To minimize maintenance immunosuppression in upper-extremity transplantation to favor the risk-benefit balance of this procedure.
Despite favorable outcomes, broad clinical application of ...reconstructive transplantation is limited by the risks and side effects of multidrug immunosuppression. We present our experience with upper-extremity transplantation under a novel, donor bone marrow (BM) cell-based treatment protocol ("Pittsburgh protocol").
Between March 2009 and September 2010, 5 patients received a bilateral hand (n = 2), a bilateral hand/forearm (n = 1), or a unilateral (n = 2) hand transplant. Patients were treated with alemtuzumab and methylprednisolone for induction, followed by tacrolimus monotherapy. On day 14, patients received an infusion of donor BM cells isolated from 9 vertebral bodies. Comprehensive follow-up included functional evaluation, imaging, and immunomonitoring.
All patients are maintained on tacrolimus monotherapy with trough levels ranging between 4 and 12 ng/mL. Skin rejections were infrequent and reversible. Patients demonstrated sustained improvements in motor function and sensory return correlating with time after transplantation and level of amputation. Side effects included transient increase in serum creatinine, hyperglycemia managed with oral hypoglycemics, minor wound infection, and hyperuricemia but no infections. Immunomonitoring revealed transient moderate levels of donor-specific antibodies, adequate immunocompetence, and no peripheral blood chimerism. Imaging demonstrated patent vessels with only mild luminal narrowing/occlusion in 1 case. Protocol skin biopsies showed absent or minimal perivascular cellular infiltrates.
Our data suggest that this BM cell-based treatment protocol is safe, is well tolerated, and allows upper-extremity transplantation using low-dose tacrolimus monotherapy.
Spermatogonial stem cells (SSCs) maintain spermatogenesis throughout a man’s life and may have application for treating some cases of male infertility, including those caused by chemotherapy before ...puberty. We performed autologous and allogeneic SSC transplantations into the testes of 18 adult and 5 prepubertal recipient macaques that were rendered infertile with alkylating chemotherapy. After autologous transplant, the donor genotype from lentivirus-marked SSCs was evident in the ejaculated sperm of 9/12 adult and 3/5 prepubertal recipients after they reached maturity. Allogeneic transplant led to donor-recipient chimerism in sperm from 2/6 adult recipients. Ejaculated sperm from one recipient transplanted with allogeneic donor SSCs were injected into 85 rhesus oocytes via intracytoplasmic sperm injection. Eighty-one oocytes were fertilized, producing embryos ranging from four-cell to blastocyst with donor paternal origin confirmed in 7/81 embryos. This demonstration of functional donor spermatogenesis following SSC transplantation in primates is an important milestone for informed clinical translation.
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► Primate SSCs can be transplanted by ultrasound-guided rete testis injection ► Autologous SSCs regenerate spermatogenesis in chemotherapy-treated primates ► Allogeneic primate SSCs regenerate spermatogenesis in unrelated recipients ► Donor SSC-derived sperm can fertilize oocytes and lead to early embryo development
Transplantation of autologous or allogeneic spermatogonial stem cells can restore fertility after chemotherapy in rhesus macaques, paving the way for clinical translation.
Summary
Blood donors and the RBCs and other components they willingly provide are essential in the delivery of healthcare in all parts of the world. Nearly 70% of donated blood comes from repeat or ...committed donors. The amount of iron removed in the 10 min or so it takes to withdraw a unit of blood (500 ml, plus 25 ml for testing) requires over 24 weeks to replace on a “standard” diet, i.e., without added iron in the form of supplements The cumulative effect of repeat blood donations without adequate iron replacement or a longer wait between donations results in iron deficiency (ID) in many donors, low haemoglobin deferral (~8% of donation attempts), and frank anaemia in some. Moreover, ID can be associated with side effects that can impact a blood donor's health, such as fatigue, cognitive changes and other neuromuscular symptoms. In an effort to better identify and prevent ID, blood collection agencies are recommending various strategies, including changes in the donation interval, donation frequency, testing of iron status and iron supplementation. In this review, we present the evidence basis for these strategies and suggest our own approaches to improving iron balance in blood donors.
More than 9 million individuals donate blood annually in the United States. Between 200 and 250 mg of iron is removed with each whole blood donation, reflecting losses from the hemoglobin in red ...blood cells. Replenishment of iron stores takes many months, leading to a high rate of iron depletion. In an effort to better identify and prevent iron deficiency, blood collection centers are now considering various strategies to manage donor iron loss. This article highlights laboratory and genetic tests to assess the iron status of blood donors and their applicability as screening tests for blood donation.
