Category Archives: Indiana Stem Cells

Sticking thin needles all over your body as a way to relieve pain seems like a very counter-intuitive move, yet acupuncture treatment has been around for thousands of years. To be sure there are some skeptics out there who assert that it does nothing, yet some decent studies that do show something is going on. The latest in the list of positive studies comes from Indiana University, but looks at the efficacy of electro-acupuncture, instead of the traditional, non-electrified treatment.

For the study,which was recently published in the journal Stem Cells, a team of over 40 scientists in the U.S. and South Korea performed several experiments on humans, horses, and rodents and discovered that the technique sparks the hypothalamusan area in the front of the brain that releases hormones that control physiological functions like hunger, sleep, sexto release stem cells into the bloodstream. They noted that the hypothalamus becomes activated from nine to 22 minutes after electro-acupuncture application, with the stem cells showing up about two hours later.

The acupuncture stimulus were giving these animals has a rapid effect on neuroanatomical pathways that connect the stimulus point in the arm to responsive neurons in the spinal cord and into a region in the brain called the hypothalamus. In turn, the hypothalamus directs outgoing signals to stem cell niches resulting in their release, said study co-author Fletcher White, Ph.D., a neuroscientist at the Richard L. Roudebush VA Medical Center in Indianapolis.

The researchers found that the treatment also increased pain tolerance when caused by an injury, and boosted levels of collagen linked to tendon repair, plus produced more anti-inflammatory cells that are thought to be tied to faster healing outcomes. We could potentially capture [stem cells] from an individual's blood following electro-acupuncture and save the cells for future re-introduction in the patient post-surgery or to treat chronic pain due to an injury, he said.

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The UW-Madison faculty group PROFS is not an unbiased source, given that its chief focus is to serve as a union-like advocate for better pay, tenure protections and other benefits for professors.

But in a letter last week to the Republican co-chairs of the committee that shapes the 2017-19 state budget, PROFS identifies threats to more than just the alleged cushiness of its members positions.

Specifically, efforts to shape or influence the hiring of top administrators at one of the most well-regarded seekers of knowledge in the country do not inspire confidence when coming from those with a questionable faith in academic rigor.

Non-eggheads shouldnt be barred from seeking higher ed employment, and its not new for people from the worlds of business and government in particular to get hired as university presidents and chancellors.

I couldnt find any research on whether they are any better or worse for higher education than lifelong academics, but people like former Arizona Gov. and U.S. Cabinet official Janet Napolitano at the University of California, and former Indiana Gov. Mitch Daniels at Purdue dont seem to have left the places in ruin.

As for the Thompson Center, UW-Madison political science professor Ryan Owens, one of the Centers chief proponents, acknowledged that the process for hiring the centers director veers from the norm at UW-Madison. He also wasnt sure Thursday whether the center would need to go through the same internal process UW-Madison has used to approve other university centers.

But he reiterated that the center absolutely will be research-based and objective in practice.

The peoples elected representatives should have some say in the staffing of a public institution that gets more than $1 billion of taxpayer money a year. (Although given the intense gerrymandering of Assembly districts, the elected representatives arent nearly as representative as they should be.)

The problem in emphasizing nonacademic applicants to academia and in giving politicians more control over an academic hire is that the current crop of people pushing such ideas are the same people who, by their actions, tend to deride two core, interrelated functions of academia: research and the scientific method.

In the UW System, the System president and the chancellors are hired by the 18-member Board of Regents. Sixteen of those Regents are appointed by the governor, with consent of the Senate. And obviously, the governor, Assembly and Senate get major say in the budget.

The current governor, Scott Walker, oversees a Department of Natural Resources that has eliminated scientist positions and scrubbed scientifically backed language from its website identifying humans as a primary source of climate change.

State Sen. Tom Tiffany is an admitted climate change skeptic, while Sen. Alberta Darling and one of Walkers appointees to the Regents, Margaret Farrow, were part of the Wisconsin Women for Trump coalition that worked on behalf of a man whose climate change skepticism and well-documented aversion to the facts didnt keep him from becoming president.

Walker has signed a bill outlawing abortions beyond 20 weeks of gestation based on the unscientific contention that fetuses that young can feel pain, and in explaining opposition to research with embryonic cells or fetal tissue, he and Rep. Andr Jacque have promulgated scientifically questionable notions about the usefulness of adult stem cell research.

Republicans have also passed and mounted a failed defense of a law requiring abortion doctors to have hospital admitting privileges, despite medical sciences opinion that such a requirement does nothing to protect patients.

Perhaps the most egregious denial of the scientific method comes from Rep. Jesse Kremer, who has said its a fact that the Earth is 6,000 years old.

To be clear, its all well and good to have a variety of opinions on the importance of fossil fuels to the economy, or on whether abortion is moral or the Bible adds meaning to life.

But people unwilling to accept the widely accepted results of widely used and rigorous academic research methods probably shouldnt be messing around with academia.

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Chris Rickert: Science skeptics shouldn't steer UW hiring - Madison.com

What is a Stem Cell?

The National Institute of Health defines a Stem Cell in this way: Stem cells have the remarkable potential to develop into many different cell types in the body. Serving as a sort of repair system for the body, they can theoretically divide without limit or replenish other cells as long as the person is still alive. When a stem cell divides, each new cell has the potential to remain either a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell or a brain cell.

Adult Stem Cells are predominantly formed in the bone marrow. And, just as in the beginnings of life, adult stem cells can literally change into any type of cell in the body throughout life. The adult stem cells are released from the bone marrow then move into circulation in the blood stream to seek out problem areas, then renew and restore those tissues in need of repair.

Example -Repairing The Heart muscle: When circulating stem cells find the heart in reduced health, they exit the bloodstream, attach to the heart and actually become brand new heart muscle cells, analogous to the original cells that originally created the once infant heart. They then begin dividing into still more new heart muscle cells.

The same process occurs in the liver, the kidneys, the brain, the skin, eyes, any organ, tissue, muscle, bone, connective tissue literally any part of the body that is in need of restoration.

The National Institute of Health identifies 74 treatable diseases using adult stem cells in therapy. These costly and complex therapies typically deliver a large quantity of adult stem cells to the area undergoing treatment. Most require that stem cells be harvested from the patient or adult donor, programmed in a lab to become a specific type and cell and then injected into the body. For treatment of disease these therapies are many times the best method of recovery, producing truly remarkable results. Thankfully, most of us dont have issues that require these extensive procedures.

What do the experts say?One of the USAs leading experts in adult stem cell science is Dr. David A Prentice, Ph.D., a professor at Indiana University School of Medicine. The National Institute of Health funds much of his research. In 2003, he presented a detailed paper to the Presidents Council on Bioethics, referring to many studies. In closing, he added:

Adult stem cells have significant capabilities for growth, repair and regeneration of damaged cells and tissues in the body, akin to a built-in repair kit or maintenance crew that needs only activation and stimulation to accomplish repair of damage. Direct stimulation of endogenous (already present in the body) adult stem cells within a tissue may be the easiest, safest and most efficient way to stimulate tissue regeneration. Such stimulation need not rely on any added stem cells

He could not have known then that in 2006, stem cell technology would provide a product as simple as a daily supplement in capsule form that would directly suport the natural release of stem cells in the manner he was describing.

According to medical science, adult stem cells assist in: Cancer, leukaemia, auto immune disease including diabetes, lupus, Crohns disease and arthritis; cardiovascular disease, including acute heart damage and chronic coronary artery disease; corneal regeneration; Parkinson's, stroke; anaemia and other blood conditions; liver and blood disease and many many more conditions.

For those of us just wanting to maintain optimal health or fight the effects of ageing, injury and day to day wear and tear, a smaller but steady release of our existing stem cells into the blood stream can produce considerable health benefits.

When stem cell nutrition is used as a daily supplement over time, the stimulation of billions of additional stem cells in the blood stream could be one of the safest and most efficient methods for maintaining optimal health and wellbeing that science has ever discovered.

