Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes

In rodent graft-versus-host disease (GVHD) models, anti-IL-21 neutralizing mAb treatment ameliorates lethality and is associated with decreases in Th1 cytokine production and gastrointestinal tract injury. GVHD prevention was dependent on the in vivo generation of donor-inducible regulatory T cells (Tregs). To determine whether the IL-21 pathway might be targeted for GVHD prevention, skin and colon samples obtained from patients with no GVHD or grade 2 to 4 GVHD were analyzed for IL-21 protein expression. By immunohistochemistry staining, IL-21 protein-producing cells were present in all gastrointestinal tract samples and 54% of skin samples obtained from GVHD patients but not GVHD-free controls. In a human xenogeneic GVHD model, human IL-21-secreting cells were present in the colon of GVHD recipients and were associated with elevated serum IL-21 levels. A neutralizing anti-human IL-21 mAb given prophylactically significantly reduced GVHD-associated weight loss and mortality, resulting in a concomitant increase in Tregs and a decrease in T cells secreting IFN-γ or granzyme B. Based on these findings, anti-IL-21 mAb could be considered for GVHD prevention in the clinic.     

Presentation and outcome of severe anticholinesterase insecticide poisoning.

AIMS: To document the patterns of presentation and outcome of severe anticholinesterase insecticide poisoning in children requiring intensive care. METHODS: Retrospective case note review of all 5541 children admitted to the paediatric intensive care unit (PICU) of a university hospital during the 10 years from January 1990 to May 2000. Fifty four children (1%) with anticholinesterase insecticide poisoning were identified. Presenting features, route of exposure, treatment, complications, and mortality were recorded. Data were analysed by the Fisher's exact and Mann-Whitney tests. RESULTS: More children than expected were from a rural area (46% versus 25%). Decontamination occurred in 50% of children prior to PICU admission. Enteral exposure was most common (n = 27; 50%). Median pseudocholinesterase level was 185 IU/l (range 75-7404). Median total dose of atropine required to maintain mydriasis was 0.3 mg/kg (range 0.03-16.7) over a median of 10 hours (range 1-160). Complications included coma (31%), seizures (30%), shock (9%), arrhythmias (9%), and respiratory failure requiring ventilation (35%). No significant differences were detected in incidence of seizures, cardiac arrhythmias, respiratory failure, mortality, duration of ventilation, or PICU stay, according to route of exposure, or state of decontamination. Four children died (7%). Mortality was associated with the presence of a cardiac arrhythmia (likelihood ratio 8.3) and respiratory failure (likelihood ratio 3.3). CONCLUSION: The mortality and morbidity of severe anticholinesterase insecticide poisoning in childhood is not related to route of exposure, or to delay in decontamination. However, the presence of either a cardiac arrhythmia or respiratory failure is associated with a poor prognosis.     

Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis

OBJECTIVE: Osteoarthritis (OA) is the most common form of arthritis and a primary cause of disability, however, there are no treatments that can slow disease progression or repair damaged joint cartilage. Fibroblast growth factor-18 (FGF18) has been reported to have significant anabolic effects on cartilage. We therefore examined its effects on repair of cartilage damage in a rat meniscal tear model of OA. DESIGN: Surgical damage to the meniscus in rats leads to joint instability and significant damage to the articular cartilage at 3 weeks post-surgery. At this time, animals received bi-weekly intra-articular injections of FGF18 for 3 weeks, and the knee joints were then harvested for histologic examination. RESULTS: FGF18-induced dose-dependent increases in cartilage thickness of the tibial plateau, due to new cartilage formation at the articular surface and the joint periphery. The generation of new cartilage resulted in significant reductions in cartilage degeneration scores. The highest dose of FGF18 also induced an increase in chondrophyte size and increased remodeling of the subchondral bone. CONCLUSIONS: The results of this study demonstrate that FGF18 can stimulate repair of damaged cartilage in a setting of rapidly progressive OA in rats.     

Correction of the anion gap for albumin in order to detect occult tissue anions in shock.

