Biomedical subjects

Alicia M Mohr

Publications and source records attributed to Alicia M Mohr.

11 recordsLinked to original sources

PubMed2026

A murine model of sepsis induces age- and sex-specific chromatin remodeling in myeloid-derived suppressor cells.

INTRODUCTION: Sepsis survivors frequently develop long-term immune dysfunction, but the epigenetic mechanisms underlying persistent myeloid suppression remain unclear. Myeloid-derived suppressor cells (MDSCs), whose function is shaped by host age and sex, are key contributors to post-sepsis immune dysregulation. METHODS: Here, we present a high-resolution epigenetic map targeting gene promoters of MDSCs after sepsis and daily chronic stress using MAPit-FENGC, a single-molecule assay that simultaneously profiles DNA methylation and chromatin accessibility. In a clinically relevant murine model, including young and older adult male and female mice, splenic MDSCs were isolated for MAPit-FENGC and single-cell RNA sequencing. RESULTS: Unsupervised clustering identified nine promoter classes reflecting chromatin dynamics: age- and sex-dependent sepsis-induced opening (Classes 1-4), persistent closure with varying levels of DNA methylation (Classes 5-7), and constitutive openness post-sepsis (Classes 8, 9). Transcriptomic profiling corroborated these promoter states, linking accessibility with gene expression. CONCLUSIONS: These findings define promoter-level epigenetic classes across a targeted locus panel in splenic CD11b+Gr1+ cells within this murine sepsis model and generate mechanistic hypotheses regarding age- and sex-associated chromatin states.

Animals↗

PubMed2006

Bone marrow failure in male rats following trauma/hemorrhagic shock (T/HS) is mediated by mesenteric lymph and modulated by castration.

Bone marrow (BM) suppression occurs following trauma/hemorrhagic shock (T/HS) in experimental animals as well as following severe injury in humans. Although the pathophysiology of BM suppression remains poorly understood, mesenteric lymph is thought to play an important role in T/HS-induced BM suppression; however, the direct effect of mesenteric lymph on BM in vitro has never been studied. In addition, recent studies in rats have also shown that female and castrated male rats are protected against T/HS-induced BM failure. We therefore hypothesized that mesenteric lymph is a source of factor(s) causing direct BM suppression and that the effects of mesenteric lymph are gender dependent. To test this hypothesis, we subjected noncastrated (NC) and castrated (C) male and proestrus female rats to T/HS or trauma sham shock (T/SS). Mesenteric lymph collected 3 h postshock was plated (4% v/v) with BM cells collected from unmanipulated male or female rats for granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) colony growth. The T/HS lymph collected from NC-male rats but not from female rats caused a 50% inhibition of CFU-GM and BFU-E colony growth compared with cells cultured without lymph (P < 0.05 versus all other groups (ANOVA + Tukey). T/HS lymph collected from C-male rats also caused no significant inhibition of CFU-GM and BFU-E colony growth compared with cells cultured without lymph. Female and male BM progenitor cells had a similar response to mesenteric lymph from all groups tested. These results show that mesenteric lymph from NC-male rats suppresses CFU-GM and BFU-E progenitor growth in vitro, whereas the lymph from C-male and female rats did not. The effects of mesenteric lymph were the same regardless of whether the target BM was from male or female rats. The results therefore indicate that BM failure in male rats is directly mediated by factors present within the mesenteric lymph that appear to be modulated by castration, and protection against BM failure in female rats occurs at a systemic rather than a local level. Further studies are needed to elucidate potential therapeutic effects of lymph manipulation in hematopoiesis after injury.

Animals↗

PubMed2005

Recombinant activated factor VIIa and hemostasis in critical care: a focus on trauma.

In this article we describe the current use of recombinant activated factor VII (rFVIIa; NovoSeven) in trauma patients. Emphasis is placed on current uses as defined by key studies, efficacy data, and safety data. Most published studies in trauma patients are retrospective case studies and reports, although an international, double-blind, randomized, controlled, phase II study has been conducted that reported on the efficacy of rFVIIa in reducing the amount of blood products transfused in blunt trauma patients. That study demonstrated the efficacy and safety profile of this hemostatic agent as compared with placebo as adjunctive therapy in the management of severe bleeding associated with trauma. Further prospective, randomized, and placebo-controlled clinical trials will yield more information on the role of rFVIIa in the management of traumatic bleeding.