The most recent evolution of Stem Cell Nutrition is calledCeruleStemEnhance Ultraand You can enhance the Ability of Stem Cells to find tissues in need of repair and also to calm inflammation withCeruleCyactive. You can improve the ability of Stem Cells to move around your bloodstream to get to the repair sites withCerulePlasmaFlo

Young, old, weak, strong, elite athlete, casual athlete, non-athlete, someone recovering from injury, everyone enjoys having strength, flexibility and stamina. For professional athletes and the weekend warriors fast healing and complete recovery is in demand. The opportunities for Stem Cells to enhance this procedure and shorten time-frames for recovery are becoming evident. The numbers of your own stem cells available in your body can be enhanced by an average of 25% within 1 hour Adult Stem Cells the best anti-ageing system ever known. Knowing what adult stem cells do in the human body, doesnt it make sense that having more of them in the blood stream will undoubtedly have profound effects on your health, wellbeing, and provide an until now, untapped resource for fighting the effects of ageing?

PubMed.gov From the National Library of Medicine and The National Institutes of HealthThe documentation of adult stem cell function by mainstream science and medical research are virtually endless. To find more, just visit the science and medical communitys online source for retrieving such papers and articles https://www.ncbi.nlm.nih.gov/pubmed Type "stem cells" in the search box and have access to more than 265,000 studies. A search there for "Adult stem cells" will yield 53,000+ papers.

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The Benefits of Stem Cell Science to Your Health

Persons using assistive technology might not be able to fully access information in this file. For assistance, please send e-mail to: mmwrq@cdc.gov. Type 508 Accommodation and the title of the report in the subject line of e-mail.

Please note: An erratum has been published for this article. To view the erratum, please click here.

Clare A. Dykewicz, M.D., M.P.H. Harold W. Jaffe, M.D., Director Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases Division of HIV/AIDS Prevention --- Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention

Clare A. Dykewicz, M.D., M.P.H., Chair Harold W. Jaffe, M.D. Thomas J. Spira, M.D. Division of AIDS, STD, and TB Laboratory Research

William R. Jarvis, M.D. Hospital Infections Program National Center for Infectious Diseases, CDC

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases Division of HIV/AIDS Prevention --- Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention, CDC

Brian R. Edlin, M.D. Division of HIV/AIDS Prevention---Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention, CDC

Robert T. Chen, M.D., M.A. Beth Hibbs, R.N., M.P.H. Epidemiology and Surveillance Division National Immunization Program, CDC

Raleigh A. Bowden, M.D. Keith Sullivan, M.D. Fred Hutchinson Cancer Research Center Seattle, Washington

David Emanuel, M.B.Ch.B. Indiana University Indianapolis, Indiana

David L. Longworth, M.D. Cleveland Clinic Foundation Cleveland, Ohio

Philip A. Rowlings, M.B.B.S., M.S. International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry Milwaukee, Wisconsin

Robert H. Rubin, M.D. Massachusetts General Hospital Boston, Massachusetts and Massachusetts Institute of Technology Cambridge, Massachusetts

Kent A. Sepkowitz, M.D. Memorial-Sloan Kettering Cancer Center New York, New York

John R. Wingard, M.D. University of Florida Gainesville, Florida

John F. Modlin, M.D. Dartmouth Medical School Hanover, New Hampshire

Donna M. Ambrosino, M.D. Dana-Farber Cancer Institute Boston, Massachusetts

Norman W. Baylor, Ph.D. Food and Drug Administration Rockville, Maryland

Albert D. Donnenberg, Ph.D. University of Pittsburgh Pittsburgh, Pennsylvania

Pierce Gardner, M.D. State University of New York at Stony Brook Stony Brook, New York

Roger H. Giller, M.D. University of Colorado Denver, Colorado

Neal A. Halsey, M.D. Johns Hopkins University Baltimore, Maryland

Chinh T. Le, M.D. Kaiser-Permanente Medical Center Santa Rosa, California

Deborah C. Molrine, M.D. Dana-Farber Cancer Institute Boston, Massachusetts

Keith M. Sullivan, M.D. Fred Hutchinson Cancer Research Center Seattle, Washington

CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation have cosponsored these guidelines for preventing opportunistic infections (OIs) among hematopoietic stem cell transplant (HSCT) recipients. The guidelines were drafted with the assistance of a working group of experts in infectious diseases, transplantation, and public health. For the purposes of this report, HSCT is defined as any transplantation of blood- or marrow-derived hematopoietic stem cells, regardless of transplant type (i.e., allogeneic or autologous) or cell source (i.e., bone marrow, peripheral blood, or placental or umbilical cord blood). Such OIs as bacterial, viral, fungal, protozoal, and helminth infections occur with increased frequency or severity among HSCT recipients. These evidence-based guidelines contain information regarding preventing OIs, hospital infection control, strategies for safe living after transplantation, vaccinations, and hematopoietic stem cell safety. The disease-specific sections address preventing exposure and disease for pediatric and adult and autologous and allogeneic HSCT recipients. The goal of these guidelines is twofold: to summarize current data and provide evidence-based recommendations regarding preventing OIs among HSCT patients. The guidelines were developed for use by HSCT recipients, their household and close contacts, transplant and infectious diseases physicians, HSCT center personnel, and public health professionals. For all recommendations, prevention strategies are rated by the strength of the recommendation and the quality of the evidence supporting the recommendation. Adhering to these guidelines should reduce the number and severity of OIs among HSCT recipients.

In 1992, the Institute of Medicine (1) recommended that CDC lead a global effort to detect and control emerging infectious agents. In response, CDC published a plan (2) that outlined national disease prevention priorities, including the development of guidelines for preventing opportunistic infections (OIs) among immunosuppressed persons. During 1995, CDC published guidelines for preventing OIs among persons infected with human immunodeficiency virus (HIV) and revised those guidelines during 1997 and 1999 (3--5). Because of the success of those guidelines, CDC sought to determine the need for expanding OI prevention activities to other immunosuppressed populations. An informal survey of hematology, oncology, and infectious disease specialists at transplant centers and a working group formed by CDC determined that guidelines were needed to help prevent OIs among hematopoietic stem cell transplant (HSCT)* recipients.

The working group defined OIs as infections that occur with increased frequency or severity among HSCT recipients, and they drafted evidence-based recommendations for preventing exposure to and disease caused by bacterial, fungal, viral, protozoal, or helminthic pathogens. During March 1997, the working group presented the first draft of these guidelines at a meeting of representatives from public and private health organizations. After review by that group and other experts, these guidelines were revised and made available during September 1999 for a 45-day public comment period after notification in the Federal Register. Public comments were added when feasible, and the report was approved by CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. The pediatric content of these guidelines has been endorsed also by the American Academy of Pediatrics. The hematopoietic stem cell safety section was endorsed by the International Society of Hematotherapy and Graft Engineering.

The first recommendations presented in this report are followed by recommendations for hospital infection control, strategies for safe living, vaccinations, and hematopoietic stem cell safety. Unless otherwise noted, these recommendations address allogeneic and autologous and pediatric and adult HSCT recipients. Additionally, these recommendations are intended for use by the recipients, their household and other close contacts, transplant and infectious diseases specialists, HSCT center personnel, and public health professionals.

For all recommendations, prevention strategies are rated by the strength of the recommendation (Table 1) and the quality of the evidence (Table 2) supporting the recommendation. The principles of this rating system were developed by the Infectious Disease Society of America and the U.S. Public Health Service for use in the guidelines for preventing OIs among HIV-infected persons (3--6). This rating system allows assessments of recommendations to which adherence is critical.

HSCT is the infusion of hematopoietic stem cells from a donor into a patient who has received chemotherapy, which is usually marrow-ablative. Increasingly, HSCT has been used to treat neoplastic diseases, hematologic disorders, immunodeficiency syndromes, congenital enzyme deficiencies, and autoimmune disorders (e.g., systemic lupus erythematosus or multiple sclerosis) (7--10). Moreover, HSCT has become standard treatment for selected conditions (7,11,12). Data from the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry indicate that approximately 20,000 HSCTs were performed in North America during 1998 (Statistical Center of the International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry, unpublished data, 1998).

HSCTs are classified as either allogeneic or autologous on the basis of the source of the transplanted hematopoietic progenitor cells. Cells used in allogeneic HSCTs are harvested from a donor other than the transplant recipient. Such transplants are the most effective treatment for persons with severe aplastic anemia (13) and offer the only curative therapy for persons with chronic myelogenous leukemia (12). Allogeneic donors might be a blood relative or an unrelated donor. Allogeneic transplants are usually most successful when the donor is a human lymphocyte antigen (HLA)-identical twin or matched sibling. However, for allogeneic candidates who lack such a donor, registry organizations (e.g., the National Marrow Donor Program) maintain computerized databases that store information regarding HLA type from millions of volunteer donors (14--16). Another source of stem cells for allogeneic candidates without an HLA-matched sibling is a mismatched family member (17,18). However, persons who receive allogeneic grafts from donors who are not HLA-matched siblings are at a substantially greater risk for graft-versus-host disease (GVHD) (19). These persons are also at increased risk for suboptimal graft function and delayed immune system recovery (19). To reduce GVHD among allogeneic HSCTs, techniques have been developed to remove T-lymphocytes, the principal effectors of GVHD, from the donor graft. Although the recipients of T-lymphocyte--depleted marrow grafts generally have lower rates of GVHD, they also have greater rates of graft rejection, cytomegalovirus (CMV) infection, invasive fungal infection, and Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (20).

