Differing Effects of Interleukin-10 on Cutaneous and Pulmonary Francisella tularensis Live Vaccine Strain Infection

We investigated the role of interleukin-10 (IL-10) in cutaneous and pulmonary infection with Francisella tularensis. We found that after intradermal challenge of mice with the live vaccine strain (LVS) of F. tularensis, splenic IL-10 levels increased rapidly and reached a peak 5 days after infection. However, IL-10 expression after infection was detrimental, since IL-10^−/− mice showed increased bacterial clearance and were resistant to an infectious dose (>10⁶ CFU/mouse) that was uniformly lethal for IL-10^+/+ mice. Furthermore, IL-10^+/+ mice treated with neutralizing anti-IL-10R monoclonal antibody were able to survive lethal cutaneous LVS challenge. The presence of IL-10 appeared to restrain the expression of IL-17, since high levels of splenic IL-17 were observed after intradermal LVS infection only in IL-10^−/− mice. Furthermore, treatment with neutralizing anti-IL-17R antibody ablated the enhanced survival observed in IL-10^−/− mice. However, neutralization of IL-10 activity in IL-17R^−/− mice failed to provide protection. Thus, IL-10 suppresses a protective IL-17 response that is necessary for resistance to cutaneous LVS infection. Surprisingly, however, IL-10^−/− mice were significantly more susceptible to pulmonary infection with LVS. Finally, although IL-10 is a critical and novel regulator of immunity to F. tularensis LVS infection, its effects were masked during infection with the highly virulent SchuS4 strain. Taken together, these findings suggest that differentially regulating expression of the IL-10 pathway in various tissues could ultimately have prophylactic and therapeutic benefits for protection against tularemia.     

Prediction of surface area size in orbital floor and medial orbital wall fractures based on topographical subregions

ObjectiveThis retrospective study evaluates the occurrence and frequency of different fracture patterns in a series of computed tomography (CT) scans in terms of the AOCMF Trauma Classification (TC) orbit module and correlates the assigned defects with measurements of the fracture area in order to get an approximate guideline for fracture size predictions on the basis of the classification.Material and methodsCT scans of patients with orbital floor fractures were evaluated using the AOCMFTC to determine the topographical subregions. The coding consisted of: W = orbital wall, 1 = anterior orbit, 2 = midorbit, i = inferior, m = medial. The 3-dimensional surface area size of the fractures was quantified by the “defect body” method (Brainlab, Munich, Germany). The fracture area size and its confidence and prediction interval within each topographical subregion was estimated by regression analysis.ResultsA total of 137 CT scans exhibited 145 orbital floor fractures, which were combined with 34 medial orbital wall fractures in 31 patients. The floor fractures – W1(i)2(i) (n = 86) and W1(i) (n = 19) were the most frequent patterns. Combined floor and medial wall fractures most frequently corresponded to the pattern W1 (im)2 (im) (n = 15) ahead of W1 (im) 2(i) (n = 10). The surface area size ranged from 0.11 cm² to 6.09 cm² for orbital floor and from 0.29 cm² to 5.43 cm² for medial wall fractures.The prediction values of the mean fracture area size within the subregions were computed as follows: W1(i) = 2.25 cm², W2(i) = 1.64 cm², W1(i)2(i) = 3.10 cm², W1(m) = 1.36 cm², W2(m) = 1.65 cm², W1(m)2(m) = 2.98 cm², W1 (im) = 3.35 cm², W1 (im) 2(i) = 4.63 cm², W1 (im)2(m) = 4.06 cm² and W1 (im)2 (im) = 7.16 cm².ConclusionThe AOCMFTC orbital module offers a suitable framework for topographical allocation of fracture patterns inside the infero-medial orbital cavity. The involvement of the subregions is of predictive value providing estimations of the mean 3-D fracture area size.     

Effects on the buoyant density of rabbit platelets of ADP and agents that increase the concentration of cyclic AMP

Rabbit platelets were aggregated by adenosine diphosphate (ADP), allowed to deaggregate and then separated into density subpopulations by centrifugation through discontinuous Stractan density gradients. Although ADP causes little or no release of the contents of the amine storage granules of rabbit platelets, ADP caused a decrease in platelet density as compared with control platelets subjected to the same procedures except for exposure to ADP. The density change persisted for at least four hours. The apparent size of platelets stimulated with ADP increased initially, but returned to control values during a one-hour period. A similar decrease in platelet density was observed with an albumin density gradient. Under conditions in which aggregation did not occur in response to ADP with ethylenediaminetetraacetic acid (EDTA) in the medium, little or no decrease in platelet density was observed. Agglutination with polylysine did not change platelet density. Thus, not only agents such as thrombin and plasmin that cause the release of the contents of the platelet granules decrease platelet density, but ADP also has this effect. Platelets would be exposed to all of these stimuli during thromboembolic processes, and their effect on platelets may account for the decrease in platelet density observed previously in experiments with rabbits with indwelling aortic catheters. Agents that increase the concentration of cyclic AMP (cAMP) in platelets (PGE1, adenosine, dibutyryl cAMP, forskolin, and papaverine) also decreased platelet density. This effect persisted when the platelets were washed and resuspended in fresh medium and was also demonstrable in plasma. Platelet size was gradually increased by prostaglandin E1 (PGE1) which maintains platelets in a disc shape and does not cause the release of granule contents, indicating that the decrease in platelet density caused by PGE1 may be attributable to platelet swelling.     