Blood Coagulation↗

PubMed2005

The impact of a hypercatecholamine state on erythropoiesis following severe injury and the role of IL-6.

BACKGROUND: Severe traumatic injury can lead to hemorrhagic shock-induced bone marrow (BM) dysfunction resulting in persistent anemia. The hypercatacholamine state that accompanies severe injury has been shown to impact the growth of erythroid progenitors. IL-6 has a role both in the acute phase response of trauma and has been implicated in the development of anemia. The aim of this study was to investigate the severity of a hyper-adrenergic stimulus on pluripotent progenitors (GEMM-CFU) as well as erythroid progenitors (BFU-E and CFU-E) and the potential regulatory role of IL-6. METHODS: Normal human BM mononuclear cells were isolated and erythropoiesis was assessed by the growth of GEMM-CFU, BFU-E and CFU-E in the presence of adrenergic agonists, norepinephrine (NE) and epinephrine (EPI), at increasing concentrations. Similarly, normal BM stroma cells were grown to confluence then incubated with NE and EPI. Supernatant was harvested and IL-6 levels were determined using ELISA. RESULTS: Under physiologic conditions (10(-7) M), NE and EPI increase BFU-E and CFU-E growth (374% and 177% versus 100% control). At severe stress levels (10(-3) M), NE and EPI completely inhibited BFU-E and CFU-E growth (5% and 4% versus 100% control). GEMM-CFU growth was increased by NE and not EPI at 10(-7) M. The presence of NE and EPI increased IL-6 levels in a dose-dependent fashion. CONCLUSIONS: The proliferative effect of adrenergic agonists at physiologic levels on normal erythropoiesis begins early during erythroid differentiation. At severe stress levels, BFU-E and CFU-E growth is inhibited. The erythropoietic dysfunction and resultant anemia seen following severe injury may be due to the presence of a severe hypercatecholamine state and may be mediated by IL-6.

Bone Marrow Cells↗

PubMed2005

Civilian craniocerebral gunshot wounds: an update in predicting outcomes.

Given the high mortality in patients sustaining intracranial injury secondary to gunshot wounds (GSWs), predictors to identify patients at increased risk of death are needed to assist clinicians early in determining optimal treatment. There have been few recent studies involving penetrating craniocerebral injuries, and most studies have been restricted to small numbers of patients, which do not allow for adequate prediction of mortality. A retrospective chart review of 298 patients who sustained GSWs to the head between 1992 and 2003 was conducted at a level 1 trauma center. Demographics, bullet trajectory, admitting Glasgow Coma Scale (GCS), head Abbreviated Injury Score (AIS), as well as admission blood pressure and respiratory rate were evaluated. Univariate testing followed by multivariate logistic regression was performed to identify independent predictors of death. In-hospital mortality for patients with intracranial injury secondary to GSW was 51 per cent. A GCS <5 on admission and a high Injury Severity Score (ISS >25) was associated with mortality as compared with survivors (P < 0.05). Of those patients presenting with a GCS of 3, there were seven survivors to discharge. Logistic regression identified the following variables as predictors of death: respiratory arrest on admission, hypotension on admission, transhemispheric and transventricular GSW. Identification of those patients at the highest risk of death secondary to a craniocerebral GSW allows clinicians to better predict outcome and prognosis. This is not only important in determining treatment algorithms for physicians but also for appropriate counseling of family members to educate them with regard to patients' outcomes.

Adolescent↗

PubMed2004

Value of repeat cranial computed axial tomography scanning in patients with minimal head injury.

BACKGROUND: Patients with minimal head injury (MHI) and a cranial computed axial tomography (CAT) scan positive for the presence of intracranial injury routinely undergo a repeat CAT scan within 24 hours after injury. The value of this repeat cranial CAT scan is unclear in those patients who are neurologically normal or improving. METHODS: A retrospective analysis of all adult patients admitted to a level-1 trauma center with MHI and a positive cranial CAT scan during a 32-month period was performed. The need for neurosurgical intervention after repeat CAT scan in patients with a persistently normal or improved neurological examination was recorded. RESULTS: One hundred fifty-one patients had a persistently normal or improved neurological examination, but none of these patients required neurosurgical intervention after the repeat cranial CAT scan. CONCLUSIONS: A persistently normal or improving neurological examination in a patient with MHI appears to exclude the need for neurosurgical intervention and thus a repeat cranial CAT scan.