The patient's own cells are used in an autologous HSCT. Similar to autologous transplants are syngeneic transplants, among whom the HLA-identical twin serves as the donor. Autologous HSCTs are preferred for patients who require high-level or marrow-ablative chemotherapy to eradicate an underlying malignancy but have healthy, undiseased bone marrows. Autologous HSCTs are also preferred when the immunologic antitumor effect of an allograft is not beneficial. Autologous HSCTs are used most frequently to treat breast cancer, non-Hodgkin's lymphoma, and Hodgkin's disease (21). Neither autologous nor syngeneic HSCTs confer a risk for chronic GVHD.

Recently, medical centers have begun to harvest hematopoietic stem cells from placental or umbilical cord blood (UCB) immediately after birth. These harvested cells are used primarily for allogeneic transplants among children. Early results demonstrate that greater degrees of histoincompatibility between donor and recipient might be tolerated without graft rejection or GVHD when UCB hematopoietic cells are used (22--24). However, immune system function after UCB transplants has not been well-studied.

HSCT is also evolving rapidly in other areas. For example, hematopoietic stem cells harvested from the patient's peripheral blood after treatment with hematopoietic colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF or filgastrim] or granulocyte-macrophage colony-stimulating factor [GM-CSF or sargramostim]) are being used increasingly among autologous recipients (25) and are under investigation for use among allogeneic HSCT. Peripheral blood has largely replaced bone marrow as a source of stem cells for autologous recipients. A benefit of harvesting such cells from the donor's peripheral blood instead of bone marrow is that it eliminates the need for general anesthesia associated with bone marrow aspiration.

GVHD is a condition in which the donated cells recognize the recipient's cells as nonself and attack them. Although the use of intravenous immunoglobulin (IVIG) in the routine management of allogeneic patients was common in the past as a means of producing immune modulation among patients with GVHD, this practice has declined because of cost factors (26) and because of the development of other strategies for GVHD prophylaxis (27). For example, use of cyclosporine GVHD prophylaxis has become commonplace since its introduction during the early 1980s. Most frequently, cyclosporine or tacrolimus (FK506) is administered in combination with other immunosuppressive agents (e.g., methotrexate or corticosteroids) (27). Although cyclosporine is effective in preventing GVHD, its use entails greater hazards for infectious complications and relapse of the underlying neoplastic disease for which the transplant was performed.

Although survival rates for certain autologous recipients have improved (28,29), infection remains a leading cause of death among allogeneic transplants and is a major cause of morbidity among autologous HSCTs (29). Researchers from the National Marrow Donor Program reported that, of 462 persons receiving unrelated allogeneic HSCTs during December 1987--November 1990, a total of 66% had died by 1991 (15). Among primary and secondary causes of death, the most common cause was infection, which occurred among 37% of 307 patients (15).**

Despite high morbidity and mortality after HSCT, recipients who survive long-term are likely to enjoy good health. A survey of 798 persons who had received an HSCT before 1985 and who had survived for >5 years after HSCT, determined that 93% were in good health and that 89% had returned to work or school full time (30). In another survey of 125 adults who had survived a mean of 10 years after HSCT, 88% responded that the benefits of transplantation outweighed the side effects (31).

During the first year after an HSCT, recipients typically follow a predictable pattern of immune system deficiency and recovery, which begins with the chemotherapy or radiation therapy (i.e., the conditioning regimen) administered just before the HSCT to treat the underlying disease. Unfortunately, this conditioning regimen also destroys normal hematopoiesis for neutrophils, monocytes, and macrophages and damages mucosal progenitor cells, causing a temporary loss of mucosal barrier integrity. The gastrointestinal tract, which normally contains bacteria, commensal fungi, and other bacteria-carrying sources (e.g., skin or mucosa) becomes a reservoir of potential pathogens. Virtually all HSCT recipients rapidly lose all T- and B-lymphocytes after conditioning, losing immune memory accumulated through a lifetime of exposure to infectious agents, environmental antigens, and vaccines. Because transfer of donor immunity to HSCT recipients is variable and influenced by the timing of antigen exposure among donor and recipient, passively acquired donor immunity cannot be relied upon to provide long-term immunity against infectious diseases among HSCT recipients.

During the first month after HSCT, the major host-defense deficits include impaired phagocytosis and damaged mucocutaneous barriers. Additionally, indwelling intravenous catheters are frequently placed and left in situ for weeks to administer parenteral medications, blood products, and nutritional supplements. These catheters serve as another portal of entry for opportunistic pathogens from organisms colonizing the skin (e.g., . coagulase-negative Staphylococci, Staphylococcus aureus, Candida species, and Enterococci) (32,33).

Engraftment for adults and children is defined as the point at which a patient can maintain a sustained absolute neutrophil count (ANC) of >500/mm3 and sustained platelet count of >20,000, lasting >3 consecutive days without transfusions. Among unrelated allogeneic recipients, engraftment occurs at a median of 22 days after HSCT (range: 6--84 days) (15). In the absence of corticosteroid use, engraftment is associated with the restoration of effective phagocytic function, which results in a decreased risk for bacterial and fungal infections. However, all HSCT recipients and particularly allogeneic recipients, experience an immune system dysfunction for months after engraftment. For example, although allogeneic recipients might have normal total lymphocyte counts within >2 months after HSCT, they have abnormal CD4/CD8 T-cell ratios, reflecting their decreased CD4 and increased CD8 T-cell counts (27). They might also have immunoglobulin G (IgG)2, IgG4, and immunoglobulin A (IgA) deficiencies for months after HSCT and have difficulty switching from immunoglobulin M (IgM) to IgG production after antigen exposure (32). Immune system recovery might be delayed further by CMV infection (34).

During the first >2 months after HSCT, recipients might experience acute GVHD that manifests as skin, gastrointestinal, and liver injury, and is graded on a scale of I--IV (32,35,36). Although autologous or syngeneic recipients might occasionally experience a mild, self-limited illness that is acute GVHD-like (19,37), GVHD occurs primarily among allogeneic recipients, particularly those receiving matched, unrelated donor transplants. GVHD is a substantial risk factor for infection among HSCT recipients because it is associated with a delayed immunologic recovery and prolonged immunodeficiency (19). Additionally, the immunosuppressive agents used for GVHD prophylaxis and treatment might make the HSCT recipient more vulnerable to opportunistic viral and fungal pathogens (38).

Certain patients, particularly adult allogeneic recipients, might also experience chronic GVHD, which is graded as either limited or extensive chronic GVHD (19,39). Chronic GVHD appears similar to autoimmune, connective-tissue disorders (e.g., scleroderma or systemic lupus erythematosus) (40) and is associated with cellular and humoral immunodeficiencies, including macrophage deficiency, impaired neutrophil chemotaxis (41), poor response to vaccination (42--44), and severe mucositis (19). Risk factors for chronic GVHD include increasing age, allogeneic HSCT (particularly those among whom the donor is unrelated or a non-HLA identical family member) (40), and a history of acute GVHD (24,45). Chronic GVHD was first described as occurring >100 days after HSCT but can occur 40 days after HSCT (19). Although allogeneic recipients with chronic GVHD have normal or high total serum immunoglobulin levels (41), they experience long-lasting IgA, IgG, and IgG subclass deficiencies (41,46,47) and poor opsonization and impaired reticuloendothelial function. Consequently, they are at even greater risk for infections (32,39), particularly life-threatening bacterial infections from encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis). After chronic GVHD resolves, which might take years, cell-mediated and humoral immunity function are gradually restored.