Although blood donation is allowed every 8 weeks in the United States, recovery of hemoglobin to the currently accepted standard (12.5 g/dL) is frequently delayed, and some donors become anemic.
To ...determine the effect of oral iron supplementation on hemoglobin recovery time (days to recovery of 80% of hemoglobin removed) and recovery of iron stores in iron-depleted ("low ferritin," ≤26 ng/mL) and iron-replete ("higher ferritin," >26 ng/mL) blood donors.
Randomized, nonblinded clinical trial of blood donors stratified by ferritin level, sex, and age conducted in 4 regional blood centers in the United States in 2012. Included were 215 eligible participants aged 18 to 79 years who had not donated whole blood or red blood cells within 4 months.
One tablet of ferrous gluconate (37.5 mg of elemental iron) daily or no iron for 24 weeks (168 days) after donating a unit of whole blood (500 mL).
Time to recovery of 80% of the postdonation decrease in hemoglobin and recovery of ferritin level to baseline as a measure of iron stores.
The mean baseline hemoglobin levels were comparable in the iron and no-iron groups and declined from a mean (SD) of 13.4 (1.1) g/dL to 12.0 (1.2) g/dL after donation in the low-ferritin group and from 14.2 (1.1) g/dL to 12.9 (1.2) g/dL in the higher-ferritin group. Compared with participants who did not receive iron supplementation, those who received iron supplementation had shortened time to 80% hemoglobin recovery in both the low-ferritin (mean, 32 days, interquartile range IQR, 30-34, vs 158 days, IQR, 126->168) and higher-ferritin groups (31 days, IQR, 29-33, vs 78 days, IQR, 66-95). Median time to recovery to baseline ferritin levels in the low-ferritin group taking iron was 21 days (IQR, 12-84). For participants not taking iron, recovery to baseline was longer than 168 days (IQR, 128->168). Median time to recovery to baseline in the higher-ferritin group taking iron was 107 days (IQR, 75-141), and for participants not taking iron, recovery to baseline was longer than 168 days (IQR, >168->168). Recovery of iron stores in all participants who received supplements took a median of 76 days (IQR, 20-126); for participants not taking iron, median recovery time was longer than 168 days (IQR, 147->168 days; P < .001). Without iron supplements, 67% of participants did not recover iron stores by 168 days.
Among blood donors with normal hemoglobin levels, low-dose iron supplementation, compared with no supplementation, reduced time to 80% recovery of the postdonation decrease in hemoglobin concentration in donors with low ferritin (≤26 ng/mL) or higher ferritin (>26 ng/mL).
clinicaltrials.gov Identifier: NCT01555060.
Serum albumin (SA), the most abundant soluble protein in the body, maintains plasma oncotic pressure and regulates the distribution of vascular fluid and has a range of other important functions. The ...goals of this review are to expand clinical knowledge regarding the functions of SA, elucidate effects of dysregulated SA concentration, and discuss the clinical relevance of hypoalbuminemia resulting from various diseases. We discuss potential repercussions of SA dysregulation on cholesterol levels, liver function, and other processes that rely on its homeostasis, as decreased SA concentration has been shown to be associated with increased risk for cardiovascular disease, hyperlipidemia, and mortality. We describe the anti-inflammatory and antioxidant properties of SA, as well as its ability to bind and transport a plethora of endogenous and exogenous molecules. SA is the primary serum protein involved in binding and transport of drugs and as such has the potential to affect, or be affected by, certain medications. Of current relevance are antibody-based inhibitors of the neonatal Fc receptor (FcRn), several of which are under clinical development to treat immunoglobulin G (IgG)-mediated autoimmune disorders; some have been shown to decrease SA concentration. FcRn acts as a homeostatic regulator of SA by rescuing it, as well as IgG, from intracellular degradation
via
a common cellular recycling mechanism. Greater clinical understanding of the multifunctional nature of SA and the potential clinical impact of decreased SA are needed; in particular, the potential for certain treatments to reduce SA concentration, which may affect efficacy and toxicity of medications and disease progression.
Hemostatic abnormalities are common among critically ill patients and are associated with a high risk of bleeding. The abnormalities range from isolated thrombocytopenia or prolongation of global ...coagulation assays to complex disease states, such as thrombotic microangiopathic syndromes, and can be associated with a wide range of conditions, including trauma, surgery, acute disease processes, cardiopulmonary bypass, and exposure to drugs and blood products. Prompt identification of underlying causes is important because treatment strategies vary. Moreover, prompt initiation of both supportive and specific treatments is vital to decrease the morbidity and mortality in the intensive care unit.
