Managing central venous access during a health care crisis.

OBJECTIVE: During the COVID-19 pandemic, central venous access line teams were implemented at many hospitals throughout the world to provide access for critically ill patients. The objective of this study was to describe the structure, practice patterns, and outcomes of these vascular access teams during the COVID-19 pandemic. METHODS: We conducted a cross-sectional, self-reported study of central venous access line teams in hospitals afflicted with the COVID-19 pandemic. To participate in the study, hospitals were required to meet one of the following criteria: development of a formal plan for a central venous access line team during the pandemic; implementation of a central venous access line team during the pandemic; placement of central venous access by a designated practice group during the pandemic as part of routine clinical practice; or management of an iatrogenic complication related to central venous access in a patient with COVID-19. RESULTS: Participants from 60 hospitals in 13 countries contributed data to the study. Central venous line teams were most commonly composed of vascular surgery and general surgery attending physicians and trainees. Twenty sites had 2657 lines placed by their central venous access line team or designated practice group. During that time, there were 11 (0.4%) iatrogenic complications associated with central venous access procedures performed by the line team or group at those 20 sites. Triple lumen catheters, Cordis (Santa Clara, Calif) catheters, and nontunneled hemodialysis catheters were the most common types of central venous lines placed by the teams. Eight (14%) sites reported experience in placing central venous lines in prone, ventilated patients with COVID-19. A dedicated line cart was used by 35 (59%) of the hospitals. Less than 50% (24 [41%]) of the participating sites reported managing thrombosed central lines in COVID-19 patients. Twenty-three of the sites managed 48 iatrogenic complications in patients with COVID-19 (including complications caused by providers outside of the line team or designated practice group). CONCLUSIONS: Implementation of a dedicated central venous access line team during a pandemic or other health care crisis is a way by which physicians trained in central venous access can contribute their expertise to a stressed health care system. A line team composed of physicians with vascular skill sets provides relief to resource-constrained intensive care unit, ward, and emergency medicine teams with a low rate of iatrogenic complications relative to historical reports. We recommend that a plan for central venous access line team implementation be in place for future health care crises.

Leukocyte-Associated Ig-like Receptor 1 Inhibits Th1 Responses but Is Required for Natural and Induced Monocyte-Dependent Th17 Responses.

Leukocyte-associated Ig-like receptor 1 (LAIR1) is an ITIM-bearing collagen receptor expressed by leukocytes and is implicated in immune suppression. However, using a divalent soluble LAIR1/Fc recombinant protein to block interaction of cell surface LAIR1 with matrix collagen, we found that whereas Th1 responses were enhanced as predicted, Th17 responses were strongly inhibited. Indeed, LAIR1 on both T cells and monocytes was required for optimal Th17 responses to collagen type (Col)V. For pre-existing "natural" Th17 response to ColV, the LAIR1 requirement was absolute, whereas adaptive Th17 and Th1/17 immune responses in both mice and humans were profoundly reduced in the absence of LAIR1. Furthermore, the addition of C1q, a natural LAIR1 ligand, decreased Th1 responses in a dose-dependent manner, but it had no effect on Th17 responses. In IL-17-dependent murine organ transplant models of chronic rejection, LAIR1+/+ but not LAIR1-/- littermates mounted strong fibroproliferative responses. Surface LAIR1 expression was higher on human Th17 cells as compared with Th1 cells, ruling out a receptor deficiency that could account for the differences. We conclude that LAIR1 ligation by its natural ligands favors Th17 cell development, allowing for preferential activity of these cells in collagen-rich environments. The emergence of cryptic self-antigens such as the LAIR1 ligand ColV during ischemia/reperfusion injury and early acute rejection, as well as the tendency of macrophages/monocytes to accumulate in the allograft during chronic rejection, favors Th17 over Th1 development, posing a risk to long-term graft survival.

Open repair of an abdominal aortic and right common iliac artery aneurysm with idiopathic retroperitoneal fibrosis in a 19-month-old infant.

An abdominal aortic aneurysm (AAA) in children is a rare clinical condition, with idiopathic AAAs even more atypical. We report a case of a 19-month-old girl with incidental findings of an infrarenal AAA and right common iliac artery aneurysm during workup for heart failure. Extensive genetic testing was unremarkable for connective tissue disorders. An aortic bi-iliac artery bypass with a Dacron graft from the infrarenal aorta to the right external iliac artery and left common iliac artery was performed. The patient achieved complete recovery and only required one oral hypertensive medication at 30 days of follow-up. Wide patency of the graft was observed on the 3-month follow-up computed tomography angiogram.