Adult↗

PubMed2004

Adrenergic modulation of erythropoiesis following severe injury is mediated through bone marrow stroma.

BACKGROUND: Severe trauma leads to hematopoietic failure and bone marrow (BM) dysfunction that manifests clinically as a persistent anemia and leukopenia. The impact of severe trauma and its associated hyperadrenergic state on erythropoiesis has not been described. The aim of this study was to demonstrate the effects of adrenergic agonists and antagonists on erythropoiesis, both in normal bone marrow mononuclear cells (BMNC) and stroma-depleted BM. METHODS: Urine epinephrine (EPI) and norepinephrine (NE) excretion from severely injured patients was assessed via enzyme-linked immunoadsorbent assay (ELISA). Erythropoiesis was assessed by the growth of erythroid progenitors-erythroid burst forming units and colony forming units (BFU-E and CFU-E)-in normal human BM in the presence of adrenergic agonists and antagonists at varying concentrations. Parallel cultures, depleted of BM stroma by passage through nylon wool columns, were compared. RESULTS: Urine NE excretion was elevated in all samples from days 1 to 10 following injury (average 139 +/- 59 mcg/day vs. control 35 +/- 9 mcg/day). In vitro doses of NE, EPI, and isoproterenol (ISO) exerted a stimulatory effect on BFU-E colony growth in BMNCs (expressed as percentage of control: 324 +/- 30, 272 +/- 16, 212 +/- 95, vs. 100%), but had no effect on stroma-depleted BM. CONCLUSIONS: There is a substantial and persistent hyperadrenergic state seen after severe injury that may last for up to a week. Adrenergic agonists have a clear stimulatory effect on the growth of primitive erythroid precursors in normal BM. The adrenergic stimulus appears to be mediated via BM stroma.

Adrenergic Agents↗

PubMed2004

Small volume albumin administration protects against hemorrhagic shock-induced bone marrow dysfunction.

BACKGROUND: Unexpected immunomodulatory effects of colloids and crystalloids prompted an investigation of albumin's ability to prevent bone marrow (BM) suppression following trauma/hemorrhagic shock (T/HS: laparotomy + MAP 30 for 90 mins). METHODS: In vitro: Normal rat BM was plated for granulocyte-macrophage (CFU-GM) and erythrocyte colony forming units (BFU-E) with 2% v/v plasma from sham (T/SS) or T/HS rats and albumin (2-8 mg/mL). In vivo: Male rats (n = 4/group) were subjected to T/SS or T/HS and resuscitated with shed blood and twice the volume as Lactated Ringer's (LR) or blood and 1, 2, or 3 mL of albumin (50 mg/mL). Bone marrow harvested 3 hours post-resuscitation was plated for CFU-GM and BFU-E. RESULTS: In vitro: T/HS plasma decreased both CFU-GM and BFU-E growth as compared with T/SS, whereas increasing doses of albumin showed dose-dependent improvement in progenitor growth (p < 0.05). In vivo: The suppression of BM red and white cell progenitor growth seen in T/HS+LR rats as compared with T/SS was fully prevented by as little as 1 mL of albumin (p < 0.05). CONCLUSIONS: Small doses of albumin fully restore CFU-GM and BFU-E to sham values. We postulate that the binding of circulating toxic factors by albumin may play a role in this prevention of T/HS-induced BM suppression.

Albumins↗

PubMed2003

Management of trauma to the male external genitalia: the usefulness of American Association for the Surgery of Trauma organ injury scales.

