The limited success in understanding the pathophysiology of major depression may result from excessive focus on the dysfunctioning of neurons, as compared with other types of brain cells. Therefore, ...we examined the role of dynamic alterations in microglia activation status in the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We report that following an initial period (2-3 days) of stress-induced microglial proliferation and activation, some microglia underwent apoptosis, leading to reductions in their numbers within the hippocampus, but not in other brain regions, following 5 weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. Blockade of the initial stress-induced microglial activation by minocycline or by transgenic interleukin-1 receptor antagonist overexpression rescued the subsequent microglial apoptosis and decline, as well as the CUS-induced depressive-like behavior and suppressed neurogenesis. Similarly, the antidepressant drug imipramine blocked the initial stress-induced microglial activation as well as the CUS-induced microglial decline and depressive-like behavior. Treatment of CUS-exposed mice with either endotoxin, macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, all of which stimulated hippocampal microglial proliferation, partially or completely reversed the depressive-like behavior and dramatically increased hippocampal neurogenesis, whereas treatment with imipramine or minocycline had minimal or no anti-depressive effects, respectively, in these mice. These findings provide direct causal evidence that disturbances in microglial functioning has an etiological role in chronic stress-induced depression, suggesting that microglia stimulators could serve as fast-acting anti-depressants in some forms of depressive and stress-related conditions.
We examined the associations of Epstein–Barr virus (EBV) status with characteristics and outcomes of posttransplantation lymphoproliferative disorder (PTLD) by studying 176 adult solid organ ...transplant recipients diagnosed with PTLD between 1990 and 2013 (58 33% EBV‐negative; 118 67% EBV‐positive). The proportion of EBV‐negative cases increased over time from 10% (1990–1995) to 48% (2008–2013) (p < 0.001). EBV‐negative PTLD had distinct characteristics (monomorphic histology, longer latency) though high‐risk features (advanced stage, older age, high lactate dehydrogenase, central nervous system involvement) were not more common compared to EBV‐positive PTLD. In multivariable analysis, EBV negativity was not significantly associated with worse response to initial therapy (adjusted odds ratio, 0.84; p = 0.75). The likelihood of achieving a complete remission (CR) was not significantly different for EBV‐negative versus EBV‐positive PTLD including when therapy was reduction of immunosuppression alone (35% vs. 43%, respectively, p = 0.60) or rituximab (43% vs. 47%, p = 1.0). EBV negativity was also not associated with worse overall survival (adjusted hazard ratio, 0.91; p = 0.71). Our findings indicate that EBV status is not prognostic or predictive of treatment response in adults with PTLD. The high proportion of EBV‐negative disease diagnosed in recent years highlights the need for new strategies for prevention and management of EBV‐negative PTLD.
In a study of 176 solid organ transplant recipients with posttransplantation lymphoproliferative disorder, the authors show that the proportion of Epstein–Barr virus–negative cases has increased over time, but Epstein–Barr virus negativity is not associated with high‐risk features, worse response to initial therapy, or worse overall survival.
Reduction of immunosuppression (RI) is commonly used to treat posttransplant lymphoproliferative disorder (PTLD) in solid organ transplant recipients. We investigated the efficacy, safety and ...predictors of response to RI in adult patients with PTLD. Sixty‐seven patients were managed with RI alone and 30 patients were treated with surgical excision followed by adjuvant RI. The response rate to RI alone was 45% (complete response—37%, partial response—8%). The relapse rate in complete responders was 17%. Adjuvant RI resulted in a 27% relapse rate. The acute rejection rate following RI‐containing strategies was 32% and a second transplant was feasible without relapse of PTLD. The median survival was 44 months in patients treated with RI alone and 9.5 months in patients who remained on full immunosuppression (p = 0.07). Bulky disease, advanced stage and older age predicted lack of response to RI. Survival analysis demonstrated predictors of poor outcome—age, dyspnea, B symptoms, LDH level, hepatitis C, bone marrow and liver involvement. Patients with none or one of these factors had a 3‐year overall survival of 100% and 79%, respectively. These findings support the use of RI alone in low‐risk PTLD and suggest factors that predict response and survival.
The authors describe the response of post‐transplant lymphoproliferative disease to reduction of immunosuppression and analyze predictors of response and survival in a large single‐center cohort.
AML is currently the most common indication for reduced-intensity conditioned (RIC) allo-SCT. Reduced-intensity regimens allow a potent GVL response to occur with minimized treatment-related toxicity ...in patients of older age or with comorbidities that preclude the use of myeloablative conditioning. Whether RIC SCT is appropriate for younger and more standard risk patients is not well defined and the field is changing rapidly; a prospective randomized trial of myeloablative vs RIC (BMT-CTN 0901) was recently closed when early results indicated better outcomes for myeloablative regimens. However, detailed results are not available, and all patients in that study were eligible for myeloablative conditioning. RIC transplants will likely remain the standard of care as many patients with AML are not eligible for myeloablative conditioning. Recent publication of mature results from retrospective and prospective cohorts provide contemporary efficacy and toxicity data for these attenuated regimens. In addition, recent studies explore the use of alternative donors, introduce regimens that attempt to reduce toxicity without reducing intensity, and identify predictive factors that pave the way to personalized approaches. These studies paint a picture of the future of RIC transplants. Here we review the current status of RIC allogeneic SCT in AML.
