Conservative Treatment of Ulnar Nerve Compression at the Elbow: A Systematic Review and Meta-Analysis.

Background The clinical results of conservative treatment options for ulnar compression at the elbow have not been clearly determined. The aim of this review was to evaluate available conservative treatment options and their effectiveness for ulnar nerve compression at the elbow. Methods In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, a systematic review and meta-analysis of studies was performed. Literature search was performed using Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). Results Of the 1,079 retrieved studies, 20 were eligible for analysis and included 687 cases of ulnar neuropathy at the elbow. Improvement of symptoms was reported in 54% of the cases receiving a steroid/lidocaine injection (95% confidence interval [CI], 41-67) and in 89% of the cases using a splint device (95% CI, 69-99). Conclusions Conservative management seems to be effective. Both lidocaine/steroid injections and splint devices gave a statistically significant improvement of symptoms and are suitable options for patients who refuse an operative procedure or need a bridge to their surgery. Splinting is preferred over injections, as it shows a higher rate of improvement.

A systematic review and meta-analysis of vascularized lymph node transfer for breast cancer-related lymphedema.

BACKGROUND: Vascularized lymph node transfer (VLNT) has become an increasingly popular technique for treating lymphedema. However, although many studies have been performed, its efficacy in increasing patients' quality of life (QoL) and reducing lymphedema in the affected body part has remained controversial. In the present systematic review, we summarized the evidence for VLNT for treating breast cancer-related lymphedema. METHODS: The MEDLINE, Embase, and Cochrane Central databases were searched for studies of patients with breast cancer-related lymphedema who had received VLNT. The study methods were assessed using the MINORS (methodologic index for nonrandomized studies) tool. The primary outcomes were the change in volume difference between the arms and QoL. The secondary outcomes were skin infection, complications, and discontinuation of compression garment use. RESULTS: A total of 17 studies were included for qualitative synthesis and 8 for meta-analysis. The average reduction rate between the healthy and affected arms in the studies included in the meta-analysis was 40.31%. Five studies had evaluated QoL, and all five studies had reported that QoL was significantly increased. Eight studies had evaluated skin infections, of which three had reported the annual infection rates before and after surgery. In these studies, infection rate had decreased significantly. Three studies had described usage of compression garments. When the patients were pooled, 27 of 60 were able to discontinue use of the compression garment. The donor and recipient complication rates were 12.1% and 7.3%, respectively. CONCLUSIONS: The current evidence indicates that VLNT can improve the volume differences between the arms in patients with unilateral lymphedema by ∼40%. In addition, although determined from a few studies, it is likely that VLNT has a positive effect on patients' QoL, the number of skin infections, and compression garment usage and coincided with a low complication rate.

Alternative Perforator Options for Insufficient Profunda Artery Perforators: A Case and Anatomical Study.

INTRODUCTION: The profunda artery perforator (PAP) flap can be an alternative to the deep inferior epigastric artery flap. However, in some cases, the PAP may not be adequate to perfuse the whole flap. In this study, we describe 3 cases in which an alternative perforator was used for PAP flap perfusion. In addition, we describe an anatomical study to explore the perforasome of the PAP and alternative perforators. MATERIALS AND METHODS: Three cases are described in which an alternative perforator was used to successfully perfuse the pap flap. For the anatomical study, 7 PAP flaps were raised from cadavers. Ink was injected in the PAP, the gracilis perforator (GP) and the descending branch of the inferior gluteal artery perforator (DBIGA). Then, perfused area of the flap by each perforator was calculated. RESULTS: The 3 patients with alternative perforators recovered without complications, in addition, no signs of fat necrosis were observed. Concerning the anatomical study, mean perfusion area of the PAP pedicle was 204 ± 90 cm (range, 141-364 cm). The GP and the DBIGA had a perfusion area of 182 ± 42 cm (range, 123-235 cm) and 157 ± 22 cm (range, 136-192), respectively. CONCLUSION: Although the PAP flap has considerable benefits over the more traditional inferior gluteal artery perforator and transverse upper gracilis flaps, a plastic surgeon might encounter a PAP flap perforator that is not deemed viable for flap perfusion. In these cases, the GP and DBIGA may be suitable "escape" alternatives to complete the reconstruction.