BACKGROUND: It is believed that hypoalbuminaemia confounds interpretation of the anion gap (AG) unless corrected for serum albumin in critically ill children with shock. Aim: To compare the ability of the AG and the albumin corrected anion gap (CAG) to detect the presence of occult tissue anions. METHODS: Prospective observational study in children with shock in a 22 bed multidisciplinary paediatric intensive care unit of a university childrenrsquo;s hospital. Blood was sampled at admission and at 24 hours, for acid-base parameters, serum albumin, and electrolytes. Occult tissue anions (lactate + truly "unmeasured" anions) were calculated from the strong ion gap. The anion gap ((Na + K) - (Cl + bicarbonate)) was corrected for serum albumin using the equation of Figge: AG + (0.25 x (44 - albumin)). Occult tissue anions (TA) predicted by the anion gap were calculated by (anion gap - 15 mEq/l). Optimal cut off values of anion gap were compared by means of receiver operating characteristic (ROC) curves. Ninety three sets of data from 55 children (median age 7 months, median weight 4.9 kg) were analysed. Data are expressed as mean (SD), and mean bias (limits of agreement). RESULTS: The incidence of hypoalbuminaemia was 76% (n = 42/55). Mean serum albumin was 25 g/l (SD 8). Mean AG was 15.0 mEq/l (SD 6.1), compared to the CAG of 19.9 mEq/l (SD 6.6). Mean TA was 10.2 mmol/l (SD 6.3). The AG underestimated TA with mean bias 10.2 mmol/l (4.1-16.1), compared to the CAG, mean bias 5.3 mmol/l (0.4-10.2). A clinically significant increase of TA >5 mmol/l was present in 83% (n = 77/93) of samples, of which the AG detected 48% (n = 36/77), and the CAG 87% (n = 67/77). Post hoc ROC analysis revealed optimal cut off values for detection of TA >5 mmol/l to be AG >10 mEq/l, and CAG >15.5 mEq/l. CONCLUSION: Hypoalbuminaemia is common in critically ill children with shock, and is associated with a low observed anion gap that may fail to detect clinically significant amounts of lactate and other occult tissue anions. We suggest that the albumin corrected anion gap should be calculated to screen for occult tissue anions in these children.     

Presentation and outcome of severe anticholinesterase insecticide poisoning

Aims: To document the patterns of presentation and outcome of severe anticholinesterase insecticide poisoning in children requiring intensive care. Methods: Retrospective case note review of all 5541 children admitted to the paediatric intensive care unit (PICU) of a university hospital during the 10 years from January 1990 to May 2000. Fifty four children (1%) with anticholinesterase insecticide poisoning were identified. Presenting features, route of exposure, treatment, complications, and mortality were recorded. Data were analysed by the Fisher''s exact and Mann–Whitney tests. Results: More children than expected were from a rural area (46% versus 25%). Decontamination occurred in 50% of children prior to PICU admission. Enteral exposure was most common (n = 27; 50%). Median pseudocholinesterase level was 185 IU/l (range 75–7404). Median total dose of atropine required to maintain mydriasis was 0.3 mg/kg (range 0.03–16.7) over a median of 10 hours (range 1–160). Complications included coma (31%), seizures (30%), shock (9%), arrhythmias (9%), and respiratory failure requiring ventilation (35%). No significant differences were detected in incidence of seizures, cardiac arrhythmias, respiratory failure, mortality, duration of ventilation, or PICU stay, according to route of exposure, or state of decontamination. Four children died (7%). Mortality was associated with the presence of a cardiac arrhythmia (likelihood ratio 8.3) and respiratory failure (likelihood ratio 3.3). Conclusion: The mortality and morbidity of severe anticholinesterase insecticide poisoning in childhood is not related to route of exposure, or to delay in decontamination. However, the presence of either a cardiac arrhythmia or respiratory failure is associated with a poor prognosis.     

TACI‐Ig prevents the development of airway hyperresponsiveness in a murine model of asthma