Elevated protein kinase C-δ contributes to aneurysm pathogenesis through stimulation of apoptosis and inflammatory signaling.

OBJECTIVE: Apoptosis of smooth muscle cells (SMCs) is a prominent pathological characteristic of abdominal aortic aneurysm (AAA). We have previously shown that SMC apoptosis stimulates proinflammatory signaling in a mouse model of AAA. Here, we test whether protein kinase C-δ (PKCδ), an apoptotic mediator, participates in the pathogenesis of AAA by regulating apoptosis and proinflammatory signals. METHODS AND RESULTS: Mouse experimental AAA is induced by perivascular administration of CaCl(2). Mice deficient in PKCδ exhibit a profound reduction in aneurysmal expansion, SMC apoptosis, and transmural inflammation as compared with wild-type littermates. Delivery of PKCδ to the aortic wall of PKCδ(-/-) mice restores aneurysm, whereas overexpression of a dominant negative PKCδ mutant in the aorta of wild-type mice attenuates aneurysm. In vitro, PKCδ(-/-) aortic SMCs exhibit significantly impaired monocyte chemoattractant protein-1 production. Ectopic administration of recombinant monocyte chemoattractant protein-1 to the arterial wall of PKCδ(-/-) mice restores inflammatory response and aneurysm development. CONCLUSIONS: PKCδ is an important signaling mediator for SMC apoptosis and inflammation in a mouse model of AAA. By stimulating monocyte chemoattractant protein-1 expression in aortic SMCs, upregulated PKCδ exacerbates the inflammatory process, in turn perpetuating elastin degradation and aneurysmal dilatation. Inhibition of PKCδ may serve as a potential therapeutic strategy for AAA.

Endovascular reconstruction of aortic bifurcation for aortic pseudoaneurysm in a pediatric trauma patient.

Endovascular treatment options for vascular injury in pediatric patients are quite limited owing to concerns regarding long-term durability and the lack of devices suitable for the pediatric anatomy. However, in rare circumstances, open surgical therapy will not be an option, and patients will require unconventional endovascular solutions for lifesaving or limb-saving therapies. In the present report, we describe an endovascular treatment of a pediatric patient for whom initial surgical management of a blunt abdominal aortic injury had failed, with subsequent development of an aortic pseudoaneurysm. A 10-year-old girl had presented after a high-speed motor vehicle accident with a seatbelt sign. Multiple abdominal injuries were identified, including blunt aortic injury, significant devitalization of the small bowel, colonic perforation with fecal contamination, multiple lumbar spine fractures, and pulmonary contusions. The patient developed bilateral lower extremity ischemia from the aortic injury and had initially undergone open repair. One month later, the patient had developed a pseudoaneurysm of the aorta near the aortic bifurcation. Because of the hostile abdomen and ensuing short gut syndrome, the pseudoaneurysm was managed using endovascular techniques. The limb of an Excluder internal iliac branch endoprosthesis (W.L. Gore & Associates, Flagstaff, AZ) was used as the endograft. The aortic bifurcation was raised and reconstructed using four Viabahn self-expanding stents (W.L. Gore & Associates). The completion angiogram showed complete resolution of the pseudoaneurysm. The follow-up computed tomography angiogram showed widely patent stent grafts with complete resolution of the pseudoaneurysm. Endovascular management of traumatic vascular injuries in pediatric patients is feasible. The likelihood of reintervention in the future is high with patient growth. However, it is a viable option in lifesaving or limb-saving situations in which open repair is high risk.

Interleukin-17-dependent autoimmunity to collagen type V in atherosclerosis.