The Long-term Patency of Lymphaticovenular Anastomosis in Breast Cancer-Related Lymphedema.

BACKGROUND AND OBJECTIVES: Lymphedema is a condition that can greatly affect patient's quality of life. Promising results have been described with lymphaticovenular anastomosis (LVA) in the treatment of lymphedema. It is currently unknown at what rate anastomoses remain functional after a longer follow-up. The aim of this study was to determine LVA patency at 1-year follow-up. METHODS: Retrospective chart review was performed on patients who underwent LVA surgery. Patients who had indocyanine green lymphography performed at 12 months' follow-up after LVA were included in this study. Volume measurements were performed prior to surgery and at 6 and 12 months' follow-up. Patients quality of life was measured prior to surgery and at 6 months' follow-up. RESULTS: Twelve patients met inclusion criteria. In total, 15 (56.5%) of 23 LVAs were considered patent. In 8 patients (66.7%), at least 1 patent LVA was visible. The volume difference between the healthy and affected arms decreased 32.3% on average. Quality of life increased with 1.4 points on average. CONCLUSIONS: This study is, to our knowledge, the first to evaluate long-term patency of LVA in upper limb lymphedema. Our study demonstrates that at least 56.5% of the anastomoses created are patent after 1-year follow-up.

A retrospective investigation of abdominal visceral fat, body mass index (BMI), and active smoking as risk factors for donor site wound healing complications after free DIEP flap breast reconstructions.

BACKGROUND: The deep inferior epigastric artery perforator (DIEP) flap is one of the most common techniques for breast reconstruction. Body mass index (BMI) is considered as an important predictor of donor site healing complications such as wound dehiscence. The use of computed tomography (CT) proved to be a precise and objective method to assess visceral adipose tissue. It remains unclear whether quantification of visceral fat provides more accurate predictions of abdominal wound healing complications than BMI. PATIENTS AND METHODS: A total of 97 patients with DIEP flap were retrospectively evaluated. Patients' abdominal visceral fat (AVF) was quantified on CT angiography (CTA). The patients were postoperatively assessed for abdominal wound healing complications. We analyzed for the correlations between AVF, BMI, and dehiscence and established a logistic regression model to assess the potential high-profile predictors in anatomic and patient characteristics such as weight, smoking, and diabetes. RESULTS: We included 97 patients, and of them, 24 patients (24.7%) had some degree of abdominal dehiscence. No significant differences were observed between the dehiscence group and the non-dehiscence group, except for smoking (p = 0.002). We found a significant correlation between AVF and BMI (R = 0.282, p = 0.005), but neither was significant in predicting donor site dehiscence. Smoking greatly increased the likelihood of developing wound dehiscence (OR = 11.4, p = < 0.001). CONCLUSIONS: AVF and BMI were not significant predictors of abdominal wound healing complications after DIEP flap reconstruction. This study established active smoking (OR = 11.4, p = < 0.001) as the significant risk factor that contributed to the development of abdominal wound dehiscence in patients with DIEP.

Ex-vivo oxygenated perfusion of free flaps during ischemia time: a feasibility study in a porcine model and preliminary results.

BACKGROUND: Under ideal circumstances, creation of the anastomosis during free flap transfer is a routine task and can be performed under short ischemia time. However, vessels may be in suboptimal state due to atherosclerosis, radiotherapy or trauma, increasing difficulties regarding receptor vessel identification, and anastomosis which in turn may lead to lengthening of ischemia time resulting in postoperative wound problems or even flap loss. In the current pilot study, a modified heart-lung machine was assembled to achieve continuous oxygenated extracoporeal perfusion using porcine myocutaneous rectus abdominis flaps, aimed at minimizing tissue damage occurring during ischemia time. MATERIALS AND METHODS: Different pilot test groups with n = 2 were created, including oxygenated perfusion with heparinized autologous blood or organ preservation solutions. Control groups included short flush with preservation solution followed by cold storage. RESULTS: Flaps were successfully attached to the modified heart-lung machine while maintaining stable flow throughout the 24-h experiments. Flaps undergoing continuous oxygenated perfusion with preservation solutions showed minimal or no signs of cell necrosis during the 24-h experiment, in contrast to using heparinized autologous blood or flushing and cold storage. CONCLUSIONS: The use of a modified heart-lung machine for oxygenated perfusion of free flaps provides new possibilities to minimize tissue damage during ischemia time, and further study of its use is warranted.

