We retrospectively analyzed the prognostic significance of mixed chimerism and associated clinical parameters in 80 patients following unmanipulated allogenic stem cell transplantation. Chimerism studies were performed on marrow aspirates using fluorescent in situ hybridization and variable number tandem repeats techniques at day þ 30, day þ 90 and þ 12 months. The median overall survival (OS) was 24 months (range, 1-56 months). Mixed chimerism was found in 23, 28 and 14% of patients at day þ 30 (1 month), þ 90 (3 months), and þ 12 months, respectively. Day þ 30 chimerism studies failed to provide any prognostic information. Day þ 90 mixed chimeras (MC) had significantly higher relapse rates compared to day þ 90 complete chimeras (CC) at 6 months (P ¼ 0.03) and 18 months when compared to MC (P ¼ 0.03) following transplant. The median OS in day þ 90 MC and day þ 90 CC were, respectively (95% CI, 2-35 months), compared to 47 months (95% CI, 20-74 months) (P ¼ 0.02). In conclusion, chimerism studies on day þ 30 could be reserved for patients who fail to demonstrate engraftment. Day þ 90 MC had higher relapse rates and lower OS, and therefore may be considered for novel therapies and future studies.

No abstract

Growing evidence indicates that PPARγ agonists, including rosiglitazone (RSG), induce adipose mitochondrial biogenesis. By systematically analyzing mitochondrial gene expression in two common murine adipocyte models, the current study aimed to further establish the direct role of RSG and capture temporal changes in gene transcription. Microarray profiling revealed that in fully differentiated 3T3-L1 and C3H/10T1/2 adipocytes treated with RSG or DMSO vehicle for 1, 2, 4, 7, 24, and 48 hrs, RSG overwhelmingly increased mitochondrial gene transcripts time dependently. The timing of the increases was consistent with the cascade of organelle biogenesis, that is, initiated by induction of transcription factor(s), followed by increases in the biosynthesis machinery, and then by increases in functional components. The transcriptional increases were further validated by increased mitochondrial staining, citrate synthase activity, and O2 consumption, and were found to be associated with increased adiponectin secretion. The work provided further insight on the mechanism of PPARγ-induced mitochondrial biogenesis in differentiated adipocytes.

There is strong circumstantial evidence that multiple sclerosis (MS) is an autoimmune disease. Nonspecific immunosuppressive therapy has not been successful in altering the natural course of the illness. Bone marrow transplantation has heretofore been a radical therapy used in patients with life-threatening malignancies but has potential as a treatment for human autoimmunity. In MS there have been no controlled studies. We report here four patients with MS undergoing bone marrow transplantation with 6-48 months of follow-up. In three this was carried out for co-existing malignancy and in one as an experimental treatment for MS using the patient's unaffected identical twin as a donor. The limited outcome that can be evaluated in these patients supports further experimentation into this treatment modality in MS patients with poor prognostic indications.

The gastrointestinal tract microbiome has been suggested as a potential therapeutic target for metabolic diseases such as obesity and Type 2 diabetes mellitus (T2DM). However, the relationship between changes in microbial communities and metabolic disease-phenotypes are still poorly understood. In this study, we used antibiotics with markedly different antibacterial spectra to modulate the gut microbiome in a diet-induced obesity mouse model and then measured relevant biochemical, hormonal and phenotypic biomarkers of obesity and T2DM. Mice fed a high-fat diet were treated with either ceftazidime (a primarily anti-Gram negative bacteria antibiotic) or vancomycin (mainly anti-Gram positive bacteria activity) in an escalating three-dose regimen. We also dosed animals with a well-known prebiotic weight-loss supplement, 10% oligofructose saccharide (10% OFS). Vancomycin treated mice showed little weight change and no improvement in glycemic control while ceftazidime and 10% OFS treatments induced significant weight loss. However, only ceftazidime showed significant, dose dependent improvement in key metabolic variables including glucose, insulin, protein tyrosine tyrosine (PYY) and glucagon-like peptide-1 (GLP-1). Subsequently, we confirmed the positive hyperglycemic control effects of ceftazidime in the Zucker diabetic fatty (ZDF) rat model. Metagenomic DNA sequencing of bacterial 16S rRNA gene regions V1-V3 showed that the microbiomes of ceftazidime dosed mice and rats were enriched for the phylum Firmicutes while 10% OFS treated mice had a greater abundance of Bacteroidetes. We show that specific changes in microbial community composition are associated with obesity and glycemic control phenotypes. More broadly, our study suggests that in vivo modulation of the microbiome warrants further investigation as a potential therapeutic strategy for metabolic diseases.

