weeks) with rofecoxib, pioglitazone and either capecitabine (group A with gastrointestinal and urological cancer, n = 50) or trofosfamide (group B with non-gastrointestinal/non-urological cancer, n = 37) and followed for further 6 months. RESULTS: Baseline serum creatinine concentration was 0.81 ± 0.28 mg/dl, and increased by about 0.15 mg/dl during months 1-3. Accordingly estimated glomerular filtration rate (eGFR) decreased from 90.3 ml/min ± 3.6 ml/min at baseline by about 10 ml/min during months 1-3. Renal function decreased in 75 patients (86%) in the first month (p < 0.0001). This decrease went along with clinical signs of volume expansion. Renal function tended to recover after discontinuation of the study medication. CONCLUSIONS: Therapy with rofecoxib in an antiangiogenic/antiinflammatory setting results in a decrease of renal function in nearly every patient. TRIAL REGISTRATION NUMBER: German Clinical Trials Register DRKS: DRKS00000119.

Impact of Toll-like receptor 2 expression in renal allograft rejection.

BACKGROUND: An important role of TLR2 has been shown in various experimental models of renal ischaemia/reperfusion injury. To study the expression of TLR2 in renal allograft rejection systematically, we established an experimental rat transplantation model. METHODS: TLR2 expression was analysed in 99 human renal allograft biopsies, and in rat allografts at Day 6 and 28 after experimental renal transplantation. To discriminate whether regulation of TLR2 was following immunological processes after allogeneic transplantation or was a consequence from ischaemia/reperfusion injury, control animals subjected to syngeneic transplantation or to ischaemia/reperfusion damage were also investigated. RESULTS: TLR2 mRNA was significantly elevated in rat allografts with acute rejection on Day 6 and decreased spontaneously towards Day 28. TLR2 induction correlated with renal function and TLR2 excretion in the urine of transplanted rats. TLR2 staining was also significantly increased in human allografts with acute rejection. TLR2 protein could be localized in tubular epithelial cells and vascular endothelial cells, and in CD68- and CD4-positive infiltrating cells. CONCLUSIONS: TLR2 is markedly up-regulated in both experimental and human acute renal allograft rejection. Our data suggest a role for TLR2 during allogen-dependent graft damage after renal transplantation.

Impact of chemokine receptor CX3CR1 in human renal allograft rejection.

Chemokine receptors play pivotal roles for leukocyte recruitment in acute and chronic inflammatory processes. This study was performed to analyze the expression, distribution and cellular localization of CX3CR1 in human renal transplant biopsies and to assess its role as potential diagnostic and prognostic marker. CX3CR1 was prospectively analyzed in 174 renal graft biopsies from patients with normal morphology (n=76), antibody-mediated acute rejection (n=6), acute tubulointerstitial rejection (n=27), acute vascular rejection (n=31), and with acute tubulus necrosis (n=34). Double immunofluorescence was additionally performed for CX3CR1 and CD4, CD8, CD20, CD68, and CD209/DC-SIGN. The number of CX3CR1 positive interstitial cells was significantly higher in the biopsies with acute tubulointerstitial and acute vascular rejection as compared to normal renal allograft biopsies. CX3CR1 positive cells were mainly CD68 positive monocytes/macrophages and CD209/DC-SIGN positive dendritic cells. The percentage of the CX3CR1 positive staining area was a predictor for steroid responsiveness and for worse clinical outcome 3 and 12 months after transplantation. CX3CR1 positive macrophages and/or dendritic cells are significantly elevated in acute renal allograft rejection. As CX3CR1 was associated with outcome parameters, it has to be further evaluated as a prognostic marker in human renal transplantation.

Prenatal and postnatal tobacco exposure and behavioral problems in 10-year-old children: results from the GINI-plus prospective birth cohort study.

BACKGROUND: Prenatal and postnatal tobacco exposure have been reported to be associated with behavioral problems. However, the magnitude of the association with tobacco exposure at specific periods of exposure is unclear. OBJECTIVE: We assessed the relative risk of behavioral problems in children who had been exposed to tobacco smoke in utero and postnatally. METHODS: We analyzed data from a prospective birth cohort study in two cities in Germany: the German Infant Nutrition Intervention. Our sample included 5,991 children born between 1995 and 1998 as well as their parents. We measured behavioral problems using the Strength and Difficulties Questionnaire (SDQ) at follow-up 10 years after birth. According to prespecified SDQ cutoff values, children were classified as "normal," "borderline," or "abnormal" according to the subscales "emotional symptoms," "conduct problems," "hyperactivity/inattention," "peer-relationship problems," and a total difficulties score. Smoke exposure and further covariates were assessed using parent questionnaires. RESULTS: Compared with children not exposed to tobacco smoke, children exposed both pre- and postnatally to tobacco smoke had twice the estimated risk [95% confidence interval (CI), 1.4-3.1] of being classified as abnormal according to the total difficulties score of the SDQ at 10 years of age. Children who were only prenatally exposed had a 90% higher relative risk (95% CI, 0.9-4.0), whereas children who were only postnatally exposed had a 30% higher relative risk (95% CI, 0.9-1.9). These results could not be explained by confounding by parental education, father's employment, child's time spent in front of computer or television screen, being a single father or mother, or mother's age. CONCLUSIONS: Prenatal exposure to tobacco smoke is associated with behavioral problems in school-age children. Although our findings do not preclude the influence of postnatal exposure, prenatal exposure seems to be more important.

Osteopontin as two-sided mediator of intestinal inflammation.

Osteopontin (OPN) is characterized as a major amplifier of Th1-immune responses. However, its role in intestinal inflammation is currently unknown. We found considerably raised OPN levels in blood of wild-type (WT) mice with dextran sodium sulfate (DSS)-induced colitis. To identify the role of this mediator in intestinal inflammation, we analysed experimental colitis in OPN-deficient (OPN(-/-)) mice. In the acute phase of colitis these mice showed more extensive colonic ulcerations and mucosal destruction than WT mice, which was abrogated by application of soluble OPN. Within the OPN(-/-) mice, infiltrating macrophages were not activated and showed impaired phagocytosis. Reduced mRNA expression of interleukin (IL)-1 beta and matrix metalloproteinases was found in acute colitis of OPN(-/-) mice. This was associated with decreased blood levels of IL-22, a Th17 cytokine that may mediate epithelial regeneration. However, OPN-(/-) mice showed increased serum levels of tumour necrosis factor (TNF)-alpha, which could be due to systemically present lipopolysaccharide translocated to the gut. In contrast to acute colitis, during chronic DSS-colitis, which is driven by a Th1 response of the lamina propria infiltrates, OPN(-/-) mice were protected from mucosal inflammation and demonstrated lower serum levels of IL-12 than WT mice. Furthermore, neutralization of OPN in WT mice abrogated colitis. Lastly, we demonstrate that in patients with active Crohn's disease OPN serum concentration correlated significantly with disease activity. Taken together, we postulate a dual function of OPN in intestinal inflammation: During acute inflammation OPN seems to activate innate immunity, reduces tissue damage and initiates mucosal repair whereas during chronic inflammation it promotes the Th1 response and strengthens inflammation.