An approach to the asthma-protective farm effect by geocoding: Good farms and better farms.

BACKGROUND: The highly consistent association of growing up on a farm with a reduced asthma risk has so far been attributed to direct farm exposure. In contrast, geographic determinants of the larger environment have never been assessed. In this study, the effects of proximity to farms and environmental variables in relation to the residential address on asthma and atopy were assessed. METHODS: Addresses of 2265 children of the Bavarian arm of the GABRIELA study were converted into geocodes. Proximity to the nearest cow farm was calculated, and environmental characteristics were derived from satellite data or terrestrial monitoring. Bacterial diversity in mattress dust samples was assessed in 501 children by sequencing of the 16S rRNA amplicons. Logistic regression models were used to calculate associations between outcomes and exposure variables. RESULTS: Asthma and atopy were inversely associated with the presence of a farm within a radius of maximum 100 m. The environmental variables greenness, tree cover, soil sealing, altitude, air pollution differed not only between farm and non-farm children but also between farm children with and without another farm nearby. The latter distinction revealed strong associations with characteristics of traditional farms including a broader diversity of microbial exposure, which mainly contributed to the protective effect on asthma. In non-farm children, the protective effect of a farm nearby was completely explained by consumption of farm milk. CONCLUSIONS: Clustering of farms within a neighborhood of 100 m is strongly associated with the protective effect on asthma and may represent a more traditional style of farming with broader microbial exposure.

Safety and Outcomes in 100 Consecutive Donation After Circulatory Death Liver Transplants Using a Protocol That Includes Thrombolytic Therapy.

Donation after circulatory death (DCD) liver transplantation (LT) reportedly yields inferior survival and increased complication rates compared with donation after brain death (DBD). We compare 100 consecutive DCD LT using a protocol that includes thrombolytic therapy (late DCD group) to an historical DCD group (early DCD group n = 38) and a cohort of DBD LT recipients (DBD group n = 435). Late DCD LT recipients had better 1- and 3-year graft survival rates than early DCD LT recipients (92% vs. 76.3%, p = 0.03 and 91.4% vs. 73.7%, p = 0.01). Late DCD graft survival rates were comparable to those of the DBD group (92% vs. 93.3%, p = 0.24 and 91.4% vs. 88.2%, p = 0.62). Re-transplantation occurred in 18.4% versus 1% for the early and late DCD groups, respectively (p = 0.001). Patient survival was similar in all three groups. Ischemic-type biliary lesions (ITBL) occurred in 5%, 3%, and 0.2% for early DCD, late DCD, and DBD groups, respectively, but unlike in the early DCD group, in the late DCD group ITBL was endoscopically managed and resolved in each case. Using a protocol that includes a thrombolytic therapy, DCD LT yielded patient and graft survival rates comparable to DBD LT.

Environmental and mucosal microbiota and their role in childhood asthma.

BACKGROUND: High microbial diversity in the environment has been associated with lower asthma risk, particularly in children exposed to farming. It remains unclear whether this effect operates through an altered microbiome of the mucosal surfaces of the airways. METHODS: DNA from mattress dust and nasal samples of 86 school age children was analyzed by 454 pyrosequencing of the 16S rRNA gene fragments. Based on operational taxonomic units (OTUs), bacterial diversity and composition were related to farm exposure and asthma status. RESULTS: Farm exposure was positively associated with bacterial diversity in mattress dust samples as determined by richness (P = 8.1 × 10-6 ) and Shannon index (P = 1.3 × 10-5 ). Despite considerable agreement of richness between mattress and nasal samples, the association of richness with farming in nasal samples was restricted to a high gradient of farm exposure, that is, exposure to cows and straw vs no exposure at all. In mattress dust, the genera Clostridium, Facklamia, an unclassified genus within the family of Ruminococcaceae, and six OTUs were positively associated with farming. Asthma was inversely associated with richness [aOR = 0.48 (0.22-1.02)] and Shannon index [aOR = 0.41 (0.21-0.83)] in mattress dust and to a lower extent in nasal samples [richness aOR 0.63 = (0.38-1.06), Shannon index aOR = 0.66 (0.39-1.12)]. CONCLUSION: The stronger inverse association of asthma with bacterial diversity in mattress dust as compared to nasal samples suggests microbial involvement beyond mere colonization of the upper airways. Whether inhalation of metabolites of environmental bacteria contributes to this phenomenon should be the focus of future research.

