Current Practice in Vitamin D Management in Allogeneic Hematopoietic Stem Cell Transplantation: A Survey by the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation

Beyond its impact on bone health, numerous studies have investigated the immune-regulatory properties of vitamin D and shown how its deficiency can affect outcomes in allogeneic hematopoietic stem cell transplantation (HSCT), particularly in acute or chronic graft-versus-host disease. This survey, carried out by the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation (EBMT), describes the current clinical practice discrepancies across the EBMT HSCT programs. We therefore recommend the development of evidence-based guidelines to standardize evaluation criteria and to harmonize the management of vitamin D deficiency in patients undergoing allogeneic HSCT.     

Not All Masks Are Created Equal: Masking Success in Clinical Trials of Children and Adolescents

The current study assessed the success of masking omega-3 (Ω3) and psychotherapy in clinical trials of youth with depression or bipolar spectrum disorder. Participants were youth ages 7–14 with DSM-IV-TR diagnosed depressive (n = 72) or bipolar spectrum (n = 23) disorders. Inclusion diagnoses were depressive disorder, cyclothymic disorder, or bipolar disorder not otherwise specified. Exclusion diagnoses included bipolar I or II disorder, chronic medical condition or autism. Youth participated in 2 × 2 randomized controlled trials, in which they received Ω3 or placebo (PBO) and psychoeducational psychotherapy (PEP) or active monitoring (AM). Participants and study staff (including independent interviewers) were masked to Ω3/PBO allocation. Besides the masked independent interviewers, one coprincipal investigator (Co-PI) was fully masked to both conditions and completed all consensus conference ratings postrandomization. At the endpoint assessment or last completed interview, interviewers and the masked Co-PI guessed whether each child was assigned to Ω3 or PBO and to PEP or AM. Masking failure was calculated using the degree of correct guesses above chance level using binomial tests across all participants for Ω3 versus PBO and PEP versus AM. For all guessers, Ω3 allocation was guessed correctly approximately half the time (50%–52.5%). Rates of correct guessing were higher for PEP, but only the interviewer guesses were correct significantly more often (58.5%–68.7%) than chance. Reporting of masking success should be an essential element of RCTs. Psychotherapy is generally more difficult to mask, but with attentive masking procedures reasonable masking can be achieved.     

Effects of plane of nutrition and arginine on ovarian follicles in non-pregnant sheep: Cell proliferation,and expression of endothelial nitric oxide and its receptor

The aim of this study was to investigate the role of the nitric oxide (NO) system in ovarian function, by determining if arginine (Arg) supplementation impacts follicle number, cell proliferation, and expression of the NO system members in nutritionally compromised ewes. Ewes were randomly assigned into maintenance (C, 100% requirements), excess (O; 2xC), or restricted (U; 0.6xC) diets 8 weeks prior to Arg treatment. Ewes were individually fed twice daily with pelleted diets. Ewes from each nutritional group were randomly assigned to one of two treatments: saline or Arg, which was initiated on day 0 of the estrous cycle and administered 3 times per day. Ovaries were collected at the early-luteal, mid-luteal and late-luteal/follicular phases of the estrous cycle to determine 1) the number of surface follicles, 2) follicle cell proliferation marked by Ki67 protein expression, and 3) expression of endothelial nitric oxide (eNOS; NOS3) and soluble guanylyl cyclase beta (sGC; GUCY1B3) protein and mRNA in granulosa (G) and theca (T) layers using immunohistochemistry followed by image analysis and qPCR, respectively. During nutritional treatment, C maintained body weight, O gained 6±1.2 kg, and U lost 14±1.3 kg. Our data show that: 1) Ki67 was expressed in all ovarian compartments, eNOS protein was detected in blood vessels of T and stroma, and sGC protein was detected in T cells, and blood vessels of T layer and other ovarian compartments; 2) plane of nutrition affected the number of surface follicles, and thus folliculogenesis, cell proliferation in the T layer, eNOS and sGC protein expression in T, and NOS3 and GUCY1B3 mRNA expression in G; 3) Arg treatment affected cell proliferation in G and T, eNOS and sGC protein expression in T, mRNA expression of NOS3 in T in all groups, and GUCY1B3 in G depending on the stage of the estrous cycle; and 4) G and T cell proliferation, and expression of eNOS and sGC protein in T was affected by the stage of the estrous cycle. Our data demonstrated that plane of nutrition and Arg are involved in the regulation of follicular functions in non-pregnant sheep.     

Acute phase protein, α – 1- acid glycoprotein (AGP-1), has differential effects on TLR-2 and TLR-4 mediated responses

Alpha-1-acid glycoprotein (AGP-1) is a major positive acute phase glycoprotein with unknown functions that likely play a role in inflammation. We tested its involvement in a variety of inflammatory responses using human AGP-1 purified to apparent homogeneity and confirmed its identity by immunoblotting and mass spectrometry. AGP-1 alone upregulated MAPK signaling in murine peritoneal macrophages. However, when given in combination with TLR ligands, AGP-1 selectively augmented MAPK activation induced by ligands of TLR-2 (Braun lipoprotein) but not TLR-4 (lipopolysaccharide). In vivo treatment of AGP-1 in a murine model of sepsis with or without TLR-2 or TLR-4 ligands, selectively potentiated TLR-2-mediated mortality, but was without significant effect on TLR-4-mediated mortality. Furthermore, in vitro, AGP-1 selectively potentiated TLR-2 mediated adhesion of human primary immune cell, neutrophils. Hence, our studies highlight a new role for the acute phase protein AGP-1 in sepsis via its interaction with TLR-2 signaling mechanisms to selectively promote responsiveness to one of the two major gram-negative endotoxins, contributing to the complicated pathobiology of sepsis.