RATIONALE: Considerable evidence shows atherosclerosis to be a chronic inflammatory disease in which immunity to self-antigens contributes to disease progression. We recently identified the collagen type V [col(V)] α1(V) chain as a key autoantigen driving the Th17-dependent cellular immunity underlying another chronic inflammatory disease, obliterative bronchiolitis. Because specific induction of α1(V) chains has previously been reported in human atheromas, we postulated involvement of col(V) autoimmunity in atherosclerosis. OBJECTIVE: To determine whether col(V) autoimmunity may be involved in the pathogenesis of atherosclerosis. METHODS AND RESULTS: Here, we demonstrate Th17-dependent anti-col(V) immunity to be characteristic of atherosclerosis in human coronary artery disease (CAD) patients and in apolipoprotein E-null (ApoE(-/-)) atherosclerotic mice. Responses were α1(V)-specific in CAD with variable Th1 pathway involvement. In early atherosclerosis in ApoE(-/-) mice, anti-col(V) immunity was tempered by an interleukin (IL)-10-dependent mechanism. In support of a causal role for col(V) autoimmunity in the pathogenesis of atherosclerosis, col(V) sensitization of ApoE(-/-) mice on a regular chow diet overcame IL-10-mediated inhibition of col(V) autoimmunity, leading to increased atherosclerotic burden in these mice and local accumulation of IL-17-producing cells, particularly in the col(V)-rich adventitia subjacent to the atheromas. CONCLUSIONS: These findings establish col(V) as an autoantigen in human CAD and show col(V) autoimmunity to be a consistent feature in atherosclerosis in humans and mice. Furthermore, data are consistent with a causative role for col(V) in the pathogenesis of atherosclerosis.

The Spread of a Released Clone of Gibberella zeae from Different Amounts of Infested Corn Residue.

Corn residue is a significant source of inoculum for epidemics of Fusarium head blight (FHB) in wheat and barley, but little is known about the influence of different amounts of corn residue on FHB. We monitored the spread of a released clone of Gibberella zeae (Fusarium graminearum), causal agent of FHB, from small 0.84-m-diameter research plots containing 45, 200, or 410 g of infested corn stalk pieces in winter wheat and barley fields in Virginia over 3 years (2008 to 2010). The fungus was recaptured through the collection of wheat and barley spikes at 0 and 3 m from the source and the released clone was identified in heterogeneous background populations using amplified fragment length polymorphisms. Results showed a slightly greater intensity of recovery of the clone at a greater distance when more infested residue was present. Plots containing larger amounts of inoculum (410 g) generally resulted in a smaller decline of recovery of the clone at 3 m from the source, indicating a greater spread from the larger inoculum source. The clone was also recovered at distances ≥18 m from inoculum sources. Larger amounts of corn residue generally had less influence on clone recovery in plots containing a moderately resistant wheat cultivar than those containing a susceptible wheat cultivar.

Local Distance of Wheat Spike Infection by Released Clones of Gibberella zeae Disseminated from Infested Corn Residue.

Knowledge of the movement of Gibberella zeae (Fusarium graminearum) from a local source of inoculum in infested cereal debris is critical to the management of Fusarium head blight (FHB) of wheat. Previous spatial dissemination and infection studies were unable to completely distinguish the contributions of released inocula from those of background inocula. Clones of G. zeae were released and recaptured in five wheat fields in New York and Virginia in 2007 and 2008. Amplified fragment length polymorphisms were used to track and unambiguously identify the released clones in heterogeneous populations of the fungus recovered from infected wheat spikes collected at 0, 3, 6, and ≥24 m from small-area sources of infested corn residues. The percent recovery of the released clones decreased significantly at fairly short distances from the inoculum sources. Isolates of G. zeae recovered at 0, 3, 6, and ≥24 m from the center of source areas shared 65, 19, 13, and 5% of the genotypes of the released clones, respectively. More importantly, the incidence of spike infection attributable to released clones averaged 15, 2, 1, and <1% at 0, 3, 6, and ≥24 m from source areas, respectively. Spike infection attributable to released clones decreased an average of 90% between 3 and 6 m from area sources of inoculum, and the spike infection potential of inocula dispersed at this range did not differ significantly from background sources. Our data suggest that FHB field experiments including a cereal debris variable should incorporate debris-free borders and interplots of at least 3 m and preferably 6 m to avoid significant interplot interference from spores originating from within-field debris.

Impact of Menstrual Blood Loss and Oral Contraceptive Use on Oxygen-carrying Capacity.