Phaeohyphomycosis fungal infections in solid organ transplant recipients: clinical presentation, pathology, and treatment.

BACKGROUND: Dematiaceous, or dark-pigmented, fungi are known to cause infections such as phaeohyphomycosis, chromoblastomycosis, and mycetoma. These fungi are becoming increasingly important opportunistic pathogens in solid organ transplant recipients (SOTR). We present a retrospective chart review of 27 SOTR who developed phaeohyphomycosis infections post transplant from 1988 to 2009. METHODS: Cases were reviewed for fungal species isolated, date and source of culture, immunosuppressive and fungal therapy used, and outcome. The majority of isolates obtained were from the skin and soft tissue, with 3 pulmonary and brain abscesses. RESULTS: The time from transplantation to onset of infection ranged from 2 months to 11 years. The species isolated were Exophiala (11), Ochroconis (3), Alternaria (2), Phoma (2), Wangiella (1), Cladosporium (1), Aureobasidium (1), Chaetomium (1), Coniothyrium (1), and non-sporulating fungi (2). An additional 4 patients had infections confirmed by pathology, but no cultures were done. Most of the affected skin lesions were surgically debrided and treated with itraconazole; 2 patients were treated with voriconazole and 2 with amphotericin D. Death from fungal disease occurred only in patients with pulmonary and brain abscesses. CONCLUSIONS: As the number of SOTR increases, so does the incidence of fungal infections in that population. Surgery, along with antifungal therapy and a reduction in immunosuppression, are the cornerstones of treatment.

Soluble immunoglobulin A in breast milk is inversely associated with atopic dermatitis at early age: the PASTURE cohort study.

BACKGROUND: The role of breastfeeding for the development of atopic diseases in childhood is contradictory. This might be due to differences in the composition of breast milk and levels of antimicrobial and anti-inflammatory components. OBJECTIVE: The objective of this study was to examine whether levels of total immunoglobulin A (IgA) or transforming growth factor-ß1 (TGF-ß1) in breast milk were associated with the risk of developing atopic dermatitis (AD), atopic sensitization or asthma at early age taking breastfeeding duration into account. METHODS: The birth cohort study PASTURE conducted in Finland, France, Germany and Switzerland provided 610 breast milk samples collected 2 months after delivery in which soluble IgA (sIgA) and TGF-ß1 levels were measured by ELISA. Duration of breastfeeding was assessed using weekly food frequency diaries from month 3 to month 12. Data on environmental factors, AD and asthma were collected by questionnaires from pregnancy up to age 6. Atopic status was defined by specific IgE levels in blood collected at the ages of 4 and 6 years. Multivariate logistic regression models were used for statistical analysis. RESULTS: Soluble IgA and TGF-ß1 levels in breast milk differed between countries, and sIgA levels were associated with environmental factors related to microbial load, for example, contact to farm animals or cats during pregnancy, but not with raw milk consumption. sIgA levels were inversely associated with AD up to the of age 2 years (P-value for adjusted linear trend: 0.005), independent of breastfeeding duration. The dose of sIgA ingested in the first year of life was associated with reduced risk of AD up to the age of 2 (aOR, 95% CI: 0.74; 0.55-0.99) and 4 years (0.73; 0.55-0.96). No clear associations between sIgA and atopy or asthma up to age 6 were observed. TGF-ß1 showed no consistent association with any investigated health outcome. CONCLUSION AND CLINICAL RELEVANCE: IgA in breast milk might protect against the development of AD.

Excellent liver retransplantation outcomes in hepatitis C-infected recipients.

