Dima Youssef

Antimicrobial implications of vitamin D

Evidence exists that vitamin D has a potential antimicrobial activity and its deficiency has deleterious effects on general well-being and longevity. Vitamin D may reduce the risk of infection through multiple mechanisms. Vitamin D boosts innate immunity by modulating production of anti-microbial peptides (AMPs) and cytokine response. Vitamin D and its analogues via these mechanisms are playing an increasing role in the management of atopic dermatitis, psoriasis, vitiligo, acne and rosacea. Vitamin D may reduce susceptibility to infection in patients with atopic dermatitis and the ability to regulate local immune and inflammatory responses offers exciting potential for understanding and treating chronic inflammatory dermatitides. Moreover, B and T cell activation as well as boosting the activity of monocytes and macrophages also contribute to a potent systemic anti-microbial effect. The direct invasion by pathogenic organisms may be minimized at sites such as the respiratory tract by enhancing clearance of invading organisms. A vitamin D replete state appears to benefit most infections, with the possible noteworthy exception of Leishmaniasis. Antibiotics remain an expensive option, and misuse of these agents results in significant antibiotic resistance and contributes to escalating health care costs. Vitamin D constitutes an inexpensive prophylactic option and possibly therapeutic product either by itself or as a synergistic agent to traditional antimicrobial agents. This review outlines the specific antimicrobial properties of vitamin D in combating a wide range of organisms. We discuss the possible mechanisms by which vitamin D may have a therapeutic role in managing a variety of infections.

Healthcare costs of Staphylococcus aureus and Clostridium difficile infections in Veterans: role of vitamin D deficiency

Clostridium difficile and staphylococcal infections are associated with increased morbidity, mortality and healthcare costs. Vitamin D deficiency may also contribute to increased healthcare costs. There is increasing evidence that vitamin D may have an antimicrobial role. We examined the relationship of serum 25(OH)D levels to staphylococcal and C. difficile infections to determine if vitamin D deficiency was associated with adverse outcomes. In the outpatient setting, vitamin D deficiency in patients with C. difficile and staphylococcal infections were associated with significantly increased total outpatients costs and fee-based consultation. Laboratory expenses had a trend towards higher costs in the vitamin D-deficient group but did not reach statistical significance. The differences were most clearly seen in the in-patient group with enhanced laboratory, pharmacy and radiology costs. These differences resulted in vitamin D-deficient patients with C. difficile or staphylococcal infections having costs more than five times higher than the non-deficient patients. The total length of hospital stay was four times greater in the vitamin D-deficient group. In addition, the total number of hospitalizations was also significantly greater in the vitamin D-deficient group. Surgery costs demonstrated a tendency to be higher in the vitamin D-deficient group but failed to reach statistical significance. Vitamin D deficiency is intimately linked to adverse health outcomes and costs in Veterans with staphylococcal and C. difficile infections in North East Tennessee. We recommend that vitamin D status be checked in patients with these infections and appropriate therapy be instituted to restore vitamin D level to normal in an expeditious manner.

Secondary hyperparathyroidism: benign bystander or culpable contributor to adverse health outcomes?

Abstract Elevation in serum parathyroid hormone (PTH) often accompanies vitamin D deficiency and renal impairment. PTH elevation in renal failure is viewed as an unfavorable development. Evidence is increasing that PTH elevation may be associated with increased morbidity and mortality. In many instances these PTH effects appear to be independent of vitamin D status. PTH mediates its effects through the ubiquitous type 1 PTH/PTH–related peptide receptor, which is notably present in the cardiovascular system. Increased PTH may promote cardiovascular disease through diminished cardiac contractility, enhanced coronary risk, and cardiac valvular and vascular calcification. High PTH levels appear to be linked to the metabolic syndrome and are aligned with hyperlipidemia, decreased insulin sensitivity, and, perhaps, decreased insulin secretion. Increased PTH also is associated with neuroendocrine activation, increased sympathetic activity, and endothelial stress. The relation between PTH and vitamin D is complex and may show significant threshold variations, especially when calcium intake, age, and race are considered. Moreover, evidence is increasing that fragments of PTH may not only be hormonally active but also may have opposing effects to PTH. Despite these caveats, PTH values provide useful clinical diagnostic and prognostic information in monitoring many chronic ailments such as heart and renal failure and multiple sclerosis.