HSCT recipients experience certain infections at different times posttransplant, reflecting the predominant host-defense defect(s) (Figure). Immune system recovery for HSCT recipients takes place in three phases beginning at day 0, the day of transplant. Phase I is the preengraftment phase (<30 days after HSCT); phase II, the postengraftment phase (30--100 days after HSCT); and phase III, the late phase (>100 days after HSCT). Prevention strategies should be based on these three phases and the following information:

Preventing infections among HSCT recipients is preferable to treating infections. How ever, despite recent technologic advances, more research is needed to optimize health outcomes for HSCT recipients. Efforts to improve immune system reconstitution, particularly among allogeneic transplant recipients, and to prevent or resolve the immune dysregulation resulting from donor-recipient histoincompatibility and GVHD remain substantial challenges for preventing recurrent, persistent, or progressive infections among HSCT patients.

Preventing Exposure

Because bacteria are carried on the hands, health-care workers (HCWs) and others in contact with HSCT recipients should routinely follow appropriate hand-washing practices to avoid exposing recipients to bacterial pathogens (AIII).

Preventing Disease

Preventing Early Disease (0--100 Days After HSCT). Routine gut decontamination is not recommended for HSCT candidates (51--53) (DIII). Because of limited data, no recommendations can be made regarding the routine use of antibiotics for bacterial prophylaxis among afebrile, asymptomatic neutropenic recipients. Although studies have reported that using prophylactic antibiotics might reduce bacteremia rates after HSCT (51), infection-related fatality rates are not reduced (52). If physicians choose to use prophylactic antibiotics among asymptomatic, afebrile, neutropenic recipients, they should routinely review hospital and HSCT center antibiotic-susceptibility profiles, particularly when using a single antibiotic for antibacterial prophylaxis (BIII). The emergence of fluoquinolone-resistant coagulase-negative Staphylococci and Es. coli (51,52), vancomycin-intermediate Sta. aureus and vancomycin-resistant Enterococcus (VRE) are increasing concerns (54). Vancomycin should not be used as an agent for routine bacterial prophylaxis (DIII). Growth factors (e.g., GM-CSF and G-CSF) shorten the duration of neutropenia after HSCT (55); however, no data were found that indicate whether growth factors effectively reduce the attack rate of invasive bacterial disease.

Physicians should not routinely administer IVIG products to HSCT recipients for bacterial infection prophylaxis (DII), although IVIG has been recommended for use in producing immune system modulation for GVHD prevention. Researchers have recommended routine IVIG*** use to prevent bacterial infections among the approximately 20%--25% of HSCT recipients with unrelated marrow grafts who experience severe hypogamma-globulinemia (e.g., IgG < 400 mg/dl) within the first 100 days after transplant (CIII). For example, recipients who are hypogammaglobulinemic might receive prophylactic IVIG to prevent bacterial sinopulmonary infections (e.g., from Stre. pneumoniae) (8) (CIII). For hypogammaglobulinemic allogeneic recipients, physicians can use a higher and more frequent dose of IVIG than is standard for non-HSCT recipients because the IVIG half-life among HSCT recipients (generally 1--10 days) is much shorter than the half-life among healthy adults (generally 18--23 days) (56--58). Additionally, infections might accelerate IgG catabolism; therefore, the IVIG dose for a hypogammaglobulinemic recipient should be individualized to maintain trough serum IgG concentrations >400--500 mg/dl (58) (BII). Consequently, physicians should monitor trough serum IgG concentrations among these patients approximately every 2 weeks and adjust IVIG doses as needed (BIII) (Appendix).

Preventing Late Disease (>100 Days After HSCT). Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic resistance patterns. In the absence of severe demonstrable hypogammaglobulinemia (e.g., IgG levels < 400 mg/dl, which might be associated with recurrent sinopulmonary infections), routine monthly IVIG administration to HSCT recipients >90 days after HSCT is not recommended (60) (DI) as a means of preventing bacterial infections.

Other Disease Prevention Recommendations. Routine use of IVIG among autologous recipients is not recommended (61) (DII). Recommendations for preventing bacterial infections are the same among pediatric or adult HSCT recipients.

Preventing Exposure

Appropriate care precautions should be taken with hospitalized patients infected with Stre. pneumoniae (62,63) (BIII) to prevent exposure among HSCT recipients.

Preventing Disease

Information regarding the currently available 23-valent pneumococcal polysaccharide vaccine indicates limited immunogenicity among HSCT recipients. However, because of its potential benefit to certain patients, it should be administered to HSCT recipients at 12 and 24 months after HSCT (64--66) (BIII). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, and Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Trimethoprim-sulfamethasaxole (TMP-SMZ) administered for Pneumocystis carinii pneumonia (PCP) prophylaxis will also provide protection against pneumococcal infections. However, no data were found to support using TMP-SMZ prophylaxis among HSCT recipients solely for the purpose of preventing Stre. pneumoniae disease. Certain strains of Stre. pneumoniae are resistant to TMP-SMZ and penicillin. Recommendations for preventing pneumococcal infections are the same for allogeneic or autologous recipients.

As with adults, pediatric HSCT recipients aged >2 years should be administered the current 23-valent pneumococcal polysaccharide vaccine because the vaccine can be effective (BIII). However, this vaccine should not be administered to children aged <2 years because it is not effective among that age population (DI). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among pediatric HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Preventing Exposure

Because Streptococci viridans colonize the oropharynx and gut, no effective method of preventing exposure is known.

Preventing Disease

Chemotherapy-induced oral mucositis is a potential source of Streptococci viridans bacteremia. Consequently, before conditioning starts, dental consults should be obtained for all HSCT candidates to assess their state of oral health and to perform any needed dental procedures to decrease the risk for oral infections after transplant (67) (AIII).

Generally, HSCT physicians should not use prophylactic antibiotics to prevent Streptococci viridans infections (DIII). No data were found that demonstrate efficacy of prophylactic antibiotics for this infection. Furthermore, such use might select antibiotic-resistant bacteria, and in fact, penicillin- and vancomycin-resistant strains of Streptococci viridans have been reported (68). However, when Streptococci viridans infections among HSCT recipients are virulent and associated with overwhelming sepsis and shock in an institution, prophylaxis might be evaluated (CIII). Decisions regarding the use of Streptococci viridans prophylaxis should be made only after consultation with the hospital epidemiologists or infection-control practitioners who monitor rates of nosocomial bacteremia and bacterial susceptibility (BIII).

HSCT physicians should be familiar with current antibiotic susceptibilities for patient isolates from their HSCT centers, including Streptococci viridans (BIII). Physicians should maintain a high index of suspicion for this infection among HSCT recipients with symptomatic mucositis because early diagnosis and aggressive therapy are currently the only potential means of preventing shock when severely neutropenic HSCT recipients experience Streptococci viridans bacteremia (69).

Preventing Exposure

Adults with Ha. influenzae type b (Hib) pneumonia require standard precautions (62) to prevent exposing the HSCT recipient to Hib. Adults and children who are in contact with the HSCT recipient and who have known or suspected invasive Hib disease, including meningitis, bacteremia, or epiglottitis, should be placed in droplet precautions until 24 hours after they begin appropriate antibiotic therapy, after which they can be switched to standard precautions. Household contacts exposed to persons with Hib disease and who also have contact with HSCT recipients should be administered rifampin prophylaxis according to published recommendations (70,71); prophylaxis for household contacts of a patient with Hib disease are necessary if all contacts aged <4 years are not fully vaccinated (BIII) (Appendix). This recommendation is critical because the risk for invasive Hib disease among unvaccinated household contacts aged <4 years is increased, and rifampin can be effective in eliminating Hib carriage and preventing invasive Hib disease (72--74). Pediatric household contacts should be up-to-date with Hib vaccinations to prevent possible Hib exposure to the HSCT recipient (AII).

Preventing Disease

Although no data regarding vaccine efficacy among HSCT recipients were found, Hib conjugate vaccine should be administered to HSCT recipients at 12, 14, and 24 months after HSCT (BII). This vaccine is recommended because the majority of HSCT recipients have low levels of Hib capsular polysaccharide antibodies >4 months after HSCT (75), and allogeneic recipients with chronic GVHD are at increased risk for infection from encapsulated organisms (e.g., Hib) (76,77). HSCT recipients who are exposed to persons with Hib disease should be offered rifampin prophylaxis according to published recommendations (70) (BIII) (Appendix).