UNLABELLED: Survival outcomes for liver retransplantation (LRTx) after graft loss in HCV patients (HCV-LRTx) are generally considered inferior to those after non-HCV-LRTx. Between January 1, 2005 and June 30, 2011, our center performed 663 LTx, including 116 (17.5%) LRTx, 41 (35.3%) of which were more than 90 d after the LTx. Twenty-nine (70.7%) LRTx were performed in HCV antibody-positive individuals. We compared patient demographics, baseline characteristics and outcomes of our HCV-LRTx group with the HCV-LRTx patients from the most recent OPTN database covering the same time period. Our Kaplan-Meier HCV-LRTx one-, three-, and five-yr HCV-LRTx patient survival rates were 86.2%, 79.0%, and 72.4%, respectively compared with the OPTN one-, three-, and five-yr HCV-LRTx survival rates of 73.3%, 59.0%, and 51.3% respectively. Likewise, our graft survival rates were higher than OPTN rates at all time points studied. We performed a higher percentage of HCV-LRTx as simultaneous liver/kidney transplants (SLK) (37.9% vs. 21.8%) and recorded shorter warm (30 ± 4 vs. 45 ± 23 min) and cold ischemic times (5:44 ± 1:53 vs. 7:36 ± 3:12 h:min). CONCLUSION: In our experience, HCV-LRTx patient and graft survival rates are comparable to LTx survival rates and are higher than the rates described by OPTN.

Short communication: appropriate and alternative methods to determine viable bacterial counts in cow milk samples.

Farm milk consumption is reported to be inversely related to the development of asthma and atopy in children and it has been hypothesized that microorganisms in milk might contribute to this protective effect. The GABRIEL study was designed to investigate this hypothesis in a large population of European children, calling for a rapid alternative to classical culture techniques to determine bacteriological properties of milk samples. One objective was to evaluate 2 different rapid methods to determine bacteriological properties in a large number of cow milk samples collected under field conditions. BactoScan (Foss Analytical, Hillerød, Denmark), an automated standard flow cytometric method utilized for routine testing of milk quality, and TEMPO (bioMérieux, Marcy l'Etoile, France), an automated most-probable-number method, were used to assess the total viable bacterial count in farm and commercial milk samples. Both methods were compared with standard plate count method and each other. Measurements based on the TEMPO method were in good agreement with the standard plate count method and showed reliable results, whereas BactoScan results did not correlate with standard plate count measurements and yielded higher bacteria counts in heat-treated milk samples compared with raw milk samples. Most likely, these discrepant results were due to inferences with staining reactions and detection of bacteria in heat-treated milk samples. We conclude that, in contrast to the routinely used BactoScan method, the TEMPO method is an inexpensive and rapid alternative to standard culture methods suitable to assess total bacterial counts in processed and raw milk samples.

Reduction of immunosuppression for transplant-associated skin cancer: expert consensus survey.

BACKGROUND: Reduction of immunosuppression is considered a reasonable adjuvant therapeutic strategy in solid-organ transplant recipients experiencing multiple or high-risk skin cancers. However, the literature provides no guidance about what threshold of cancer development would warrant initiation of reduction of immunosuppression. OBJECTIVES: To develop expert consensus guidelines for initiation of reduction of transplant-associated immunosuppression for solid-organ transplant recipients with severe skin cancer. METHODS: An expert consensus panel was convened by the International Transplant Skin Cancer Collaborative and Skin Care for Organ Transplant Patients Europe Reduction of Immunosuppression Task Force. Thirteen hypothetical patient scenarios with graduated morbidity and mortality risks were presented and mean and mode expert opinions about appropriate level of reduction of systemic immunosuppression (mild, moderate, severe) were generated. RESULTS: Mild reduction of transplant-associated immunosuppression was considered warranted once multiple skin cancers per year developed or with individual high-risk skin cancers. Moderate reduction was considered appropriate when patients experienced > 25 skin cancers per year or for skin cancers with a 10% 3-year risk of mortality. Severe reduction was considered warranted only for life-threatening skin cancers. CONCLUSIONS: Reduction of immunosuppression is considered a reasonable adjuvant management strategy for transplant recipients with numerous or life-threatening skin cancers. Proposed guidelines are presented for the graduated reduction of immunosuppression coincident with the increasing skin cancer risks.