Vitamin D's potential to reduce the risk of hospital-acquired infections.

Health care–associated and hospital-acquired infections are two entities associated with increased morbidity and mortality. They are highly costly and constitute a great burden to the health care system. Vitamin D deficiency (< 20 ng/ml) is prevalent and may be a key contributor to both acute and chronic ill health. Vitamin D deficiency is associated with decreased innate immunity and increased risk for infections. Vitamin D can positively influence a wide variety of microbial infections. Herein we discuss hospital-acquired infections, such as pneumonia, bacteremias, urinary tract and surgical site infections, and the potential role vitamin D may play in ameliorating them. We also discuss how vitamin D might positively influence these infections and help contain health care costs. Pending further studies, we think it is prudent to check vitamin D status at hospital admission and to take immediate steps to address existing insufficient 25-hydroxyvitamin D levels.

Stat3 and C/EBPβ synergize to induce miR-21 and miR-181b expression during sepsis.

Myeloid‐derived suppressor cells (MDSCs) increase late sepsis immunosuppression and mortality in mice. We reported that microRNA (miR) 21 and miR‐181b expression in Gr1+CD11b+ myeloid progenitors increase septic MDSCs in mice by arresting macrophage and dendritic cell differentiation. Here, we report how sepsis regulates miR‐21 and miR‐181b transcription. In vivo and in vitro binding studies have shown that C/EBPα transcription factor, which promotes normal myeloid cell differentiation, binds both miRNA promoters in Gr1+CD11b+ cells from sham mice. In contrast, in sepsis Gr1+CD11b+ MDSCs miR‐21 and miR‐181b promoters bind both transcription factors Stat3 and C/EBPβ, which co‐imunoprecipitate as a single complex. Mechanistically, transcription factor Rb phosphorylation supports Stat3 and C/EBPβ accumulation at both miRNA promoters, and C/EBPβ or Stat3 depletion by siRNA in sepsis Gr1+CD11b+ MDSCs inhibits miR‐21 and miR‐181b expression. To further support this molecular path for MDSC accumulation, we found that Stat3 and C/EBP binding at miR‐21 or miR‐181b promoter was induced by IL‐6, using a luciferase reporter gene transfection into naive Gr1+CD11b+ cells. Identifying how sepsis MDSCs are generated may inform new treatments to reverse sepsis immunosuppression.

Vitamin D deficiency: Implications for acute care in the elderly and in patients with chronic illness

There is evidence that the vast majority of hospitalized patients have vitamin D deficiency. Vitamin D deficiency is a poorly recognized pandemic with evidence to indicate inadequate testing and monitoring of response to treatment in high‐risk populations. Vitamin D receptors are ubiquitous in the human body and while the endocrine effects of vitamin D are well recognized, the autocrine and paracrine effects of this steroid hormone are less well appreciated. These functions include antimicrobial and immunomodulation effects as well benefits on cardiovascular health, autoimmune disease, cancer and metabolism. Vitamin D deficiency increases mortality and even a modest amount of vitamin D may enhance longevity. Emerging evidence suggests that a vitamin D replete state carries significant health benefits in acute illness. In this review, we discuss the role of vitamin D deficiency and potential benefits in treating this deficiency focusing on the implications for managing acute illness in elderly patients and those with an underlying chronic illness. Geriatr Gerontol Int 2011; 11: 395–407.

Healthcare costs of methicillin resistant Staphylococcus aureus and Pseudomonas aeruginosa infections in veterans: role of vitamin D deficiency.

Methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (P. aeruginosa) infections are frequently associated with hospitalization and increased healthcare costs. Vitamin D deficiency may contribute to increased costs for patients with these infections and there is evidence that vitamin D may have an antimicrobial role. To evaluate the role of vitamin D deficiency in the costs incurred with these infections, we studied the relationship of serum 25(OH)D levels to healthcare costs in veterans in the southeastern United States. Patients with both infections were vitamin D deficient to a similar extent and so were combined for further analysis. Vitamin D deficient patients had higher costs and service utilization than those who were not vitamin D deficient. Those with vitamin D deficiency had higher inpatient costs compared to the non-deficient group, and this difference was across most categories except for the number of inpatient hospitalizations or total number of days as an inpatient. Vitamin D deficiency was not significantly related to outpatient cost or service utilization parameters. We conclude that vitamin D deficiency is intimately linked to adverse healthcare costs in veterans with MRSA and P. aeruginosa infections. Vitamin D status should be assayed in patients with these infections.