PURPOSE: Injury to the male external genitalia is rare and, therefore, there are little data in the literature regarding the options for nonoperative management and outcome. To assist in defining the indications for nonoperative management the usefulness of the American Association for the Surgery of Trauma (AAST) organ injury scales for these injuries was examined. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 116 male patients with trauma to the external genitalia in a 10-year period and classified injuries according to the organ injury severity scales (scrotum, testis, penis and urethra) of the AAST. Based on AAST grading management and outcome was reviewed. RESULTS: Mean patient age was 28 years and 79% of the injuries were due to gunshot wounds. A total of 87 patients (75%) underwent surgery, while 27 penile injuries and 8 scrotal/testicular injuries were managed nonoperatively. There were 54 scrotal explorations, 33 testicular injuries and 20 orchiectomies (bilateral in 1) for a testicular salvage rate of 39%. Documented followup by the trauma or genitourinary service was achieved in 47 of 110 survivors. No patient reported impotence or difficulty with fertility. CONCLUSIONS: The AAST grading for male external genital trauma readily characterizes patients with high grade injuries that require operative management as well as select patients in whom injury can be safely managed nonoperatively.

Adolescent↗

PubMed2003

Angiographic embolization for liver injuries: low mortality, high morbidity.

OBJECTIVE: Angiographic embolization (AE) is a safe and effective method for controlling hemorrhage in both blunt and penetrating liver injuries. Improved survival after hepatic injuries has been documented using a multimodality approach; however, patients still have significant long-term morbidity. This study examines further the role of AE in both blunt and penetrating liver injuries and the outcomes of its use. METHODS: The medical records of 37 consecutive patients admitted from 1995 to 2002 to a Level I trauma center who underwent hepatic angiography with the intent to embolize were reviewed. Demographic and clinical information including Injury Severity Score, length of stay, mortality, intra-abdominal complications, admission physiologic variables, and the number and type of abdominal operations performed were collected. RESULTS: Thirty-seven patients underwent hepatic angiography and 26 patients had hepatic embolization performed. Eleven patients underwent early-AE, immediately after computed tomographic scanning, and 15 underwent late-AE, after liver-related operations or later in their hospital course. There was a 27% mortality rate overall. There were 11 liver-related complications in the 26 embolizations. Excluding the early deaths, the associated morbidity was 58%, which included hepatic necrosis, hepatic abscesses, and bile leaks. CONCLUSION: There is increasing adjunctive use of AE in patients managed both operatively and nonoperatively. Intra-abdominal complications are common in these salvaged patients with severe liver injuries. Those patients that underwent early-AE received significantly fewer blood transfusions and more commonly had sterile hepatic collections. Only 26% of patients required liver-related surgery after AE. Therefore, the integration of AE as an adjunctive modality for patients with high-grade liver injuries is a safe and effective therapeutic option.

Adolescent↗

PubMed2002

Delayed differentiation of HL-60 cells following exposure to hypoxia.

OBJECTIVE: Hemorrhagic shock and hypoxia have been shown to alter immune and hematopoietic functions. Cellular hypoxia is thought to be the primary defect and has been shown to induce a variety of biological alterations. In this study, we examined if this defect is at the stage of terminal differentiation with the myelomonocytic cell line HL-60. METHODS: After hypoxia, HL-60 cells were induced with 1.25% dimethyl sulfoxide (DMSO) to differentiate toward neutrophils (PMN). The ability to differentiate was evaluated by nitroblue tetrazolium staining. The function of the differentiated cells was determined by intracellular calcium levels after exposure to different chemotactic factors, and levels of Id-2 mRNA, a factor associated with terminal differentiation of myeloid cells, were assessed with Northern analysis. RESULTS: At 48 h following exposure to hypoxia, HL-60 differentiation was significantly blunted (hypoxia 51 +/- 1%, normoxia 69 +/- 1%; P < 0.001). Intracellular calcium levels in DMSO-treated cells stimulated with 1 microM bacterial tripeptide, fMLP, were significantly reduced in the hypoxic cells (381 +/- 11 nM vs 449 +/- 10 nM; P < 0.01). No difference was noted for two other chemotactic factors, C5a and platelet-activating factor. Using Northern analysis to determine the levels of Id-2 mRNA, we demonstrated that hypoxia reduced the levels by 20% over normoxic cells. CONCLUSION: This study demonstrates that hypoxia blunts the differentiation of HL-60 cells to PMN. This altered function of hypoxia appears to be reversible since hypoxia prolonged the time for HL-60 cells to differentiate and this may be partly explained by the premature downregulation of Id-2 expression.

Biological Transport↗