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic-resistance patterns. Recommendations for preventing Hib infections are the same for allogeneic or autologous recipients. Recommendations for preventing Hib disease are the same for pediatric or adult HSCT recipients, except that any child infected with Hib pneumonia requires standard precautions with droplet precautions added for the first 24 hours after beginning appropriate antibiotic therapy (62,70) (BIII). Appropriate pediatric doses should be administered for Hib conjugate vaccine and for rifampin prophylaxis (71) (Appendix).

Preventing Exposure

HSCT candidates should be tested for the presence of serum anti-CMV IgG antibodies before transplantation to determine their risk for primary CMV infection and reactivation after HSCT (AIII). Only Food and Drug Administration (FDA) licensed or approved tests should be used. HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others, including family members, to decrease the risk for CMV exposure (BIII).

Sexually active patients who are not in long-term monogamous relationships should always use latex condoms during sexual contact to reduce their risk for exposure to CMV and other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for CMV infections. Therefore, during periods of immuno-compromise, sexually active HSCT recipients in monogamous relationships should ask partners to be tested for serum CMV IgG antibody, and discordant couples should use latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII).

After handling or changing diapers or after wiping oral and nasal secretions, HSCT candidates and recipients should practice regular hand washing to reduce the risk for CMV exposure (AII). CMV-seronegative recipients of allogeneic stem cell transplants from CMV-seronegative donors (i.e., R-negative or D-negative) should receive only leukocyte-reduced or CMV-seronegative red cells or leukocyte-reduced platelets (<1 x 106 leukocytes/unit) to prevent transfusion-associated CMV infection (78) (AI). However, insufficient data were found to recommend use of leukocyte-reduced or CMV-seronega tive red cells and platelets among CMV-seronegative recipients who have CMV-seropositive donors (i.e., R-negative or D-positive).

All HCWs should wear gloves when handling blood products or other potentially contaminated biologic materials (AII) to prevent transmission of CMV to HSCT recipients. HSCT patients who are known to excrete CMV should be placed under standard precautions (62) for the duration of CMV excretion to avoid possible transmission to CMV-seronegative HSCT recipients and candidates (AIII). Physicians are cautioned that CMV excretion can be episodic or prolonged.

Preventing Disease and Disease Recurrence

HSCT recipients at risk for CMV disease after HSCT (i.e., all CMV-seropositive HSCT recipients, and all CMV-seronegative recipients with a CMV-seropositive donor) should be placed on a CMV disease prevention program from the time of engraftment until 100 days after HSCT (i.e., phase II) (AI). Physicians should use either prophylaxis or preemptive treatment with ganciclovir for allogeneic recipients (AI). In selecting a CMV disease prevention strategy, physicians should assess the risks and benefits of each strategy, the needs and condition of the patient, and the hospital's virology laboratory support capability.

Prophylaxis strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients involves administering ganciclovir prophylaxis to all allogeneic recipients at risk throughout phase II (i.e., from engraftment to 100 days after HSCT). The induction course is usually started at engraftment (AI), although physicians can add a brief prophylactic course during HSCT preconditioning (CIII) (Appendix).

Preemptive strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients is preferred over prophylaxis for CMV-seronegative HSCT recipients of seropositive donor cells (i.e., D-positive or R-negative) because of the low attack rate of active CMV infection if screened or filtered blood product support is used (BII). Preemptive strategy restricts ganciclovir use for those patients who have evidence of CMV infection after HSCT. It requires the use of sensitive and specific laboratory tests to rapidly diagnose CMV infection after HSCT and to enable immediate administration of ganciclovir after CMV infection has been detected. Allogeneic recipients at risk should be screened >1 times/week from 10 days to 100 days after HSCT (i.e., phase II) for the presence of CMV viremia or antigenemia (AIII).

HSCT physicians should select one of two diagnostic tests to determine the need for preemptive treatment. Currently, the detection of CMV pp65 antigen in leukocytes (antigenemia) (79,80) is preferred for screening for preemptive treatment because it is more rapid and sensitive than culture and has good positive predictive value (79--81). Direct detection of CMV-DNA (deoxyribonucleic acid) by polymerase chain reaction (PCR) (82) is very sensitive but has a low positive predictive value (79). Although CMV-DNA PCR is less sensitive than whole blood or leukocyte PCR, plasma CMV-DNA PCR is useful during neutropenia, when the number of leukocytes/slide is too low to allow CMV pp65 antigenemia testing.

Virus culture of urine, saliva, blood, or bronchoalveolar washings by rapid shell-vial culture (83) or routine culture (84,85) can be used; however, viral culture techniques are less sensitive than CMV-DNA PCR or CMV pp65 antigenemia tests. Also, rapid shell-viral cultures require >48 hours and routine viral cultures can require weeks to obtain final results. Thus, viral culture techniques are less satisfactory than PCR or antigenemia tests. HSCT centers without access to PCR or antigenemia tests should use prophylaxis rather than preemptive therapy for CMV disease prevention (86) (BII). Physicians do use other diagnostic tests (e.g., hybrid capture CMV-DNA assay, Version 2.0 [87] or CMV pp67 viral RNA [ribonucleic acid] detection) (88); however, limited data were found regarding use among HSCT recipients, and therefore, no recommendation for use can be made.

Allogeneic recipients <100 days after HSCT (i.e., during phase II) should begin preemptive treatment with ganciclovir if CMV viremia or any antigenemia is detected or if the recipient has >2 consecutively positive CMV-DNA PCR tests (BIII). After preemptive treatment has been started, maintenance ganciclovir is usually continued until 100 days after HSCT or for a minimum of 3 weeks, whichever is longer (AI) (Appendix). Antigen or PCR tests should be negative when ganciclovir is stopped. Studies report that a shorter course of ganciclovir (e.g., for 3 weeks or until negative PCR or antigenemia occurs) (89--91) might provide adequate CMV prevention with less toxicity, but routine weekly screening by pp65 antigen or PCR test is necessary after stopping ganciclovir because CMV reactivation can occur (BIII).

Presently, only the intravenous formulation of ganciclovir has been approved for use in CMV prophylactic or preemptive strategies (BIII). No recommendation for oral ganciclovir use among HSCT recipients can be made because clinical trials evaluating its efficacy are still in progress. One group has used ganciclovir and foscarnet on alternate days for CMV prevention (92), but no recommendation can be made regarding this strategy because of limited data. Patients who are ganciclovir-intolerant should be administered foscarnet instead (93) (BII) (Appendix). HSCT recipients receiving ganciclovir should have ANCs checked >2 times/week (BIII). Researchers report managing ganciclovir-associated neutropenia by adding G-CSF (94) or temporarily stopping ganciclovir for >2 days if the patient's ANC is <1,000 (CIII). Ganciclovir can be restarted when the patient's ANC is >1,000 for 2 consecutive days. Alternatively, researchers report substituting foscarnet for ganciclovir if a) the HSCT recipient is still CMV viremic or antigenemic or b) the ANC remains <1,000 for >5 days after ganciclovir has been stopped (CIII) (Appendix). Because neutropenia accompanying ganciclovir administration is usually brief, such patients do not require antifungal or antibacterial prophylaxis (DIII).

Currently, no benefit has been reported from routinely administering ganciclovir prophylaxis to all HSCT recipients at >100 days after HSCT (i.e., during phase III). However, persons with high risk for late CMV disease should be routinely screened biweekly for evidence of CMV reactivation as long as substantial immunocompromise persists (BIII). Risk factors for late CMV disease include allogeneic HSCT accompanied by chronic GVHD, steroid use, low CD4 counts, delay in high avidity anti-CMV antibody, and recipients of matched unrelated or T-cell--depleted HSCTs who are at high risk (95--99). If CMV is still detectable by routine screening >100 days after HSCT, ganciclovir should be continued until CMV is no longer detectable (AI). If low-grade CMV antigenemia (<5 positive cells/slide) is detected on routine screening, the antigenemia test should be repeated in 3 days (BIII). If CMV antigenemia indicates >5 cells/slide, PCR is positive, or the shell-vial culture detects CMV viremia, a 3-week course of preemptive ganciclovir treatment should be administered (BIII) (Appendix). Ganciclovir should also be started if the patient has had >2 consecutively positive viremia or PCR tests (e.g., in a person receiving steroids for GVHD or who received ganciclovir or foscarnet at <100 days after HSCT). Current investigational strategies for preventing late CMV disease include the use of targeted prophylaxis with antiviral drugs and cellular immunotherapy for those with deficient or absent CMV-specific immune system function.