Background
The therapeutic use of granulocyte transfusions for the treatment of infections in immunocompromised patients has been a controversial practice. Randomized controlled trials suggest that ...benefit may be provided when a high‐dose product, defined as providing a dose of at least 0.6 × 109/kg, is offered. Here we describe the collection process and granulocyte product yield over a four‐year period at a donation center supplying a large, tertiary academic medical center.
Methods
A retrospective chart review was performed for apheresis granulocyte donations collected between 2018 and 2021 following implementation of combined G‐CSF and dexamethasone donor stimulation at our institution. Data collected includes donor demographics, G‐CSF administration timeline, pre‐collection cell counts, product yields, donor adverse events, and post‐transfusion ANC increments.
Results
A total of 269 granulocyte units were collected from 184 unique donors. The median neutrophil yield (ANC) following G‐CSF implementation was 7.5 × 1010/unit. The proportion of granulocyte products meeting or exceeding a yield of 4.0 × 1010 per unit was 96.5%. These products resulted in measurable median ANC increment of 550/μL in transfused adult patients (n = 166 transfusions).
Discussion
In order to properly assess the effectiveness of granulocyte transfusions in patients, it is necessary to ensure that the products being transfused contain an adequate granulocyte dose. This study demonstrates that the combination of G‐CSF and dexamethasone donor stimulation, followed by apheresis granulocyte collection, is safe and can reliably yield a high‐dose product. Consistent production of high‐dose units allows for better assessment of patient outcomes by reducing dosage variability.
BACKGROUND
Understanding the effect of blood donation and iron supplementation on iron balance will inform strategies to manage donor iron status.
STUDY DESIGN AND METHODS
A total of 215 donors were ...randomized to receive ferrous gluconate daily (37.5 mg iron) or no iron for 24 weeks after blood donation. Iron stores were assessed using ferritin and soluble transferrin receptor. Hemoglobin (Hb) iron was calculated from total body Hb. Total body iron (TBI) was estimated by summing iron stores and Hb iron.
RESULTS
At 24 weeks, TBI in donors taking iron increased by 281.0 mg (95% confidence interval CI, 223.4‐338.6 mg) compared to before donation, while TBI in donors not on iron decreased by 74.1 mg (95% CI, −112.3 to −35.9; p < 0.0001, iron vs. no iron). TBI increased rapidly after blood donation with iron supplementation, especially in iron‐depleted donors. Supplementation increased TBI compared to controls during the first 8 weeks after donation: 367.8 mg (95% CI, 293.5‐442.1) versus −24.1 mg (95% CI, −82.5 to 34.3) for donors with a baseline ferritin level of not more than 26 ng/mL and 167.8 mg (95% CI, 116.5‐219.2) versus −68.1 mg (95% CI, −136.7 to 0.5) for donors with a baseline ferritin level of more than 26 ng/mL. A total of 88% of the benefit of iron supplementation occurred during the first 8 weeks after blood donation.
CONCLUSION
Donors on iron supplementation replaced donated iron while donors not on iron did not. Eight weeks of iron supplementation provided nearly all of the measured improvement in TBI. Daily iron supplementation after blood donation allows blood donors to recover the iron loss from blood donation and prevents sustained iron deficiency.
High-dose granulocyte transfusion therapy has been available for 20 years, yet its clinical efficacy has never been conclusively demonstrated. We report here the results of RING (Resolving Infection ...in Neutropenia with Granulocytes), a multicenter randomized controlled trial designed to address this question. Eligible subjects were those with neutropenia (absolute neutrophil count <500/μL) and proven/probable/presumed infection. Subjects were randomized to receive either (1) standard antimicrobial therapy or (2) standard antimicrobial therapy plus daily granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. The primary end point was a composite of survival plus microbial response, at 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Fifty-six subjects were randomized to the granulocyte arm and 58 to the control arm. Transfused subjects received a median of 5 transfusions. Mean transfusion dose was 54.9 × 109 granulocytes. Overall success rates were 42% and 43% for the granulocyte and control groups, respectively (P > .99), and 49% and 41%, respectively, for subjects who received their assigned treatments (P = .64). Success rates for granulocyte and control arms did not differ within any infection type. In a post hoc analysis, subjects who received an average dose per transfusion of ≥0.6 × 109 granulocytes per kilogram tended to have better outcomes than those receiving a lower dose. In conclusion, there was no overall effect of granulocyte transfusion on the primary outcome, but because enrollment was half that planned, power to detect a true beneficial effect was low. RING was registered at www.clinicaltrials.gov as #NCT00627393.
•Overall, no benefit of granulocyte transfusion therapy was observed, but the power of the study was reduced due to low accrual.•Post hoc secondary analysis suggested that patients receiving higher doses tended to have better outcomes than those receiving lower ones.
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