Induction and treatment of anergy in murine leprosy

Leprosy is a disease consisting of a spectrum of clinical, bacteriological, histopathological and immunological manifestations. Tuberculoid leprosy is frequently recognized as the benign polar form of the disease, while lepromatous leprosy is regarded as the malignant form. The different forms of leprosy depend on the genetic and immunological characteristics of the patient and on the characteristics of the leprosy bacillus. The malignant manifestations of lepromatous leprosy result from the mycobacterial‐specific anergy that develops in this form of the disease. Using murine leprosy as a model of anergy in this study, we first induced the development of anergy to Mycobacterium lepraemurium (MLM) in mice and then attempted to reverse it by the administration of dialysable leucocyte extracts (DLE) prepared from healthy (HLT), BCG‐inoculated and MLM‐inoculated mice. Mice inoculated with either MLM or BCG developed a robust cell‐mediated immune response (CMI) that was temporary in the MLM‐inoculated group and long‐lasting in the BCG‐inoculated group. DLE were prepared from the spleens of MLM‐ and BCG‐inoculated mice at the peak of CMI. Independent MLM intradermally‐inoculated groups were treated every other day with HLT‐DLE, BCG‐DLE or MLM‐DLE, and the effect was documented for 98 days. DLE administered at a dose of 1.0 U (1 × 10⁶ splenocytes) did not affect the evolution of leprosy, while DLE given at a dose of 0.1 U showed beneficial effects regardless of the DLE source. The dose but not the specificity of DLE was the determining factor for reversing anergy.     

Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule

Many factors have been shown to promote myelination, but few have been shown to be inhibitory. Here, we show that polysialylated-neural cell adhesion molecule (PSA-NCAM) can negatively regulate myelin formation. During development, PSA-NCAM is first expressed on all growing fibers; then, axonal expression is down-regulated and myelin deposition occurs only on PSA-NCAM-negative axons. Similarly, in cocultures of oligodendrocytes and neurons, PSA-NCAM expression on axons is initially high, but decreases as myelination proceeds. Importantly, if expression of PSA-NCAM is prematurely decreased in cultures, by either antibody-mediated internalization or enzymatic removal of the PSA moieties with endoneuraminidase N (endo-N), myelination increases 4- to 5-fold. In the optic nerve, premature cleavage of PSA moieties by intravitreous injection of endo-N also induces a transient increase in the number of myelinated internodes, but does not interfere with the onset of myelination. Previously, we showed that axonal electrical activity strongly induced myelination, which could be prevented by tetrodotoxin (TTX), an action potential blocker. Interestingly, removal of PSA moieties does not reverse the inhibition of myelination by TTX. Together, this suggests that myelination is tightly controlled by both positive (electrical activity) and negative (PSA-NCAM expression) regulatory signals.     

Modulation of megakaryocytopoiesis by thrombopoietin: the c-Mpl ligand

We have further characterized the biological activities, mechanism of action, and target cell populations of recombinant human and murine thrombopoietin (rhTPO and rmTPO) in in vitro human and murine model systems. Alone, hTPO or mTPO stimulated the maturation of immature murine megakaryoblasts as measured in a single cell assay. The combination of hTPO or mTPO and interleukin-6 (IL-6) resulted in a further increase in megakaryocyte differentiation in this system. Murine TPO stimulated mouse megakaryocyte progenitor development. Human megakaryocyte progenitor development was potentiated by hTPO alone and further augmented in the presence of the early-acting cytokines (IL-3) or kit ligand/stem cell factor (KL/SCF). To further define the mechanism of action of TPO, neutralization studies were performed with antisera to IL-3, granulocyte-macrophage colony-stimulating factor (GM- CSF), IL-1 beta, and IL-11. No diminution in TPO activity was observed in the presence of these antisera. Moreover, because adhesive interactions are known to modulate hematopoiesis, we studied whether hTPO might alter such interactions between human bone marrow (BM) megakaryocytes and human BM stromal fibroblasts. No changes were observed in either megakaryocyte expression of the surface molecules lymphocyte function-associated antigen-1, very late activation antigen- 4, or intercellular adhesion molecule-1 or the adhesion of megakaryocytes to stromal fibroblasts after treatment with the growth factor. Furthermore, no induction of secretion of the cytokines IL-1 alpha, IL-1 beta, GM-CSF, IL-6, granulocyte-CSF, tumor necrosis factor- alpha, transforming growth factor-beta 1, or transforming growth factor- beta 2 by primary human BM megakaryocytes was noted after treatment of the cells with hTPO. To address whether TPO affects very primitive hematopoietic progenitors, we studied the residual cells from the BMs of mice treated with high doses of 5-fluorouracil. Although no effect of mTPO alone was noted on the viability or replication of such primitive murine progenitor populations, the triple combination of IL-3 + KL/SCF + TPO stimulated growth of megakaryocyte progenitors. These results indicate that TPO is a highly lineage-specific growth factor whose primary biological effects are likely to be direct modulation of the growth and maturation of committed megakaryocyte precursors and immature megakaryoblasts.     

Trends and Differences Among Three New Indicators of HIV Infection Progression

Objective

This study proposes three indicators of, and assesses the disparities and trends in, the risk of HIV infection progression among people living with diagnosed HIV infection in the United States.