Acute toxicity and first clinical results of intensive postinduction therapy using a modified busulfan and cyclophosphamide regimen with autologous bone marrow rescue in first remission of acute myeloid leukemia [see comments]

The combination of high-dose busulfan (16 mg/kg) and 200 mg/kg cyclophosphamide is gaining increasing significance as a preparative regimen prior to autologous, syngeneic, or allogeneic marrow transplantation. A new regimen of high-dose busulfan in conjunction with a reduced dose of 120 mg/kg cyclophosphamide has recently been described as a preparative regimen prior to allogeneic transplantation. To determine the drug-related nonhematologic toxic effects of this new regimen without confounding factors associated with allogeneic transplantation, we conducted a pilot study using this new regimen in 20 patients with acute myeloid leukemia (AML) in first remission prior to autologous unpurged marrow transplantation. All patients experienced transient non-life-threatening acute drug-related toxicity with skin reactions in 20 (100%), nausea and vomiting in 20 (100%), oral mucositis in 18 (90%), hepatic functional impairment in 17 (85%), hemorrhagic cystitis in three (15%), and generalized seizures in two (10%) of these patients, respectively. Two procedural, fatal complications resulted from infectious causes that were not directly related to the speed of hematopoietic reconstitution or the toxicity of the preparative regimen. The 3-year event-free survival estimate (55% +/- 11%) and probability of leukemic recurrence (38% +/- 11%) attained with this new regimen in recipients of autografts in first remission of AML are promising and challenge comparisons with preparative regimens employing combinations of cytotoxic agents or total body irradiation (TBI).     

Immune reconstitution in severe combined immunodeficiency disease after lectin-treated, T-cell-depleted haplocompatible bone marrow transplantation

We describe our 9-year experience with lectin-treated T-cell-depleted haplocompatible parental bone marrow transplantation (BMT) for 24 patients with severe combined immunodeficiency disease (SCID). Nineteen of 21 evaluable patients had T-cell engraftment; 2 of 11 patients tested had B-cell and monocyte engraftment. Fourteen of 24 (58%) patients are alive 7 months to 9.8 years post-BMT. Seventeen of 24 patients received pretransplant conditioning with chemotherapy and/or total body irradiation, and 8 of 24 received more than one transplant. Patients who received conditioning had a survival rate of 61% versus 57% for those who received no conditioning. None received graft-versus- host disease (GVHD) prophylaxis and no patient had acute or chronic GVHD greater than grade I. Kinetics and follow-up of immune recovery were analyzed in 14 patients who are greater than 1 year from transplant. Half of the patients showed evidence of T-cell function by 3 months and normal T-cell function by 4 to 7 months post-BMT. On average, T-cell numbers and subsets became normal 10 to 12 months posttransplant. Recovery of B-cell function was more delayed, although in most patients B-cell numbers and IgM levels were normal by 12 months post-BMT. B-cell function, as determined by isohemagglutinin titers or specific antibodies to pneumococcal polysaccharide, keyhole limpet hemocyanin, or tetanus toxoid, became normal in 10 of 14 patients 2 to 8 years post-BMT. Seven of the 14 are off gammaglobulin therapy. Production of isohemagglutinins tended to predict recovery of antibody response to pneumococcal polysaccharide (P < .064). Based on these results, we believe that haplocompatible BMT is an effective, curative treatment for patients with SCID who lack an HLA-matched related donor.     

Effect of bisacodyl on postoperative bowel motility in elective colorectal surgery: a prospective, randomized trial

Background  Postoperative ileus is a common condition after abdominal surgery. Many prokinetic drugs have been evaluated including osmotic laxatives. The data on colon-stimulating laxatives are scarce. This prospective, randomized, double-blind trial investigates the effect of the colon-stimulating laxative bisacodyl on postoperative ileus in elective colorectal resections. Materials and methods  Between November 2004 and February 2007, 200 consecutive patients were randomly assigned to receive either bisacodyl or placebo. Primary endpoint was time to gastrointestinal recovery (mean time to first flatus passed, first defecation, and first solid food tolerated; GI-3). Secondary endpoints were incidence and duration of nasogastric tube reinsertion, incidence of vomiting, length of hospital stay, and visual analogue scores for pain, cramps, and nausea. Results  One hundred sixty-nine patients were analyzed, and 31 patients discontinued the study. Groups were comparable in baseline demographics. Time to GI-3 was significantly shorter in the bisacodyl group (3.0 versus 3.7 days, P = 0.007). Of the single parameters defining GI-3, there was a 1-day difference in time to defecation in favor to the bisacodyl group (3.0 versus 4.0 days, P = 0.001), whereas no significant difference in time to first flatus or tolerance of solid food was seen. No significant difference in the secondary endpoints was seen. Morbidity and mortality did not differ between groups. Conclusion  Bisacodyl accelerated gastrointestinal recovery and might be considered as part of multimodal recovery programs after colorectal surgery.