PURPOSE: The effect of menstrual blood loss on oxygen-carrying capacity remains equivocal. The purpose of this study was to determine the effect of menstrual blood loss on hemoglobin mass in young, healthy women. METHODS: Twenty-one women (age, 23 ± 6 yr; height, 168 ± 7 cm; weight, 66.1 ± 12.6 kg) with regular menstrual cycles, either using (n = 10) or not using oral contraceptives, participated in the study. Hemoglobin mass was assessed using carbon monoxide rebreathing on three separate occasions over the course of one menstrual cycle. RESULTS: Visits for women not using oral contraceptives were performed in the early follicular phase (3 ± 1 d after the onset of menses), late follicular phase (1 ± 1 d after the surge of luteinizing hormone in urine), and luteal phase (9 ± 1 d after the late follicular visit). Visits for women using oral contraceptives were performed in the early follicular phase (3 ± 1 d after the onset of menses), late follicular phase (15 ± 3 d after the onset of menses), and luteal phase (9 ± 2 d after the late follicular visit). Hemoglobin mass was not affected by menstrual cycle phase (early follicular, 618 ± 61; late follicular, 610 ± 65; luteal, 607 ± 68 g; P = 0.52). Interestingly, when normalized to weight, hemoglobin mass was 12% higher in women using oral contraceptives in comparison to nonusers (10.0 ± 1.2 vs 8.9 ± 1.2 g·kg, P < 0.05). CONCLUSION: Menstrual blood loss had no measurable effect on hemoglobin mass in eumenorrheic women. However, oral contraceptive use resulted in a greater oxygen-carrying capacity, potentially leading to a greater maximal oxygen uptake.

Analysis of indirect pathway CD4+ T cells in a patient with metastable tolerance to a kidney allograft: possible relevance to superior graft survival of HLA class II closely matched renal allografts.

MHC class I mismatched, but class II matched kidney transplants are tolerogenic in large animal models. CD4(+) T regulatory cells specific for HLA-B1501-derived peptide p37-MA (DSDAASPRMAPRAPWIEQ) developed in a long term (>12 years) tolerant patient who received an HLA-B1501 mismatched, HLA class II closely matched renal allograft. We hypothesized that class II matching favored T regulatory cell development by allowing allopeptide presentation on either recipient (DR4/DQ7(+)) or donor (DR4/DQ8(+)) antigen presenting cells (APC). Indirect pathway CD4(+) T cell clones were generated from recipient PBMC by sorting antigen-stimulated, proliferating cells. Most clones responded to p37-MA-pulsed B1501(-) autologous, but not to DQ8(+)B1501(+) donor B-lymphoblastoid cell lines (B-LCL). However, some clones responded to both; in fact, one responded even more strongly to donor B-LCL than to p37-MA-pulsed autologous B-LCL. P37-MA contained a DQ8-binding motif and induced strong TH1 responses from DQ8 but not DQ6 transgenic mice. Microchimerism was found to be enriched in the dendritic cells (DC) cultured from adherent PBMC. This indicates donor APC could possibly present p37-MA peptide directly to p37-MA specific T cells. These data support the concept that, when the donor is MHC class II closely matched, a "hybrid" form of allorecognition (direct/indirect) occurs. This may favor the generation of a beneficial form of indirect pathway alloreactivity, i.e. allopeptide-specific CD4(+) T regulatory cells, in the context of long term DC microchimerism.

Characterization of CD 200-receptor expression in the murine epidermis.

CD 200 is a widely expressed transmembrane glycoprotein that transmits an inhibitory signal after ligation of the structurally homologous CD 200-receptor-1 (CD 200 R1). Recently, we showed that CD 200 is expressed on keratinocytes and plays a role in protecting hair follicles from autoimmune attack. Here, we report the characterization of cell surface and mRNA expression of CD 200 R1 by cells of the murine epidermis. In addition, we report mRNA expression for other members of the CD 200 R-family (R2-R4) by quantitative real-time RT-PCR. Variable levels of CD 200 R1, R2, R3, and R4 mRNA were detected in bulk epidermal cell suspensions. Freshly isolated Langerhans cells (LC) preferentially expressed CD 200 R1. Consistent with an inhibitory role for CD 200:CD 200 R1 interaction, LC obtained from mice deficient in CD 200 (CD 200(-/-)) were in a heightened state of activation as compared with wild-type (CD 200(+/+)) cells. Freshly isolated dendritic epidermal T cells (DETC) expressed low levels of CD 200 R1, R2, and R3 mRNA, but they preferentially increased cell surface and mRNA expression of CD 200 R1 upon activation in vitro. In functional assays using sub-optimal CD3 signaling, immobilized CD 200 inhibited DETC proliferation and cytokine secretion. Collectively, these results suggest that CD 200:CD 200 R interactions may play a role in regulating both LC and DETC in cutaneous immune reactions.

Bidirectional neural interface: Closed-loop feedback control for hybrid neural systems.