The proximally based long peroneal muscle turnover flap: A novel salvage flap for small to medium-sized defects of the knee.

BACKGROUND AND AIM: Coverage of soft-tissue defects of the knee due to multiple operations, trauma, and infection remains a surgical challenge. Often, these defects are repaired using free tissue transfer. The aim of this study was to find an easy and reliable local method of repair for small to medium-sized defects. The authors describe a new surgical option for tissue coverage using a proximally based long peroneal muscle turnover flap (LPTF) with split-thickness skin graft. METHODS: Proximally based LPTFs were harvested and transposed into same-size created defects in five cadavers. After optimizing this technique, it was clinically used in two patients with defects secondary to total knee replacement revisions. RESULTS: Average cadaver flap size was 4.7 × 15.8 cm allowing reach of all knee joint areas and was based consistently on a sufficient (2-mm-diameter average) proximal arterial branch of the anterior tibial artery. Donor sites were closed without tension. Subsequent application of the flap on two patients resulted in good functional outcome. CONCLUSION: The proximally based LPTF is a new option available in the reconstruction of knee defects and should be added to the reconstructive surgeon's armamentarium of pedicled flaps, providing short operating time and promising clinical outcome.

Breast Reconstruction Using the Geometrically Modified Profunda Artery Perforator Flap From the Posteromedial Thigh Region: Combining the Benefits of Its Predecessors.

BACKGROUND: Occasionally, the deep inferior epigastric perforator flap is unavailable for autologous breast reconstruction. Alternative options, such as gluteal artery perforator flaps, the transverse upper gracilis flap, and the profunda artery perforator (PAP) flap, have been well documented. In our initial experience, the PAP flap was associated with limitations at the donor site. Therefore, a geometrically modified PAP flap was evaluated. METHODS: Forty geometrically modified PAP flap reconstructions were performed on 30 patients. Our modification comprised flap harvest from a more cranial area, hereby adding abundant inferior gluteal tissue to the flap while sparing superior thigh tissue. Patient characteristics, anatomical variables, and clinical outcome were prospectively evaluated. RESULTS: Mean patient age was 44 years, and mean body mass index (BMI) was 23.3 kg/m. Mean flap size was 32 × 12 cm, and mean weight was 385 g. Mean number of suitable perforators (diameter ≥ 0.5 mm) in the adductor magnus area was 1.7 per thigh. All flaps survived completely. Wound dehiscence at the donor site occurred after 4 unilateral reconstructions. Transient lymphedema of the leg occurred after 4 other unilateral reconstructions. Other wound morbidity or systemic complications did not occur. Secondary breast surgery for symmetry and volume was indicated after 16 reconstructions. Preoperative bra size was unchanged or larger in 36 reconstructions. Scar position in the crease was achieved after 39 reconstructions. Sensibility changes of the posteromedial thigh region were not observed. CONCLUSIONS: The geometrically modified PAP flap ensures in-the-crease scar positioning and provides sufficient tissue to restore preoperative bra size.

Large Contaminated Ventral Hernia Repair Using Component Separation Technique with Synthetic Mesh.