Steroid-free liver transplantation using rabbit antithymocyte globulin induction: results of a prospective randomized trial.

Steroids have been 1 of the primary modes of immunosuppression since the inception of transplantation and have been credited with both the prevention and treatment of rejection. Steroids also have been held responsible for increased infections, posttransplantation diabetes, and recurrent hepatitis after orthotopic liver transplantation (OLT). The purpose of this ongoing prospective randomized trial is to eliminate steroid use in OLT through induction with rabbit antithymocyte globulin (RATG). This is the first report of a prospective randomized trial in OLT achieving complete absence of steroids. Seventy-one adult patients were prospectively randomized to administration of RATG or steroids. Thirty-six patients were randomized to the administration of RATG induction at a dose of 1.5 mg/kg intravenously (IV) beginning during the anhepatic phase. No steroids were administered. Patients were administered a second 1.5-mg/kg dose of RATG post-OLT day 1. Thirty-five patients were randomized to the administration of methylprednisolone, which had been our standard immunosuppressive protocol. These patients were administered methylprednisolone, 1,000 mg IV, initiated during the anhepatic phase and followed by steroid taper. Maintenance immunosuppression consisted of tacrolimus and mycophenolate, with or without prednisone. Three patients died in each group, for an overall survival rate of 91% in each group. One patient in each group required re-OLT, for a graft survival rate of 89% in each group. Seven patients administered RATG had biopsy-proven rejection (20.5%), all of whom were successfully treated by increasing tacrolimus doses. Eleven patients administered steroid had biopsy-proven rejection (32%), 7 (64%) of whom required additional steroids for treatment, whereas 4 patients (36%) were successfully treated by increasing tacrolimus doses. The incidence of rejection was not statistically significant; however, there was a significant difference in the incidence of steroid-requiring rejection (P =.01). The incidence of recurrent hepatitis C was 50% in RATG patients and 71% in steroid patients (P = not significant). The incidence and severity of infectious complications were slightly lower in RATG patients, accounted for by a greater incidence of cytomegalovirus (CMV) infection in the steroid patients. RATG induction enables complete avoidance of steroid use in OLT with a trend toward a lower rejection rate, decreased incidence of post-OLT diabetes and recurrent hepatitis C, and decreased CMV infection. This prospective randomized trial gives encouraging support that steroids can be safely eliminated in OLT.

Transplantation of livers from hbc Ab positive donors into HBc Ab negative recipients: a strategy and preliminary results.

Here we describe a strategy for using livers from hepatitis B core antibody (anti-HBc) positive donors in anti-HBc negative recipients and report our preliminary results. Adult anti-HBc negative recipients were immunized against hepatitis B virus (HBV) prior to transplantation. Liver biopsies from anti-HBc positive, HBs Ag negative donors were performed at the time of procurement to rule out acute hepatitis or chronic liver disease. Donor serum and liver samples were collected for HBV DNA analysis by PCR. Recipients were given HBIG (10000 units, i.v.) during the anhepatic phase of transplantation. Patients were treated with lamivudine (150 mg) beginning on postoperative day (POD) 1. If HBV DNA was not detected in either donor liver or serum by PCR, recipient antiviral therapy was stopped. If donor liver and serum were positive for HBV DNA by PCR, the recipient was maintained on combination lamivudine and HBIG therapy. If HBV DNA was detected in donor liver but not in donor serum, the patient was managed on lamivudine therapy alone. Between February 1999 and June 2000, six anti-HBc negative recipients received liver transplants from anti-HBc positive donors. PCR analysis of serum from the six donors was negative for HBV DNA in each, while donor liver PCR analysis was positive in five of six for HBV DNA. Accordingly, all patients were given HBIG in the anhepatic phase of transplantation and five of six were maintained on daily lamivudine therapy. Follow-up periods have ranged from 2 to 18 months. There has been no emergence of de novo hepatitis B. Serial serum HBs Ag and HBV DNA assays have all proven negative. Moreover, while on lamivudine therapy, 2 patients now have undetectable HBV DNA in hepatic allograft biopsies by PCR analysis. Our strategy for using livers from anti-HBc donors has yielded promising initial results. De novo hepatitis B has not occurred and our data suggest residual hepatitis B virus may be eradicated in recipients maintained on lamivudine therapy.