Closed-loop neural prostheses enable bidirectional communication between the biological and artificial components of a hybrid system. However, a major challenge in this field is the limited understanding of how these components, the two separate neural networks, interact with each other. In this paper, we propose an in vitro model of a closed-loop system that allows for easy experimental testing and modification of both biological and artificial network parameters. The interface closes the system loop in real time by stimulating each network based on recorded activity of the other network, within preset parameters. As a proof of concept we demonstrate that the bidirectional interface is able to establish and control network properties, such as synchrony, in a hybrid system of two neural networks more significantly more effectively than the same system without the interface or with unidirectional alternatives. This success holds promise for the application of closed-loop systems in neural prostheses, brain-machine interfaces, and drug testing.

Visual outcomes following macular translocation with 360-degree peripheral retinectomy.

OBJECTIVE: To evaluate visual outcomes following macular translocation with 360 degrees peripheral retinectomy in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. METHODS: In a prospective study, 15 consecutive patients with large subfoveal choroidal neovascularization underwent macular translocation with 360 degrees peripheral retinectomy and silicone oil tamponade. Preoperative and postoperative photographs and fluorescein angiograms were obtained to evaluate lesion size and characteristics and translocation results. Standardized near and distance visual acuity and reading speed were measured preoperatively and 6 and 12 months postoperatively. MAIN OUTCOME MEASURES: Changes in and final levels of near and distance visual acuity and reading speed. RESULTS: Median lesion size was 9 Macular Photocoagulation Study disc areas (range, 4-16 disc areas). In all patients, the fovea was successfully translocated off the subfoveal lesion. The median near visual acuity logMAR score (logarithm of the minimum angle of resolution) improved significantly from 0.54 units to 0.40 units (Snellen equivalent, 20/70 to 20/50; P =.02) at the 6-month follow-up and stabilized at 0.54 (12 months postoperatively; Snellen equivalent, 20/70). Seven (54%) of 13 patients and 7 (58%) of 12 patients achieved reading speeds of 70 words/min or greater at the 6-month and 12-month postoperative visits, respectively. Median preoperative distance visual acuity (20/100) was maintained at both the 6-month and 12-month examinations. No postoperative retinal detachments occurred in this series. CONCLUSION: Macular translocation with 360 degrees peripheral retinectomy and silicone oil tamponade stabilizes and can sometimes improve near and distance visual acuity and reading speed in patients with vision loss from subfoveal neovascular age-related macular degeneration.

Patterns of early mortality after trauma in a neighborhood urban trauma center: can we improve outcomes?

Even with specialized trauma systems, a significant number of deaths occur within the early postinjury period. Our goal was to examine deaths within this period for cause and determine if care could improve outcomes. A retrospective chart review was performed on all patients who were dead on arrival or died within 4 hours of arrival between January 1, 2005, and December 31, 2011. Survival probabilities and Injury Severity Score (ISS) were calculated. Chart review and trauma review processes were used to determine cases with opportunities for care improvement. Two hundred eighty-nine patients were dead on arrival (DOA), and 176 patients died within 4 hours of arrival. The most common mechanism of injury was gunshot wounds (68.4%). The most common causes of death were uncontrolled hemorrhage (68.2%) and neurologic trauma (23.4%). Average ISS was 32. Twenty-nine patients had survival probability percentages over 50. Ten of 176 (5.7%) deaths were found to have opportunities for care improvement. In three cases (1.7%), errors contributed to death. The majority of trauma patients DOA or dying within 4 hours of hospital arrival have nonsurvivable injuries. Regular trauma review processes are invaluable in determining opportunities for care improvement. Autopsy information increases the reliability of the review process.

Epitope analysis of the collagen type V-specific T cell response in lung transplantation reveals an HLA-DRB1*15 bias in both recipient and donor.