If viremia persists after 4 weeks of ganciclovir preemptive therapy or if the level of antigenemia continues to rise after 3 weeks of therapy, ganciclovir-resistant CMV should be suspected. If CMV viremia recurs during continuous treatment with ganciclovir, researchers report restarting ganciclovir induction (100) or stopping ganciclovir and starting foscarnet (CIII). Limited data were found regarding the use of foscarnet among HSCT recipients for either CMV prophylaxis or preemptive therapy (92,93).

Infusion of donor-derived CMV-specific clones of CD8+ T-cells into the transplant recipient is being evaluated under FDA Investigational New Drug authorization; therefore, no recommendation can be made. Although, in a substantial cooperative study, high-dose acyclovir has had certain efficacy for preventing CMV disease (101), its utility is limited in a setting where more potent anti-CMV agents (e.g., ganciclovir) are used (102). Acyclovir is not effective in preventing CMV disease after autologous HSCT (103) and is, therefore, not recommended for CMV preemptive therapy (DII). Consequently, valacyclovir, although under study for use among HSCT recipients, is presumed to be less effective than ganciclovir against CMV and is currently not recommended for CMV disease prevention (DII).

Although HSCT physicians continue to use IVIG for immune system modulation, IVIG is not recommended for CMV disease prophylaxis among HSCT recipients (DI). Cidofovir, a nucleoside analog, is approved by FDA for the treatment of AIDS-associated CMV retinitis. The drug's major disadvantage is nephrotoxicity. Cidofovir is currently in FDA phase 1 trial for use among HSCT recipients; therefore, recommendations for its use cannot be made.

Use of CMV-negative or leukocyte-reduced blood products is not routinely required for all autologous recipients because most have a substantially lower risk for CMV disease. However, CMV-negative or leukocyte-reduced blood products can be used for CMV-seronegative autologous recipients (CIII). Researchers report that CMV-seropositive autologous recipients be evaluated for preemptive therapy if they have underlying hematologic malignancies (e.g., lymphoma or leukemia), are receiving intense conditioning regimens or graft manipulation, or have recently received fludarabine or 2-chlorodeoxyadenosine (CDA) (CIII). This subpopulation of autologous recipients should be monitored weekly from time of engraftment until 60 days after HSCT for CMV reactivation, preferably with quantitative CMV pp65 antigen (80) or quantitative PCR (BII).

Autologous recipients at high risk who experience CMV antigenemia (i.e., blood levels of >5 positive cells/slide) should receive 3 weeks of preemptive treatment with ganciclovir or foscarnet (80), but CD34+-selected patients should be treated at any level of antigenemia (BII) (Appendix). Prophylactic approach to CMV disease prevention is not appropriate for CMV-seropositive autologous recipients. Indications for the use of CMV prophylaxis or preemptive treatment are the same for children or adults.

Preventing Exposure

All transplant candidates, particularly those who are EBV-seronegative, should be advised of behaviors that could decrease the likelihood of EBV exposure (AII). For example, HSCT recipients and candidates should follow safe hygiene practices (e.g., frequent hand washing [AIII] and avoiding the sharing of cups, glasses, and eating utensils with others) (104) (BIII), and they should avoid contact with potentially infected respiratory secretions and saliva (104) (AII).

Preventing Disease

Infusion of donor-derived, EBV-specific cytotoxic T-lymphocytes has demonstrated promise in the prophylaxis of EBV-lymphoma among recipients of T-cell--depleted unrelated or mismatched allogeneic recipients (105,106). However, insufficient data were found to recommend its use. Prophylaxis or preemptive therapy with acyclovir is not recommended because of lack of efficacy (107,108) (DII).

Preventing Exposure

HSCT candidates should be tested for serum anti-HSV IgG before transplant (AIII); however, type-specific anti-HSV IgG serology testing is not necessary. Only FDA-licensed or -approved tests should be used. All HSCT candidates, particularly those who are HSV-seronegative, should be informed of the importance of avoiding HSV infection while immunocompromised and should be advised of behaviors that will decrease the likelihood of HSV exposure (AII). HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others (BIII). Sexually active patients who are not in a long-term monogamous relationship should always use latex condoms during sexual contact to reduce the risk for exposure to HSV as well as other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for HSV infections. Therefore, during periods of immunocompromise, sexually active HSCT recipients in such relationships should ask partners to be tested for serum HSV IgG antibody. If the partners are discordant, they should consider using latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII). Any person with disseminated, primary, or severe mucocutaneous HSV disease should be placed under contact precautions for the duration of the illness (62) (AI) to prevent transmission of HSV to HSCT recipients.

Preventing Disease and Disease Recurrence

Acyclovir. Acyclovir prophylaxis should be offered to all HSV-seropositive allogeneic recipients to prevent HSV reactivation during the early posttransplant period (109--113) (AI). Standard approach is to begin acyclovir prophylaxis at the start of the conditioning therapy and continue until engraftment occurs or until mucositis resolves, whichever is longer, or approximately 30 days after HSCT (BIII) (Appendix). Without supportive data from controlled studies, routine use of antiviral prophylaxis for >30 days after HSCT to prevent HSV is not recommended (DIII). Routine acyclovir prophylaxis is not indicated for HSV-seronegative HSCT recipients, even if the donors are HSV-seropositive (DIII). Researchers have proposed administration of ganciclovir prophylaxis alone (86) to HSCT recipients who required simultaneous prophylaxis for CMV and HSV after HSCT (CIII) because ganciclovir has in vitro activity against CMV and HSV 1 and 2 (114), although ganciclovir has not been approved for use against HSV.

Valacyclovir. Researchers have reported valacyclovir use for preventing HSV among HSCT recipients (CIII); however, preliminary data demonstrate that very high doses of valacyclovir (8 g/day) were associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome among HSCT recipients (115). Controlled trial data among HSCT recipients are limited (115), and the FDA has not approved valacyclovir for use among recipients. Physicians wishing to use valacyclovir among recipients with renal impairment should exercise caution and decrease doses as needed (BIII) (Appendix).

Foscarnet. Because of its substantial renal and infusion-related toxicity, foscarnet is not recommended for routine HSV prophylaxis among HSCT recipients (DIII).

Famciclovir. Presently, data regarding safety and efficacy of famciclovir among HSCT recipients are limited; therefore, no recommendations for HSV prophylaxis with famciclovir can be made.

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Guidelines for Preventing Opportunistic Infections Among ...

Blood. 2011 May 5; 117(18): 47734777.

1Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN;

2Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN;

3Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD; and

4Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN

Received 2011 Jan 12; Accepted 2011 Mar 1.

Cryopreservation of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) is crucial for cord blood (CB) banking and transplantation. We evaluated recovery of functional HPC cryopreserved as mononuclear or unseparated cells for up to 23.5 years compared with prefreeze values of the same CB units. Highly efficient recovery (80%-100%) was apparent for granulocyte-macrophage and multipotential hematopoietic progenitors, although some collections had reproducible low recovery. Proliferative potential, response to multiple cytokines, and replating of HPC colonies was extensive. CD34+ cells isolated from CB cryopreserved for up to 21 years had long-term ( 6 month) engrafting capability in primary and secondary immunodeficient mice reflecting recovery of long-term repopulating, self-renewing HSCs. We recovered functionally responsive CD4+ and CD8+ T lymphocytes, generated induced pluripotent stem (iPS) cells with differentiation representing all 3 germ cell lineages in vitro and in vivo, and detected high proliferative endothelial colony forming cells, results of relevance to CB biology and banking.