Frontline Science: Myeloid cell-specific deletion of Cebpb decreases sepsis-induced immunosuppression in mice

Sepsis inflammation accelerates myeloid cell generation to compensate for rapid mobilization of the myeloid progenitors from bone marrow. This inflammation‐driven myelopoiesis, however, generates myeloid progenitors with immunosuppressive functions that are unable to differentiate into mature, innate immune cells. The myeloid‐derived suppressor cells (MDSCs) expand markedly in the later phases of sepsis, suppress both innate and adaptive immunity, and thus, elevate mortality. Using a murine model with myeloid‐restricted deletion of the C/EBPβ transcription factor, we show that sepsis‐induced generation of MDSCs depends on C/EBPβ. C/EBPβ myeloid cell–deficient mice did not generate MDSCs or develop immunosuppression and survived sepsis. However, septic mice still generated Gr1+CD11b+ myeloid progenitors at the steady‐state levels similar to the control sham mice, suggesting that C/EBPβ is not involved in healthy, steady‐state myelopoiesis. C/EBPβ‐deficient Gr1+CD11b+ cells generated fewer monocyte‐ and granulocyte‐like colonies than control mice did, indicating reduced proliferation potential, but differentiated normally in response to growth factors. Adoptive transfer of C/EBPβ‐deficient Gr1+CD11b+ cells from late septic mice exacerbated inflammation in control mice undergoing early sepsis, confirming they were not immunosuppressive. These results show that C/EBPβ directs a switch from proinflammatory to repressor myeloid cells and identifies a novel treatment target.

NFI-A disrupts myeloid cell differentiation and maturation in septic mice.

Mounting evidence supports that sepsis‐associated immunosuppression increases mortality. As potential contributors to poor sepsis outcomes, myeloid‐derived suppressor cells, which are Gr1+ CD11b+ innate‐immune cell progenitors unable to differentiate and possess suppressive activities, expand dramatically in septic mice by a process requiring increased microRNA‐21 and microRNA‐181b expression. The inhibition of these microRNAs in vivo in septic mice restores Gr1+ CD11b+ cell differentiation and maturation and improves survival. Here, we show that during sepsis‐induced generation of myeloid‐derived suppressor cells, transcription factor nuclear factor 1 A type represses cyclin‐dependent kinase inhibitor p21 to arrest differentiation of Gr1+ CD11b+ cells. Our findings include the following: 1) Gr1+ CD11b+ myeloid cells from late septic mice genetically lacking nuclear factor 1 A type cannot suppress CD4+ T cell proliferation and activation; 2) the reconstitution of nuclear factor 1 A type in microRNA‐21 and microRNA‐181b‐depleted Gr1+ CD11b+ myeloid‐derived suppressor cells inhibits cyclin‐dependent kinase inhibitor p21 and restores the immune‐suppressor phenotype; 3) ex vivo nuclear factor 1 A type knockdown in Gr1+ CD11b+ myeloid‐derived suppressor cells from late septic mice restores cyclin‐dependent kinase inhibitor p21 expression and promotes monocyte and dendritic cell differentiation; and 4) ectopic nuclear factor 1 A type expression in normal Gr1+ CD11b+ cells generates an immunosuppressive phenotype. We suggest that therapeutically targeting nuclear factor 1 A type during late sepsis might improve survival.

Vitamin D and Prostate Cancer Survival in Veterans

Prostate cancer remains the second most commonly diagnosed cancer among the male population worldwide. Vitamin D deficiency has been linked to prostate cancer and its aggressiveness. Herein, we initiated a retrospective study to evaluate vitamin D status and monitoring in veterans with prostate cancer, and to examine the potential link between vitamin D and survival status and length of survival in this population. We found that veterans who were initially vitamin D deficient were significantly less likely to survive than those who were not initially deficient, and that both initial and follow-up vitamin D deficiency were associated with decreased likelihood of survival after prostate cancer diagnosis. We recommend that vitamin D deficiency be replaced in veterans with prostate cancer.