BACKGROUND: Large ventral hernia repair represents a major reconstructive surgical challenge, especially under contaminated conditions. Synthetic mesh is usually avoided in these circumstances because of fear of mesh infection, although evidence is outdated and does not regard new materials and techniques. The authors evaluated the safety of synthetic mesh in large contaminated ventral hernia repair. METHODS: All large ventral hernias repaired with the components separation technique and polypropylene mesh were included in analysis. Primary outcomes were wound and medical complications, with a focus on surgical-site infection and mesh removal. For risk analysis, patients were stratified by surgical wound class, Ventral Hernia Working Group grade, and modified Ventral Hernia Working Group grade. RESULTS: One hundred thirty-seven patients were included, with a mean age of 58.6 years, mean body mass index of 26.6 cm2, and mean defect size of 235.6 cm2. Surgical-site infection and total wound complication rates were 16.1 and 48.9 percent, respectively. The surgical wound class distribution of surgical-site infections was as follows: clean, five of 56 (9.1 percent); clean-contaminated, five of 34 (14.7 percent); contaminated, three of 19 (15.8 percent); and dirty/infected, nine of 28 (32.1 percent). Seven meshes (5.1 percent) needed removal, two after clean repairs, three after clean-contaminated repairs, and two after dirty/infected repairs. Surgical wound class (OR, 1.77; 95 percent CI, 1.20 to 2.61) and Ventral Hernia Working Group grade (OR, 2.31; 95 percent CI, 1.24 to 4.28) were predictors of surgical-site infection. CONCLUSION: Rate of surgical-site infection after large contaminated ventral hernia repair with synthetic mesh is considerable but with a low mesh removal rate.

Lateral lower leg perforator flaps: an anatomical study to localize and classify lateral lower leg perforators.

Despite increasing use of lateral lower leg perforator flaps, comprehensive anatomical data are still lacking. The aim of this article was to comprehensively document the pattern of usable lateral lower leg perforators. Systematic mapping of 16 cadaver leg perforators in a well-defined area was performed to elucidate location, course, length, diameter, and origin. Overall, 197 perforators were found in 16 lateral lower legs. The mean number of perforators per leg with a diameter ≥ 0.3 mm was 13.4 ± 3.6. Most perforators were found in the distal third (39.0%), followed by the middle third (32.0%), and proximal third (29.0%). A musculocutaneous course was found in 26.9% of the perforators, whereas 73.1% revealed a septocutaneous course. Most septocutaneous perforators (50.0%) were found in the distal third and most musculocutaneous perforators (58.5%) in the proximal third (P < 0.001). The majority of perforators originated from the anterior tibial artery (53.0%), followed by the peroneal artery (41.6%), and the popliteal artery (5.1%). Popliteal artery perforators (1.64 mm) were significantly larger than anterior tibial artery (0.91 mm) and peroneal artery perforators (1.02 mm; P < 0.001). These results may facilitate tissue transfer around the lateral lower leg.

Large and complex ventral hernia repair using "components separation technique" without mesh results in a high recurrence rate.

BACKGROUND: Recurrence rates after component separation technique (CST) are low in the literature but may be underestimated because of inadequate follow-up methods. METHODS: Prospective patient follow-up was performed of consecutive patients who underwent repair of large and complex ventral hernias using CST without mesh utilization. Primary outcome was recurrent hernia determined by clinical examination at least 1 year after surgery in all living patients. Current literature underwent meta-analysis regarding outcomes and mode of follow-up. RESULTS: Seventy-five patients were included with a mean age of 52.2 years and a mean defect size of 214.9 cm(2), respectively. Twenty-nine patients (38.7%) had a recurrent hernia after a mean of 40.9-month follow-up, and this was significantly higher than in the literature (14.0%, P < .01). Sixty-four percent of studies in the literature were unclear about the method of determining recurrent hernia or included telephone follow-up and questionnaires. CONCLUSIONS: CST coincides with a high recurrence rate when clinical follow-up is longer than a year. Reported recurrence rates are probably underestimated because the method and duration of follow-up are inadequate.

Safety and durability of one-stage repair of abdominal wall defects with enteric fistulas.