The first cord blood (CB) transplantation saved the life of a young patient with Fanconi anemia using HLA-matched sibling CB cells,1 a procedure made possible by identification and cryopreservation of transplantable hematopoietic progenitor cells (HPCs) and hematopoietic stem cells (HSCs) in CB.2 More than 20 000 CB transplantations have treated the same malignant and nonmalignant disorders as bone marrow (BM).38 CB transplantation is possible because of CB banks, and how long CB can be stored in a cryopreserved state with efficient recovery of HSCs and HPCs is critical for CB banking. We reported highly efficient recovery of CB HPCs after 5,9 10,10 and 1511 years, and recovery of HSCs after 15 years.11 We now report efficient recovery of functional HPCs up to 21-23.5 years, with more in depth studies on CB HSC engraftment in immune deficient mice, recovery of responsive T cells, generation of induced pluripotent stem (iPS) cells,1214 and detection of endothelial colony forming cells (ECFCs).15

CB cells were scheduled for discard.2 The study was approved by the Institutional Review Board of Indiana University (IU). Cryopreservation, thawing, and plating were as reported.2,911 CB was assessed within 36 hours of collection. Cells were either separated into a mononuclear (MNC) fraction (Ficoll-Hypaque; Pharmacia) and aliquoted into cryotubes (Nalge Nunc) or left unseparated and aliquoted into cryo-freezer bags,2,16,17 in 10% Dimethylsulfoxide and 10% autologous plasma for eventual analysis of HPC recovery. Percent recovery from MNC or unseparated cryopreserved cells was based on total prefreeze cells per volume of the exact same CB unit.2,911 After thaw of unseparated cells, CD34+ cells were magnetic-bead separated11 for HSC engraftment and iPS cell generation studies. CD4+ and CD8+ T lymphocytes were separated from the CD34+-depleted cells and stimulated on plates precoated with anti-CD3 (OKT3, 0.5 g/mL) and anti-CD28 (clone CD28.2, 1 g/mL) with 10% FBS, 50M 2ME and 10ng/mL IL-15 as described.18 Immune-deficient mouse assay for human CB donor chimerism was as reported,11 except that recipients were NOD/SCID/IL-2Rgnull (NSG).19

At IU, CD34+ cells isolated from thawed, unseparated cells were grown with 10% FBS, 10 ng/mL human (h) SCF, 10 ng h Flt3-ligand, and 10 ng h Thrombopoietin/mL for 3 days. At day 4, cells were spin-infected (2200 rpm; 45 minutes) with concentrated lentiviral vectors Sox2-Oct4-EGFP and cMyc-Klaf4 (pc DNA-HIV-CS-CGW, provided by Dr P. Zoltick, Children's Hospital, Philadelphia; supplemental Figure 1, available on the Blood Web site; see the Supplemental Materials link at the top of the online article) in -MEM medium with polybrene (Sigma-Aldrich). Medium was replaced at 6 days with the cytokines noted in this paragraph. At day 7, cells were transferred to mitotically inactivated murine embryonic fibroblasts (MEFs) and cultured as for human embryonic stem cells (hESCs).20 iPS cells were also generated at Johns Hopkins using retroviruses expressing Oct4, Sox2, Klf4, and c-Myc.12 ECFC assay was performed with MNCs isolated from thawed, unseparated CB.15

We show efficient recovery of HPCs from 23 different collections of MNCs thawed from vials after 21-23.5 years (A) compared with the exact same unit's precryopreservation numbers, a recovery similar to 10- and 15-year thaws, that assessed the same plus additional CB units. A range of recoveries was evident, but values were similar whether the same samples were assessed 3 times over 3 years, 2 times over 1-3 years, or twice on the same day (data not shown). Recovery of CFU-GM and CFU-GEMM from unseparated cryopreserved cells (N = 3) was greater than 80% (data not shown), and consistent with recovery from MNCs. It is not clear why some samples resulted in low-efficiency recovery, but assessing the recovery of stored cells by thawing a small sample before their possible use in a clinical transplantation setting could help identify low-recovery CB units, and a decision made as to whether or not to use that unit. Proliferation of HPCs was high (B) and within range for fresh CB.2,912 Thawed CB is highly responsive to increased colonies from immature HPCs when GM-CSF plus SCF and/or FL are used to stimulate them, compared with that of only GM-CSF (C) demonstrating retention of immature HPCs.9 Thawed CB contains HPC colonies that can be replated (D), suggesting maintenance of HPCs with limited self-renewal capacity.21 Secondary CFU-GM/M colonies formed from single replated CFU-GM/M colonies. CFU-GEMM colonies gave rise to secondary colonies of CFU-GEMM, erythroid progenitors, CFU-GM, and CFU-M.

Recovery of nucleated cellularity, HPCs, HSCs, and immune cells after cryopreservation and long-term frozen storage of CB. (A) Comparative percent recovery of nucleated cells, CFU-GM, and CFU-GEMM compared with prefreeze numbers for 10, 15, and 21-23.5 ...

Using different CB collections cryopreserved as unseparated cells, isolated CD34+ cells efficiently engrafted NSG mice for 6-7 months (E). In 2 experiments, BM cells from engrafted chimeric mice repopulated secondary mice for 6 months. While we demonstrated engrafting capability of thawed CB after 15 years of storage using first generation NOD/SCID mice,11 those mice did not allow long-term primary engraftment or secondary repopulation. Thus, the current study greatly extends previous findings, and demonstrates recovery of long-term repopulating and self-renewing HSCs. We could not calculate percent recovery of HSCs as this assay was not available when cells were cryopreserved, but this engraftment is similar to fresh CB HSCs.11

Attaining vigorous T-cell responses against common viral pathogens is critical for survival after CB transplantation.22 CB T cells are almost exclusively naive cells, with few effector or memory cells.18 CB T cells are immature compared with adult T cells because of impaired cytokine production and diminished lytic activity.22,23 To verify immune capability, CD4+ and CD8+ T lymphocytes, purified from unseparated CB stored up to 21 years, were activated as assessed by CD3/CD28-induced expression of CD25 (F). This demonstrated recovery of functional T-cell subsets.

iPS cells are generated from different cell sources,24,25 including fresh CB,1214 and CB cryopreserved for 5-8 years.12,14 We generated iPS cells from CB cryopreserved for up to 21 years using Oct4, KLF-4, Sox2, and c-Myc reprogramming with lentiviral vector transduction of CD34+ cells at IU (A). iPS cell colonies stained positive for OCT4, NANOG, TRA-1-60, SSEA4, and alkaline phosphatase (B). Quantitative RT-PCR demonstrated reprogramming via expression of endogenous OCT4, SOX2, and NANOG in comparison to H9 ESC cell line and CD34+ cells from which iPS cells were generated (C). Unmethylated OCT4 promoter in 2 iPS cell lines generated from thawed CB in comparison to enhanced methylation for CD34+ cells from which iPS cell colonies were derived (D), demonstrates early stages of produced cells. Embryoid bodies developed from iPS cells after removal from MEFs (E), and expressed ectodermal, mesodermal, and endodermal proteins (E). Moreover, injection of iPS cell colonies into testis capsules of immune-deficient mice demonstrated teratomas with ectoderm, mesoderm, and endoderm, confirming reprogramming. Generation of iPS cells12 at Johns Hopkins with 21-year frozen CB from a different collection produced cells expressing TRA-1-60, SSEA4, NANOG, and OCT4 (data not shown), and produced teratomas12 with expression of endoderm, mesoderm, and ectoderm markers (G). These CB-derived iPS cells were differentiated in vitro (H). Efficiency of iPS cell generation from thawed CB ranged from 0.027%-0.05% per CD34+ cell, similar to cultured CD34+ cells from freshly isolated or shorter-term frozen CB.12 This reprogramming efficiency appears higher than from human adult blood or fibroblastic cells.12,14 If iPS cells are found to be of clinical utility, which is not yet clear,24,25 HLA-typed CB stored in banks could serve as a source of such typed cells.

Reprogramming of 21-year-old frozen human CB CD34+ cells to iPS cells (A-H) and recovery of ECFCs (I). The phase contrast images in panels B (FCB-iPS and AP stain), E (top left image), and I were viewed using a Zeiss Axiovert 25 CFL inverted microscope ...

High proliferative ECFCs have been identified in CB.15 MNCs from thawed, unseparated CB stored frozen for up to 21 years formed ECFC colonies, but their size was smaller than colonies from fresh CB (I). ECFC colony numbers from thawed CB (2-5/107 mononuclear cells) were 1/5 to 1/10 numbers from fresh CB, even when colonies from fresh cells versus those frozen and stored for up to 3-6 months were assayed. Thus, the freezing procedure that works well for efficient recovery of HPCs may not be optimal for storage of ECFCs. However, ECFCs that can be cryopreserved and recovered may be of value for regenerative medicine, if clinical applicability is proven.24 Thus, recovery of HSCs, HPCs, and other early cell types bodes well for CB banking and use.

These studies were supported by National Institutes of Health Public Health Service grants NIH R01 HL56416 and NIH R01 HL67384, and a project in NHLBI PO1 HL053586 to H.E.B., NIH R01 HL073781 to L.C., and a grant from the Riley Children's Foundation to M.C.Y. Z.Y. was supported by NIH T32 grant HL007525. The IU production of lentiviral vector was funded by NIH P40RR024928 to K.C., and S.W. is funded on a faculty recruitment grant from NIH (P30 HL101337).