No abstract

Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (EBV-LPDA 1-year-old female with malignant osteopetrosis received a conditioning regimen with high-dose cyclophosphamide and rabbit antithymocyte globulin (ATG), at a dose of 5 mg/kg of body weight/day, for 4 days followed by an HLA-matched unrelated-donor umbilical cord transplant. Immunosuppression after transplantation consisted of cyclosporine, methotrexate, and corticosteroids. The patient did not receive any additional immunosuppression besides graft-versus-host disease (GvHD) prophylaxis with cyclosporine. On day 49, she developed low-grade fever, dyspnea, and rash. The fever, dyspnea, and rash persisted even after treatment with empirical antibiotic therapy and initiation of steroids for presumptive acute GvHD. The patient subsequently deteriorated and required mechanical ventilation. Bronchoalveolar lavage fluid was used in viral and bacterial cultures and Epstein-Barr virus (EBV)-PCR. Empirical antiviral therapy with ganciclovir was started. The patient further deteriorated and died on day 54 as a result of multiorgan failure. Autopsy findings revealed extensive multiorgan involvement, including the lungs, kidneys, liver, and multiple lymph nodes, and microscopy showed disseminated polymorphous B cells (posttransplant lymphoproliferative disease [PTLD]). These cells stained strongly positive for EBER, a nontranslated RNA (Fig. 1). PCR and EBV serology results, which were consistent with the diagnosis of PTLD, were subsequently available.Case 2. A 28-year-old female with scleroderma received a conditioning regimen which included high-dose cyclophosphamide, total-body irradiation, and rabbit ATG at a dose of 5 mg/kg/day, followed by an autologous CD34 ϩ -selected bone marrow transplant (BMT). The patient received acyclovir prophylaxis (800 mg orally twice a day) for a positive herpes simplex virus serology after transplantation. On day 54, she was readmitted with fatigue, adenopathy, and fever. Empirical antibiotics and antiviral therapy with ganciclovir were initiated. A reduction in her dose of steroids, which she had been taking for pulmonary toxicity, was immediately instituted. An infusion with unprocessed autologous peripheral blood progenitor cells was given on day 60 because of a presumptive diagnosis of EBV-associated lymphoproliferative disorder (EBV-LPD). The patient required mechanical ventilation and died of multiorgan failure on day 63. Subsequent studies were positive for EBV-PCR, and an immunohistochemical examination of the lymph node was positive for EBER. Autopsy findings were consistent with EBV-LPD (Fig. 2). This case was previously reported by Nash et al. (11).Case 3. A 35-year-old female with Philadelphia chromosome-positive acute lymphoblastic leukemia in first complete remission received a conditioning regimen with cyclophosphamide, total-body irradiation, and rabbit ATG (10 mg/kg/ day), followed by matched unrelated-donor stem cell transplantation. On day 58, the patient was readmitted with fever,

We describe the clinical courses of 3 patients with hematologic malignancies (2 with acute myelogenous leukemia and 1 with multiple myeloma) who developed invasive fungal infections due to uncommon molds (Alternaria spp., Paecilomyces lilacinus, and Zygomycetes). Breakthrough invasive fungal infections of the sinus (n=1), lung (n=3), and pericardium (n=1) developed despite fluconazole prophylaxis and failed to respond to treatment with other licensed antifungal therapies, including amphotericin B (n=3), caspofungin (n=2), and voriconazole (n=3), and surgical intervention (n=2). Salvage therapy with posaconazole oral suspension resulted in successful outcomes in all 3 patients, who subsequently underwent allogeneic hematopoietic stem cell transplantation (HSCT) while on continued posaconazole therapy. The median duration of posaconazole treatment before HSCT was 5 months (range: 1.5-6 months). Posaconazole salvage therapy allowed successful allogeneic HSCT in 3 patients with refractory invasive mold infections.