OBJECTIVE: To evaluate the safety and long-term durability of 1-stage repair of enteric fistulas in the presence of an abdominal wall defect. BACKGROUND: Patients with enteric fistulas and an abdominal wall defect present an extreme challenge to surgeons and have been associated with significant morbidity and mortality. Durability of repair is unknown as studies fail to report this or use limited follow-up periods. METHODS: Chart review was done of consecutive patients who underwent 1-stage repair. Short-term outcomes included morbidity (wound and medical) and mortality. Long-term durability of repair was determined by prospective outpatient follow-up at least 3 years after surgery. RESULTS: Thirty-nine patients were included with a mean age of 61.2 years, a mean BMI of 24.4 kg/m2, and a mean abdominal wall defect size of 247.9 cm2. Component separation technique was used in 34 (87.2%) and synthetic mesh in 13 (33.3%) patients. There was 1 (2.6%) postoperative death. Twenty-four wound complications developed in 18 (46.2%) patients, including surgical-site infection in 8 (20.5%) patients. Two (5.1%) enteric fistulas recurred and were treated conservatively resulting in closure. Medical complications were seen 36 times in 23 (59%) patients. Twelve of 33 (36.4%) living patients developed a recurrent hernia after a mean follow-up of 62.7 months (range: 36-130). CONCLUSIONS: One-stage abdominal wall reconstruction with enteric fistula takedown is feasible at the cost of considerable morbidity. Our treatment strategy including component separation technique with synthetic mesh on-demand results in a durable repair in 6 to 7 of 10 patients.

Requirement for Lyl1 in a model of Lmo2-driven early T-cell precursor ALL.

Lmo2 is an oncogenic transcription factor that is frequently overexpressed in T-cell acute lymphoblastic leukemia (T-ALL), including early T-cell precursor ALL (ETP-ALL) cases with poor prognosis. Lmo2 must be recruited to DNA by binding to the hematopoietic basic helix-loop-helix factors Scl/Tal1 or Lyl1. However, it is unknown which of these factors can mediate the leukemic activity of Lmo2. To address this, we have generated Lmo2-transgenic mice lacking either Scl or Lyl1 in the thymus. We show that although Scl is dispensable for Lmo2-driven leukemia, Lyl1 is critical for all oncogenic functions of Lmo2, including upregulation of a stem cell-like gene signature, aberrant self-renewal of thymocytes, and subsequent generation of T-cell leukemia. Lyl1 expression is restricted to preleukemic and leukemic stem cell populations in this model, providing a molecular explanation for the stage-specific expression of the Lmo2-induced gene expression program. Moreover, LMO2 and LYL1 are coexpressed in ETP-ALL patient samples, and LYL1 is required for growth of ETP-ALL cell lines. Thus, the LMO2-LYL1 interaction is a promising therapeutic target for inhibiting self-renewing cancer stem cells in T-ALL, including poor-prognosis ETP-ALL cases.

Biologic grafts for ventral hernia repair: a systematic review.

BACKGROUND: Biologic grafts hold promise of a durable repair for ventral hernias with the potential for fewer complications than synthetic mesh. This systematic review was performed to evaluate the effectiveness and safety of biologic grafts for ventral hernia repair. METHODS: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched for studies on biologic grafts for the repair of ventral hernias. Outcomes are presented as weighted pooled proportions. RESULTS: Twenty-five retrospective studies were included. Recurrence depended on wound class, with an overall rate of 13.8% (95% confidence interval [CI], 7.6-21.3). The recurrence rate in contaminated/dirty repairs was 23.1% (95% CI, 11.3-37.6). Abdominal wall laxity occurred in 10.5% (95% CI, 3.7-20.3) of patients. The surgical morbidity rate was 46.3% (95% CI, 33.3-59.6). Infection occurred in 15.9% (95% CI, 9.8-23.2) of patients but only led to graft removal in 4.9% of cases. CONCLUSIONS: No randomized trials are available to properly evaluate biologic grafts for ventral hernia repair. The current evidence suggests that biologic grafts perform similarly to other surgical options. Biologic grafts are associated with a high salvage rate when faced with infection.

Surgical techniques for parastomal hernia repair: a systematic review of the literature.