Transplant therapy for type 1 diabetes mellitus.

Insulin-dependent diabetes mellitus is a devastating disease affecting more than one million patients in the United States alone. While advances have been made in exogenous insulin therapy, pancreas transplantation remains the only available treatment that restores a euglycemic state, a consistently normal glycosylated hemoglobin level, and functioning biofeedback regulatory control. New immunosuppressive regimens and improvements in surgical technique have resulted in improved patient and pancreas graft survival rates. Recent advances in islet cell purification and immunosuppressive therapies aimed at reducing rejection have renewed interest in islet cell transplantation.

Combined liver and kidney transplantation in children.

BACKGROUND: Preexisting renal dysfunction has been reported to significantly increase the morbidity and mortality associated with orthotopic liver transplantation (OLT). OLT alone has been recommended for adults and children with end-stage liver disease and reversible causes of renal failure (i.e., hepatorenal syndrome), whereas combined liver and kidney transplantation (LKT) has been shown to be an effective treatment for adults with combined end-stage liver and kidney disease. The purpose of this study was to examine the role of LKT in children. METHODS: Between October of 1984 and 1997, 385 children less than 18 years of age underwent OLT at the University of Chicago. During this same time period 12 patients underwent LKT. Data were gathered by retrospective review of the patients medical records and by interviews conducted with the patients' families. RESULTS: Actuarial patient survival was comparable for children who underwent OLT alone and LKT (69% versus 67% at 5 years). All allograft losses in the LKT group were the result of patient death and occurred within the first 90 postoperative days. Factors associated with decreased patient survival included severity of illness as reflected by United Network of Organ Sharing status and LKT after failed OLT or cadaveric renal transplant. CONCLUSIONS: In children with concomitant endstage liver and kidney disease, LKT can be considered an effective therapeutic option in selected patients. Long-term patient survival in patients undergoing LKT is comparable to that of patients with normal renal function undergoing OLT alone.

Complications in 100 living-liver donors.

OBJECTIVE: A review of 100 living-liver donors was performed to evaluate the perisurgical complications of the procedure and thus to help quantify the risks to the donor. SUMMARY BACKGROUND DATA: Despite the advantages of living-donor liver transplantation (LDLT), the procedure has received criticism for the risk it imposes on healthy persons. A paucity of data exists regarding the complications and relative safety of the procedure. METHODS: One hundred LDLTs performed between November 1989 and November 1996 were reviewed. Donor data were obtained by chart review, anesthesia records, and the computerized hospital data base. Patient variables were compared by Fisher's exact test and the Student's t test. RESULTS: There were 57 women and 43 men with a median age of 29. Donors were divided into two groups: group A (first 50 donors), and group B (last 50 donors). There were 91 left lateral segments and 9 left lobes. There were no deaths. Fourteen major complications occurred in 13 patients; 9 occurred in group A and 5 in group B. Biliary complications consisted of five bile duct injuries (group A = 4, group B = 1) and two cut edge bile leaks. Complications were more common in left lobe resections (55%) than in left lateral segment grafts (10%). Minor complications occurred in 20% of patients. A significant reduction in overall complications (major and minor) was observed between the groups (group A, n = 24 [45%] vs. group B, n = 10 [20%]). In addition, surgical time and hospital stay were both significantly reduced. CONCLUSIONS: Although the procedure is safe, many LDLT donors have a perisurgical complication. Surgical experience and technical modifications have resulted in a significant reduction in these complications, however. To minimize the risks for these healthy donors, LDLT should be performed at institutions with extensive experience.