BACKGROUND: IL-17-dependent cellular immune responses to the α1 chain of collagen type V are associated with development of bronchiolitis obliterans syndrome after lung transplantation, and with idiopathic pulmonary fibrosis and coronary artery disease, primary indications for lung or heart transplantation, respectively. METHODOLOGY/PRINCIPAL FINDINGS: We found that 30% of the patients awaiting lung transplantation exhibited a strong cell-mediated immune response to col(V). Of these, 53% expressed HLA-DR15, compared to a 28% HLA-DR15 frequency in col(V) low-responders (p=0.02). After transplantation, patients with HLA-DR1 and -DR17, not -DR15, developed anti-col(V) responses most frequently (p=0.04 and 0.01 vs. controls, respectively). However, recipients of a lung from an HLA-DR15(+)donor were at significantly elevated risk of developing anti-col(V) responses (p=0.02) and BOS (p=0.03). To determine the molecular basis of this unusual pattern of DR allele bias, a peptide library comprising the collagenous region of the α1(V) protein was screened for binding to HLA-DR0101, -DR1501, -DR0301 (DR17) or to HLA-DQ2 (DQA1*0501: DQB1*0201; in linkage disequilibrium with -DR17) and -DQ6 (DQA1*0102: DQB1*0602; linked to -DR15). Eight 15-mer peptides, six DR-binding and two DQ-binding, were identified. HLA-DR15 binding to two peptides yielded the highest binding scores: 650 (where 100 = positive control) for p799 (GIRGLKGTKGEKGED), and 193 for p1439 (LRGIPGPVGEQGLPG). These peptides, which also bound weakly to HLA-DR1, elicited responses in both HLA-DR1(+) and -DR15(+) col(V) reactive hosts, whereas binding and immunoreactivity of p1049 (KDGPPGLRGFPGDRG) was DR15-specific. Remarkably, a col(V)-reactive HLA-DR1(+)DR15(neg) lung transplant patient, whose donor was HLA-DR15(+), responded not only to p799 and p1439, but also to p1049. CONCLUSIONS/SIGNIFICANCE: HLA-DR15 and IPF disease were independently associated with pre-transplant col(V) autoimmunity. The increased risk of de novo immunity to col(V) and BOS, associated with receiving a lung transplant from an HLA-DR15(+) donor, may result from presentation by donor-derived HLA- DR15, of novel self-peptides to recipient T cells.

Loss of tolerance to self after transplant.

Organ transplantation is the widely accepted treatment for end-stage organ failure. Since the first successful kidney transplant from an identical twin donor in 1954, researchers have been studying the effects of the immune system on transplantation outcomes. Although the surgery is technically successful, the majority of grafts from genetically disparate donors are rejected due to a number of factors that stimulate recipient immune responses, ultimately resulting in graft loss despite the chronic use of immunosuppressive (IS) drugs. Unfortunately, while short-term success has greatly improved with the development of novel IS drugs, the long-term graft survival of solid organs has not improved significantly over the last few decades. The problem of late graft loss is mainly attributed to development of chronic rejection. Therefore, understanding all of the immune mechanisms involved in transplant rejection is important to prevent graft dysfunction, and eventually, graft loss. In this review, we will give an overview of allograft rejection, the progression from acute to chronic rejection, and in addition, the recent discovery of a critical role for loss of self-tolerance and development of IL-17-dependent autoimmunity in chronic rejection.

Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease.

Graft-versus-host disease (GVHD) remains the major complication after allogeneic bone marrow transplantation (BMT). The process whereby acute GVHD mediated by alloreactive donor T cells transitions into chronic GVHD, which is characterized by prominent features of auto-immunity, has long been unresolved. In this study, we demonstrate that GVHD-associated autoimmunity and, by extension, chronic GVHD is attributable to the progressive loss of CD4(+)CD25(+)Foxp3(+) regulatory T cells during the course of acute GVHD. This leads to the expansion of donor-derived CD4(+) T cells with T(H)1 and T(H)17 cytokine phenotypes that release proinflammatory cytokines and cause autoimmune-mediated pathological damage. These T cells are present early after transplantation, indicating that the pathophysiological events that lead to chronic GVHD are set in motion during the acute phase of GVHD. We conclude that the absence of CD4(+)CD25(+) regulatory T cells coupled with unregulated T(H)1 and T(H)17 cells leads to the development of autoimmunity and that donor-derived T(H)1 and T(H)17 cells serve as the nexus between acute and chronic GVHD.

HUA2 is required for the expression of floral repressors in Arabidopsis thaliana.

The HUA2 gene acts as a repressor of floral transition. Lesions in hua2 were identified through a study of natural variation and through two mutant screens. An allele of HUA2 from Landsberg erecta (Ler) contains a premature stop codon and acts as an enhancer of early flowering 4 (elf4) mutants. hua2 single mutants, in the absence of the elf4 lesion, flower earlier than wild type under short days. hua2 mutations partially suppress late flowering in FRIGIDA (FRI )-containing lines, autonomous pathway mutants, and a photoperiod pathway mutant. hua2 mutations suppress late flowering by reducing the expression of several MADS genes that act as floral repressors including FLOWERING LOCUS C (FLC ) and FLOWERING LOCUS M (FLM ).