BACKGROUND: Parastomal hernias are a frequent complication of enterostomies that require surgical treatment in approximately half of patients. This systematic review aimed to evaluate and compare the safety and effectiveness of the surgical techniques available for parastomal hernia repair. METHODS: Systematic review was performed in accordance with PRISMA. Assessment of methodological quality and selection of studies of parastomal hernia repair was done with a modified MINORS. Subgroups were formed for each surgical technique. Primary outcome was recurrence after at least 1-year follow-up. Secondary outcomes were mortality and postoperative morbidity. Outcomes were analyzed using weighted pooled proportions and logistic regression. RESULTS: Thirty studies were included with the majority retrospective. Suture repair resulted in a significantly increased recurrence rate when compared with mesh repair (odds ratio [OR] 8.9, 95% confidence interval [CI] 5.2-15.1; P < 0.0001). Recurrence rates for mesh repair ranged from 6.9% to 17% and did not differ significantly. In the laparoscopic repair group, the Sugarbaker technique had less recurrences than the keyhole technique (OR 2.3, 95% CI 1.2-4.6; P = 0.016). Morbidity did not differ between techniques. The overall rate of mesh infections was low (3%, 95% CI 2) and comparable for each type of mesh repair. CONCLUSIONS: Suture repair of parastomal hernia should be abandoned because of increased recurrence rates. The use of mesh in parastomal hernia repair significantly reduces recurrence rates and is safe with a low overall rate of mesh infection. In laparoscopic repair, the Sugarbaker technique is superior over the keyhole technique showing fewer recurrences.

Large-scale transcriptional profiling and functional assays reveal important roles for Rho-GTPase signalling and SCL during haematopoietic differentiation of human embryonic stem cells.

Understanding the transcriptional cues that direct differentiation of human embryonic stem cells (hESCs) and human-induced pluripotent stem cells to defined and functional cell types is essential for future clinical applications. In this study, we have compared transcriptional profiles of haematopoietic progenitors derived from hESCs at various developmental stages of a feeder- and serum-free differentiation method and show that the largest transcriptional changes occur during the first 4 days of differentiation. Data mining on the basis of molecular function revealed Rho-GTPase signalling as a key regulator of differentiation. Inhibition of this pathway resulted in a significant reduction in the numbers of emerging haematopoietic progenitors throughout the differentiation window, thereby uncovering a previously unappreciated role for Rho-GTPase signalling during human haematopoietic development. Our analysis indicated that SCL was the 11th most upregulated transcript during the first 4 days of the hESC differentiation process. Overexpression of SCL in hESCs promoted differentiation to meso-endodermal lineages, the emergence of haematopoietic and erythro-megakaryocytic progenitors and accelerated erythroid differentiation. Importantly, intrasplenic transplantation of SCL-overexpressing hESC-derived haematopoietic cells enhanced recovery from induced acute anaemia without significant cell engraftment, suggesting a paracrine-mediated effect.

Aberrant mast-cell differentiation in mice lacking the stem-cell leukemia gene.

The stem cell leukemia (SCL) gene encodes a basic helix-loop-helix transcription factor expressed in erythroid, megakaryocyte, and mast-cell lineages. SCL is essential for growth of megakaryocyte and erythroid progenitors. We have used a conditional knockout of SCL (SCL(-/Delta)) to examine its function in mast cells, critical effectors of the immune system. SCL(-/Delta) mice had markedly increased numbers of mast-cell progenitors (MCPs) within the peritoneal fluid, bone marrow, and spleen. Fractionation of bone marrow myeloid progenitors demonstrated that these MCPs were present in the megakaryocyte-erythroid-restricted cell fraction. In contrast, unilineage MCPs from control mice were present in the cell fraction with granulocyte-macrophage potential. The aberrant mast-cell differentiation of SCL(-/Delta) megakaryocyte-erythroid progenitors was associated with increased expression of GATA-2. Despite increased numbers of MCPs in SCL(-/Delta) mice, numbers of mature tissue mast cells were not increased unless SCL(-/Delta) mice were treated with IL-3 and stem-cell factor. In part, this may be due to a requirement for SCL in normal mast-cell maturation: SCL(-/Delta) mast cells had reduced expression of the high-affinity IgE receptor and mast cell proteases, MCP-5 and MCP-6. Together, these studies suggest that loss of SCL leads to aberrant mast-cell differentiation of megakaryocyte-erythroid progenitors.

A critical role for the transcription factor Scl in platelet production during stress thrombopoiesis.