Background Increased levels of serum IgE are associated with greater asthma prevalence and disease severity. IgE depletion using an anti‐IgE monoclonal antibody has met with success in the treatment of moderate‐to‐severe and severe persistent allergic asthma. Objective To test whether B cell‐targeted therapy is a more effective treatment for airway hyperresponsiveness (AHR) in a murine model compared with IgE‐depletion. Methods We delivered soluble mTACI‐Ig, a receptor for the B cell survival factors BLyS (B Lymphocyte Stimulator) and APRIL (A PRoliferation‐Inducing Ligand), or anti‐IgE to allergen‐sensitized mice before airway challenge with allergen. Results mTACI‐Ig treatment reduced circulating mature B cell levels in the blood, while anti‐IgE treatment had no effect on B cell counts. Both mTACI‐Ig and anti‐IgE decreased the levels of total and allergen‐specific IgE in the serum. Histopathologic analysis of lungs showed a reduction in disease severity scores for both treatment groups, but results were more pronounced in mTACI‐Ig‐treated mice. Neutrophil and eosinophil numbers in the bronchoalveolar lavage (BAL) were significantly reduced following mTACI‐Ig treatment, but not after anti‐IgE delivery. BLyS and APRIL blockade also resulted in a significant decrease in IL‐4 and eotaxin mRNA and IL‐4 and KC protein levels in total lung homogenates and BAL fluid, respectively. Finally, mTACI‐Ig treatment was more effective than anti‐IgE treatment in reducing AHR to inhaled antigen. Conclusions Our data demonstrate that delivery of mTACI‐Ig is a more effective treatment than anti‐IgE mAb in a murine model of AHR.     

Mortality and the nature of metabolic acidosis in children with shock

HYPOTHESIS: Mortality in children with shock is more closely related to the nature, rather than the magnitude (base deficit/excess), of a metabolic acidosis. OBJECTIVE: To examine the relationship between base excess (BE), hyperlactataemia, hyperchloraemia, 'unmeasured' strong anions, and mortality. DESIGN: Prospective observational study set in a multi-disciplinary Paediatric Intensive Care Unit (PICU). PATIENTS: Forty-six children, median age 6 months (1.5-14.4), median weight 5 kg (3.2-8.8), admitted to PICU with shock. INTERVENTIONS: Predicted mortality was calculated from the paediatric index of mortality (PIM) score. The pH, base excess, serum lactate, corrected chloride, and 'unmeasured' strong anions (Strong Ion Gap) were measured or calculated at admission and 24 h. MEASUREMENTS AND RESULTS: Observed mortality ( n=16) was 35%, with a standardised mortality ratio (SMR) of 1.03 (95% CI 0.71-1.35). There was no significant difference in admission pH or BE between survivors and nonsurvivors. There was no association between elevation of 'unmeasured' anions and mortality, although there was a trend towards hyperchloraemia in survivors ( P=0.08). Admission lactate was higher in nonsurvivors (median 11.6 vs 3.3 mmol/l; P=0.0003). Area under the mortality receiver operating characteristic curve for lactate was 0.83 (955 CI 0.70-0.95), compared to 0.71 (95% CI 0.53-0.88) for the PIM score. Admission lactate level >5 mmol/l had maximum diagnostic efficiency for mortality, with a likelihood ratio of 2.0. CONCLUSION: There is no association between the magnitude of metabolic acidosis, quantified by the base excess, and mortality in children with shock. Hyperlactataemia, but not elevation of 'unmeasured' anions, is predictive of a poor outcome.     

IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-γ are not

Psoriasis is a common chronic skin disease with a largely unknown pathogenesis. We demonstrate here that transgenic over-expression of interleukin (IL)-22 in mice resulted in neonatal mortality and psoriasis-like skin alterations including acanthosis and hypogranularity. This cutaneous phenotype may be caused by the direct influence of IL-22 on keratinocytes, since this cytokine did not affect skin fibroblasts, endothelial cells, melanocytes, or adipocytes. The comparison of cytokines with hypothesized roles in psoriasis pathogenesis determined that neither interferon (IFN)-γ nor IL-17, but only IL-22 and, with lower potency, IL-20 caused psoriasis-like morphological changes in a three-dimensional human epidermis model. These changes were associated with inhibited keratinocyte terminal differentiation and with STAT3 upregulation. The IL-22 effect on differentiation-regulating genes was STAT3-dependent. In contrast to IL-22 and IL-20, IFN-γ and IL-17 strongly induced T-cell and neutrophilic granulocyte-attracting chemokines, respectively. Tumor necrosis factor-α potently induced diverse chemokines and additionally enhanced the expression of IL-22 receptor pathway elements and amplified some IL-22 effects. This study suggests that different cytokines are players in the psoriasis pathogenesis although only the IL-10 family members IL-22 and IL-20 directly cause the characteristic epidermal alterations. Kerstin Wolk and Harald S. Haugen equally contributed to this work.