The online version of this article contains a data supplement.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked advertisement in accordance with 18 USC section 1734.

Contribution: H.E.B., M.-R.L., N.P., Z.Y., S.W., K.C., L.C., and M.C.Y. designed experiments; H.E.B., M.-R.L., G.H., S.C., N.P., Y.-J.K., C.M., Z.Y., S.W., K.C., L.C., and M.C.Y. performed research and analyzed and interpreted data; H.E.B. wrote the paper, and H.E.B., M.-R.L., N.P., Y.-J.K., Z.Y., S.W., K.C., L.C., and M.C.Y. edited the paper.

Conflict-of-interest disclosure: H.E.B. is on the Medical Scientific Advisory Board of Corduse, a cord blood banking company. M.C.Y. is a cofounder and consultant to EndGenitor Technologies Inc. The remaining authors declare no competing financial interests.

Correspondence: Hal E. Broxmeyer, PhD, Indiana University School of Medicine, Department of Microbiology and Immunology, 950 West Walnut St, R2-302, Indianapolis, IN 46202-5181; e-mail: ude.iupui@yemxorbh.

8. Broxmeyer HE, Smith FO. Cord Blood Hematopoietic Cell Transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, Blume KG, editors. Thomas' Hematopoietic Cell Transplantation. 4th ed. West Sussex, United Kingdom: Wiley-Blackwell; 2009. pp. 559576. Sec 4, Chap 39.

16. English D, Cooper S, Douglas G, Broxmeyer HE. Collection and processing of cord blood for preservation and hematopoietic transplantation. In: Areman E, Deeg HJ, Sacher RA, editors. Bone marrow and stem cell processing: A manual of current techniques. Philadelphia, PA: FA Davis Co; 1992. pp. 383384.

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Hematopoietic stem/progenitor cells, generation of induced ...

Indiana is working to establish itself as a leader in nonembryonic stem cell research to avoid the conflicts associated with embryonic stem cell research. Thus, researchers have supportive legislation and funding, as well as public support, with a goal of improving the economy in the biotechnology sector.

As no federal legislation in the United States regulates stem cell research (except by an executive order to not allow federal funding to be used for embryonic stem cell research except on human embryonic stem cell lines created before August 9, 2001), each state is responsible for determining policy and funding for stem cell research. In Indiana, stem cell research is permitted on adult stem cells and fetal stem cells if consent is received from the biological parent. Indiana prohibits research on human embryonic stem cells in accordance with Indiana code 31-20-2, regarding embryos from assisted reproduction. The law also prohibits the sale of oocytes, zygotes, embryos, and fetuses.

In 2007 the Indiana legislature also approved the establishment of an Adult Stem Cell Research Center at Indiana University and gave the Indiana University School of Medicine approval to administer the center, including appointing a director and accepting income from donations, gifts, and so on, to be used to support the centers activities.

BioCrossroads is a development organization to enhance economic growth in the life sciences. The organization provides money and support to business start-ups and established businesses in biotechnology by providing networking and collaboration opportunities among Indianas various academic, clinical, and industry institutions. Money is available through the Indiana Future Fund and the Indiana Seed Fund

Other services provided by BioCrossroads include the Indiana Health Information Exchange, which facilitates the sharing of clinical information among healthcare providers and other healthcare entities, and the Translational Research Initiative partnership with Indiana University, which leverages resources in promoting life science research to gain national and private grant funding.

Indiana University-Purdue University in Indianapolis was founded in 1969. The university offers bachelors, masters, doctoral, and professional degrees in a variety of disciplines including medicine, biology, engineering, math, and physical sciences. The university is home to the Indiana University School of Medicine.

The Adult Stem Cell Research Center to be established at Indiana University will fall under the purview of the School of Medicine to encourage collaboration among all of Indianas stem cell researchers. Research being done or completed by the university includes the discovery of cells that control the creation of endothelial cells and investigating the possibility of using these cells for medical treatment for circulation problems in the extremities, for heart disease, and for repair of blood vessels, and to use adult stem cells to alleviate diseases secondary to increasing age,

The Emerging Technology Center in Indianapolis allows the university to assist business startups using discoveries made by researchers at the university. EndGenitor Technologies Inc. is one such firm and has capitalized on the research performed by university professors. The start-up company intends to develop and market test kits for researchers to test samples for endothelial stem and progenitor cells.

The Indiana Cord Blood Bank collects, preserves, and stores cord blood as a source of adult stem cells for use in blood transplants for treating blood diseases and cancers, anemia, inherited metabolic disorders, and immune system deficiencies.

The Bindley Bioscience Center opened in 2005 through funding provided by a Purdue alumnus to integrate the life sciences and engineering departments for cross-discipline research at the university. The speciality of the center is basic research with a focus on translating this research to clinical application for testing, diagnosis, and treating human disease, including tissue engineering for use in regenerative medicine.

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Indiana (Stem Cell) - what-when-how

Editor-in-Chief: Graham C. Parker, PhD

Latest Impact Factor* is 3.727 *2014 Journal Citation Reports published by Thomson Reuters, 2015

Stem Cells and Development is globally recognized as the trusted source for critical, even controversial coverage of emerging hypotheses and novel findings. With a focus on stem cells of all tissue types and their potential therapeutic applications, the Journal provides clinical, basic, and translational scientists with cutting-edge research and findings.

Stem Cells and Development coverage includes:

Stem Cells and Development is under the editorial leadership of Editor-in-Chief Graham C. Parker, PhD, Wayne State University School of Medicine, Children's Hospital of Michigan; Senior Editor Hal E. Broxmeyer, PhD, Indiana University School of Medicine; and other leading investigators. View the entire editorial board.

An Official Journal of the British Society for Gene and Cell Therapy

Audience: Cell and developmental biologists, molecular biologists, regenerative medicine researchers, tissue development specialists, and genetic engineers, among others

Stem Cells and Development provides Instant Online publication 72 hours after acceptance.

The views, opinions, findings, conclusions and recommendations set forth in any Journal article are solely those of the authors of those articles and do not necessarily reflect the views, policy or position of the Journal, its Publisher, its editorial staff or any affiliated Societies and should not be attributed to any of them.

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Stem Cells and Development - Mary Ann Liebert, Inc.

The College of Science and the Center for Stem Cells and Regenerative Medicine at the University of Notre Dame invites applications for multiple tenured/tenure-track faculty positions in the area of stem cell biology. The ranks of these hires are open (Full, Associate and Assistant Professor) and will be commensurate with the experience of the successful candidate. These hires represent the beginning of a university-funded initiative in stem cell biology that will include 6 new faculty hires over the next few years. We seek candidates with research expertise and interests consistent with one or more broad areas within our initiative in adult stem cell and iPS cell biology, including, but not limited to: developmental and regenerative biology, function and regulation of the stem cell niche, mechanisms underlying cellular dedifferentiation and reprogramming, regulation of gene expression in stem cells and iPS cells, tissue engineering, stem cells in tumor formation and progression, and stem cells in disease models and therapy development.

Successful candidates will have a demonstrated record of research accomplishments and interest in collaborative and interdisciplinary research. These hires will have access to several excellent research facilities within the university, including the AAALAC-accredited Freimann Animal Facility, Center for Zebrafish Research, Notre Dame Integrated Imaging Facility, Harper Cancer Research Institute, Eck Center for Global Health, Keck Center for Transgene Research, Boler-Parseghian Center for Rare and Neglected Diseases, and the Center for the Study of Biocomplexity. The University also supports state-of-the-art genomics, bioinformatics, NMR, MS, molecular structure and imaging core facilities. Information on departments, college faculty, and facilities can be found at http://science.nd.edu. Opportunities also exist for collaboration with faculty in the University of Notre Dame College of Engineering and the adjoining Indiana University School of Medicine-South Bend. Successful candidates are also expected to contribute to our teaching program at both the undergraduate and graduate levels.

These positions include an attractive salary, competitive start-up package, and laboratory space tailored to the applicants research needs. Review of applications will commence on November 1, 2015, and continue until suitable candidates are identified. Qualified individuals should send in PDF format: a cover letter, curriculum vitae, separate statements of research and teaching interests, and arrange for three letters of reference to be submitted to: http://apply.interfolio.com/31396

The University of Notre Dame, an international Catholic research university, is an equal opportunity employer.

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Faculty Positions in Stem Cell Biology, Employment | ASCB