Nathaniel B. Langer

Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts

Defects in the availability of haem substrates or the catalytic activity of the terminal enzyme in haem biosynthesis, ferrochelatase (Fech), impair haem synthesis and thus cause human congenital anaemias. The interdependent functions of regulators of mitochondrial homeostasis and enzymes responsible for haem synthesis are largely unknown. To investigate this we used zebrafish genetic screens and cloned mitochondrial ATPase inhibitory factor 1 (atpif1) from a zebrafish mutant with profound anaemia, pinotage (pnt tq209). Here we describe a direct mechanism establishing that Atpif1 regulates the catalytic efficiency of vertebrate Fech to synthesize haem. The loss of Atpif1 impairs haemoglobin synthesis in zebrafish, mouse and human haematopoietic models as a consequence of diminished Fech activity and elevated mitochondrial pH. To understand the relationship between mitochondrial pH, redox potential, [2Fe–2S] clusters and Fech activity, we used genetic complementation studies of Fech constructs with or without [2Fe–2S] clusters in pnt, as well as pharmacological agents modulating mitochondrial pH and redox potential. The presence of [2Fe–2S] cluster renders vertebrate Fech vulnerable to perturbations in Atpif1-regulated mitochondrial pH and redox potential. Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Fech to synthesize haem, resulting in anaemia. The identification of mitochondrial Atpif1 as a regulator of haem synthesis advances our understanding of the mechanisms regulating mitochondrial haem homeostasis and red blood cell development. An ATPIF1 deficiency may contribute to important human diseases, such as congenital sideroblastic anaemias and mitochondriopathies.

Outcomes After Resection of T4 Non-Small Cell Lung Cancer Using Cardiopulmonary Bypass

BACKGROUNDnComplete, en bloc resection offers the greatest chance of long-term survival in T4 non-small cell lung cancer (NSCLC). The use of cardiopulmonary bypass (CPB) to achieve an en bloc resection is controversial because of potentially increased bleeding, lung dysfunction, and tumor dissemination. We reviewed our institutional experience to assess CPBs effect on survival.nnnMETHODSnAll patients who underwent resection for T4 NSCLC at our institution between 1980 and 2013 were retrospectively reviewed and stratified according to whether they did (CPB group, nxa0= 20) or did not (No CPB group, nxa0= 355) undergo CPB. Primary outcomes of interest were overall and disease-free survival and perioperative complications.nnnRESULTSnBaseline characteristics and medical therapy were similar between the groups. Median overall survival for all patients was 31 months, with 1-, 3-, 5-, and 10-year survival of 73%, 47%, 40%, and 26%, respectively. Median disease-free survival for all patients was 19 months, with 1-, 3-, 5-, and 10-year disease-free survival of 61%, 40%, 33%, and 21%, respectively. No difference was found in overall or disease-free survival at 1, 3, 5, and 10 years between the No CPB and CPB groups (pxa0= 0.89 and pxa0= 0.88). In addition, no differences were found in the rates of major perioperative complications.nnnCONCLUSIONSnThe use of CPB allows for complete, en bloc resection in otherwise inoperable patients with T4 NSCLC and offers similar overall and disease-free survival to patients resected without CPB. All thoracic surgeons who manage T4 NSCLC should consider the use of CPB if it is necessary to achieve a complete, en bloc resection.

Injuries to the Aorta, Aortic Annulus, and Left Ventricle During Transcatheter Aortic Valve Replacement: Management and Outcomes.

The experience with transcatheter aortic valve replacement is increasing worldwide; however, the incidence of potentially catastrophic cardiac or aortic complications has not decreased. In most cases, significant injuries to the aorta, aortic valve annulus, and left ventricle require open surgical repair. However, the transcatheter aortic valve replacement patient presents a unique challenge as many patients are at high or prohibitive surgical risk and, therefore, an open surgical procedure may not be feasible or appropriate. Consequently, prevention of these potentially catastrophic injuries is vital, and practitioners need to understand when open surgical repair is required and when alternative management strategies can be used. The goal of this article is to provide an overview of current management and prevention strategies for major complications involving the aorta, aortic valve annulus, and left ventricle.