The present study examines the thermal reaction phenomenon associated with the penetration of a hot metal solid sphere into a cold liquid reservoir. The effect of various parameters on the sudden ...collapse of the vapor film around the sphere is studied. A pre-heated metal sphere, made of aluminum, copper, or steel having different dimensions and a variable initial temperature, has been immersed in a varied degree of sub-cooled water. The evolution of the time-dependent temperature of the solid body has been recorded. Simultaneously, the film collapsing process has been recorded with a video camera. It is observed that above a certain sub-cooling degree, film collapsing noise (vapor explosion) and higher heat transfer rates are involved. The temperature, at which the film collapses, the quenching temperature, seems to be dependent on the sub-cooling degree, on the sphere material, and on the sphere size.
We found that the steam explosion is followed by an apparent “golf-ball” like boiling period. This occurs between the transition and the film boiling regimes. During the “golf-ball” boiling period, the sphere surface appears to be covered by a large number of concaved cells having a characteristic dimension of about 3
mm.
In order to explore the possible effect of the hot surface curvature of the immersed body, generalization of the pool boiling hydrodynamic theory for MHF conditions has been developed for arbitrarily curved heater geometries. The MHF is related to the mass rate of the vapor leaving the vapor film under these conditions. An account for the excess pressure acting on the base of the bubble arises from the excess pressure of the vapor film, due its curvature, has been added. The applicability of this model is presented for a horizontal plate, horizontal cylinders, and spheres. The model seems to fit well available experimental data for the different systems.
► Penetration of a hot metal solid sphere into a cold liquid reservoir is examined. ► The sudden collapse of the vapor film around the sphere is studied. ► The collapse temperature dependents on the sub-cooling, sphere material, and size. ► The steam explosion is followed by an apparent “golf-ball” like boiling period. ► Pool boiling theory is generalized for arbitrarily curved heater geometries.
There is significant variability in the serum concentrations of tacrolimus attained early post transplant due to drug interactions and genomic variation. We evaluated whether tacrolimus ...concentrations early post transplant correlated with incidence of acute GvHD in 120 consecutive patients allografted with a uniform reduced-intensity conditioning regimen. All patients received standard prophylaxis with oral tacrolimus and IV methotrexate. The primary variable of interest was mean weekly tacrolimus concentrations in the initial 4 weeks post transplant. In multivariate analysis, week 1 tacrolimus concentration was an independent predictor of acute grade 2-4 GvHD (hazard ratio (HR), 0.90; 95% confidence interval (CI), 0.84-0.97; P<0.01). This association was driven by a lower risk of acute grade 2-4 GvHD in patients with week 1 tacrolimus concentrations >12 ng/mL (HR, 0.47; 95% CI, 0.25-0.88; P=0.02). Week 1 tacrolimus concentrations were not associated with chronic GvHD, relapse or overall survival. Lower tacrolimus concentrations at weeks 2, 3 and 4 were not associated with a higher incidence of GvHD. In summary, we found that higher tacrolimus concentrations during the first week after allografting with a reduced-intensity conditioning regimen were associated with significantly reduced risk of acute grade 2-4 GvHD without increasing risk of relapse.
We present a case of Type 1 (lipogenic) Thyroid Eye Disease (TED) and our aim is to describe an atypical presentation of a rare orbital process.
A man in his 50s presented with left-sided eyelid ...drooping. His exam showed no evidence of active inflammation but did show left hyperglobus and ipsilateral upper eyelid pseudoptosis. He had no prior history or symptoms of Graves’ Disease and imaging did not show evidence of extraocular muscle enlargement, bony asymmetries, or masses in the orbit. Subsequent lab work showed a low TSH (thyroid-stimulating hormone), elevated free T4 (thyroxine) and T3 (triiodothyronine), and elevated TSI (thyroid-stimulating immunoglobulin) index.
This is a unique and atypical presentation of a patient diagnosed with Type 1 (lipogenic) TED causing hyperglobus and pseudoptosis secondary to fat expansion in the absence of other classic TED findings such as contralateral eyelid retraction or extraocular muscle enlargement. Thyroid eye disease can have a heterogenous disease presentation, as evidenced by this case, and should always be considered in the differential diagnosis of pseudoptosis.
To report two cases of thyroid eye disease (TED) associated compressive optic neuropathy (CON) that resolved after treatment with teprotumumab.
Two patients presented with active TED resulting in ...mild CON with the typical corresponding visual field (VF) defects. Both patients were initiated on intravenous (IV) corticosteroid therapy but despite treatment had persistent VF defects. Both patients were then treated with teprotumumab and demonstrated marked clinical improvement and complete resolution of TED-CON VF defects early in their infusion course.
These cases suggest that teprotumumab can be a rapid and effective treatment for TED-CON, and raises the question of whether it may be superior to IV corticosteroid therapy.
This editorial provides commentary on Finalet Ferreiro et al’s study (page 414) demonstrating that Epstein-Barr virus–positive and –negative posttransplantation lymphoproliferative disorders have ...different genetic origins, shedding light on the pathogenesis of posttransplant malignancies
PDF