The generation of platelets from megakaryocytes in the steady state is regulated by a variety of cytokines and transcription factors, including thrombopoietin (TPO), GATA-1, and NF-E2. Less is known about platelet production in the setting of stress thrombopoiesis, a pivotal event in the context of cytotoxic chemotherapy. Here we show in mice that the transcription factor Scl is critical for platelet production after chemotherapy and in thrombopoiesis induced by administration of TPO. Megakaryocytes from these mice showed appropriate increases in number and ploidy but failed to shed platelets. Ultrastructural examination of Scl-null megakaryocytes revealed a disorganized demarcation membrane and reduction in platelet granules. Quantitative real-time polymerase chain reaction showed that Scl-null platelets lacked NF-E2, and chromatin immunoprecipitation analysis demonstrated Scl binding to the NF-E2 promoter in the human megakaryoblastic-cell line Meg-01, along with its binding partners E47, Lmo2, and the cofactors Ldb1 and GATA-2. These findings suggest that Scl acts up-stream of NF-E2 expression to control megakaryocyte development and platelet release in settings of thrombopoietic stress.

Granulocyte colony-stimulating factor and stem cell factor improve endogenous repair after myocardial infarction.

OBJECTIVE: The aims of this study were, first, to determine if granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) improved left ventricular function in the setting of a reperfusion model of myocardial infarction (MI) and, second, to evaluate the effects of G-CSF/SCF on cellular repair and, in particular, the fate of bone marrow cells homing to the site of tissue injury. METHODS: MI was induced in mice by transient ligation of the left descending coronary artery. G-CSF/SCF were administered for 5 days after MI. Cardiac function was assessed 28 days after MI. The effect of G-CSF/SCF on the cellular composition of the infarct region was assessed by immunohistochemistry. MI was performed in mice reconstituted with bone marrow cells expressing DsRed to track the fate of bone marrow-derived cells within the infarct region. RESULTS: G-CSF/SCF-treated mice had significantly improved left ventricular (LV) function as determined by LV developed pressure, LV+/-dp/dt(max/min), and LV end-diastolic pressure. G-CSF alone produced similar improvements in cardiac function. These improvements in LV function were associated with 70% more blood vessels and a doubling of cells expressing cardiomyocyte-specific transcription factors GATA-4, Nkx2.5 and alpha-actinin cells within the infarct zone. Cells within the infarct expressing stromal-derived factor also increased by 200%. To elucidate the origin of these cells, bone marrow chimeras, where hematopoietic cells expressed the fluorescent marker DsRed, were treated with G-CSF/SCF after MI. Bone marrow-derived, DsRed-expressing cells in the infarct region of G-CSF/SCF-treated chimeras increased by an average of 12-fold; however, the vast majority of DsRed cells expressed the hematopoietic-specific marker CD45 but not blood vessel or cardiomyocyte markers. CONCLUSIONS: G-CSF/SCF therapy improved cardiac function when delivered after MI, increasing the number of blood vessels and cells of cardiomyogenic lineage. However, these cells were of myocardial rather than bone marrow origin.

Functional but abnormal adult erythropoiesis in the absence of the stem cell leukemia gene.

Previous studies have indicated that the stem cell leukemia gene (SCL) is essential for both embryonic and adult erythropoiesis. We have examined erythropoiesis in conditional SCL knockout mice for at least 6 months after loss of SCL function and report that SCL was important but not essential for the generation of mature red blood cells. Although SCL-deleted mice were mildly anemic with increased splenic erythropoiesis, they responded appropriately to endogenous erythropoietin and hemolytic stress, a measure of late erythroid progenitors. However, SCL was more important for the proliferation of early erythroid progenitors because the predominant defects in SCL-deleted erythropoiesis were loss of in vitro growth of the burst-forming erythroid unit and an in vivo growth defect revealed by transplant assays. With respect to erythroid maturation, SCL-deleted proerythroblasts could generate more mature erythroblasts and circulating red blood cells. However, SCL was required for normal expression of TER119, one of the few proposed target genes of SCL. The unexpected finding that SCL-independent erythropoiesis can proceed in the adult suggests that alternate factors can replace the essential functions of SCL and raises the possibility that similar mechanisms also explain the relatively minor defects previously observed in SCL-null hematopoietic stem cells.