Methods

Using data reported to national HIV surveillance through June 2012, we calculated the AIDS diagnosis hazard, HIV (including AIDS) death hazard, and AIDS death hazard for people living with diagnosed HIV infection for each calendar year from 1997 to 2010. We also calculated a stratified hazard in 2010 by age, race/ethnicity, mode of transmission, region of residence at diagnosis, and year of diagnosis.

Results

The risk of HIV infection progression among people living with diagnosed HIV infection decreased significantly from 1997 to 2010. The risks of progression to AIDS and death in 2010 were higher among African Americans and people of multiple races, males exposed through injection drug use (IDU) or heterosexual contact, females exposed through IDU, people residing in the South at diagnosis, and people diagnosed in 2009 compared with white individuals, men who have sex with men, females with infection attributed to heterosexual contact, those residing in the Northeast, and those diagnosed in previous years, respectively. People aged 15–29 years had the highest AIDS diagnosis hazard in 2010.

Conclusion

Continued efforts are needed to ensure early HIV diagnosis as well as initial linkage to and continued engagement in HIV medical care among all people living with HIV. Targeted interventions are needed to improve health-care and supportive services for those with worse health outcomes.In the United States, the number of people aged 13 years and older living with human immunodeficiency virus (HIV) infection was estimated to be more than 1.1 million as of December 2010, a 9% increase from 2006.¹ For people living with HIV, increasing their access to care and eliminating disparities are primary goals of the National HIV/AIDS Strategy (NHAS) and the Healthy People 2020 objectives.^2,3 Assuring that all people with HIV are diagnosed early, promptly linked to care, retained in care, and offered antiretroviral treatment is essential to achieve the ultimate goal of the continuum of care,⁴ leading to viral suppression, improved health, survival, and prevention of HIV transmission.Several studies have used national HIV surveillance data to examine the disparities and determinants of progression to acquired immunodeficiency syndrome (AIDS; i.e., stage 3 HIV infection⁵) and death after HIV diagnosis. These studies have focused on individuals diagnosed in a certain time period and have examined the differences in time from HIV diagnoses to AIDS and death (i.e., the number of months/years from HIV diagnosis to AIDS or death) using survival analyses, including Kaplan-Meier survival curves, the Cox proportional hazard model, or the standardized relative risk.^6–8 However, previous studies have not assessed the risks of progression to AIDS and death among all people living with HIV, and have not reported the trends in these outcomes.To fill this gap, we propose in this study three cross-sectional indicators to estimate the risks of progression to AIDS and death in a calendar year after HIV diagnoses among people living with diagnosed HIV infection, regardless of their time of diagnosis (i.e., the year when an HIV infection was first diagnosed). The results allow for an annual assessment of the risks of HIV infection progression and can be used to monitor the trends in these outcomes among people living with HIV.Specifically, this study (1) examined the disparities in the risk of progression to AIDS in 2010 among people living with diagnosed HIV (not AIDS) infection at year-end 2009 (AIDS diagnosis hazard), the risk of death in 2010 among those living with diagnosed HIV (including AIDS) infection at year-end 2009 (HIV death hazard), and the risk of death in 2010 among individuals living with AIDS at year-end 2009 (AIDS death hazard); and (2) assessed the trends in the risks of HIV infection progression among people living with diagnosed HIV infection from 1997 to 2010 using the three indicators.     

The effect of intravenous insulin,apheresis and oral lipid-lowering agents on non-fasting hypertriglyceridemia and associated pancreatitis

Objectives: There is evidence that increasing severity of hypertriglyceridemia increases the risk of acute pancreatitis. There is a debate about superiority of treatment methods and previous works have specifically called for direct comparison between IV insulin and apheresis techniques. Identify patient characteristics predictive of lipid-lowering therapy selection in a large community hospital for treatment of hypertriglyceridemia; evaluate for a concentration-dependent relationship between hypertriglyceridemia severity and risk of acute pancreatitis; assess for differences in clinical outcomes between patients treated with IV insulin versus apheresis.

Methods: Single center, retrospective cohort study including patients with hypertriglyceridemia between January 2007 and December 2016. Main measures included frequency of pancreatitis, choice of lipid-lowering therapy, and clinical comparisons of diet, oral lipid-lowering agents, IV insulin, and apheresis.

Results: Initial serum triglyceride level and disease acuity was higher among patients in insulin and apheresis groups. Neither triglyceride level, Charlson comorbidity index, age, BISAP score, nor initial CRP predicted use of IV insulin versus apheresis. Prevalence of pancreatitis increased with higher triglyceride level, reaching 48% with triglycerides >2000 md/dL (p < 0.001). There was a significant decrease in serum triglycerides at each time interval (p < 0.05) in patients treated with IV insulin and apheresis, but no difference in clearance rate between the two. Length of stay did not differ between IV insulin and apheresis.

Conclusion: The presence of pancreatitis, hyperglycemia, and hypertriglyceridemia severity influenced selection of therapies like IV insulin and apheresis. We found no superiority of either IV insulin or apheresis in the treatment of severe hypertriglyceridemia among patients hospitalized for pancreatitis.