The importance of capillary density–stroke work mismatch for right ventricular adaptation to chronic pressure overload

Objective: Mechanisms of right ventricular (RV) adaptation to chronic pressure overload are not well understood. We hypothesized that a lower capillary density (CD) to stroke work ratio would be associated with more fibrosis and RV maladaptive remodeling. Methods: We induced RV chronic pressure overload over a 20‐week period in 2 piglet models of pulmonary hypertension; that is, a shunt model (n = 5) and a chronic thromboembolic pulmonary hypertension model (n = 5). We assessed hemodynamic parameters and RV remodeling as well as RV CD, fibrosis, and angiogenic factors expression. Results: Although RV was similarly hypertrophied in both models, maladapted RV remodeling with impaired systolic function was only seen in chronic thromboembolic pulmonary hypertension group members who had lower CD (484 ± 99 vs 1213 ± 74 cap/mm2; P < .01), lower CD to stroke work ratio (0.29 ± 0.07 vs 0.82 ± 0.16; P = .02), higher myocardial fibrosis (15.4% ± 3.8% vs 8.0% ± 2.5%; P < .01), as well as a higher angiogenic and fibrosis factors expression. Conclusions: The RV adaptive response to chronic pressure overload differs between 2 different piglet models of PH. Mismatch between angiogenesis and workload (CD to stroke work ratio) was associated with greater degree of myocardial fibrosis and RV dysfunction and could be a promising index of RV maladaptation. Further studies are needed to understand the underlying mechanisms.

A Severe Case of Cefoxitin-Induced Immune Hemolytic Anemia

Drug-induced immune hemolytic anemia is a rare but underdiagnosed and potentially fatal condition. We report a case of severe hemolytic anemia induced by cefoxitin in a 45-year-old woman admitted with menometrorrhagia. Hemoglobin levels reached a nadir of 4.7 g/dl approximately 72 h after cefoxitin initiation, and hemolysis resolved when cefoxitin was discontinued and prednisone 1 mg/kg was initiated. A transfusion reaction workup revealed no abnormalities. Direct antiglobulin testing was weakly positive with anti-C3. The patient’s plasma and RBC eluate reacted with cefoxitin-treated RBCs but not with untreated RBCs in the presence or absence of cefoxitin.

Cardiogenic Shock From Coronary Compression: A Difficult Diagnosis But Easy Fix

Two patients experienced compression of a coronary artery bypass graft or native coronary artery by mediastinal drains placed after cardiac surgery. Both events were identified in the catheterization laboratory and resolved after removal of the drains. One patient required concomitant percutaneous thrombectomy of the bypass graft. Although both patients cardiac function was initially severely impaired, neither patient had permanent cardiac damage and both were successfully discharged home.

Minimally Invasive Cardiovascular Surgery: Incisions and Approaches.

Throughout the modern era of cardiac surgery, most operations have been performed via median sternotomy with cardiopulmonary bypass. This paradigm is changing, however, as cardiovascular surgery is increasingly adopting minimally invasive techniques. Advances in patient evaluation, instrumentation, and operative technique have allowed surgeons to perform a wide variety of complex operations through smaller incisions and, in some cases, without cardiopulmonary bypass. With patients desiring less invasive operations and the literature supporting decreased blood loss, shorter hospital length of stay, improved postoperative pain, and better cosmesis, minimally invasive cardiac surgery should be widely practiced. Here, we review the incisions and approaches currently used in minimally invasive cardiovascular surgery.

Ewing Sarcoma of the Chest Wall: Prognostic Factors of Multimodal Therapy Including En Bloc Resection

BACKGROUNDnRadiotherapy has long been the treatment of choice for local control of Ewing sarcoma of the chest wall (ESCW). However, there is debate regarding the use of surgery versus radiotherapy. The objective of this study was to identify risk factors that may affect long-term outcomes of nonmetastatic ESCW treated with preoperative chemotherapy (CT) followed by en bloc resection and adjuvant CT or chemoradiation.nnnMETHODSnBetween 1996 and 2014, 30 patients with a median age of 25 years (SD ± 8.9 years) were treated at Marie-Lannelongue Hospital in Le Plessis-Robinson, France. Adjuvant therapy was used in 27 patients: CT for 6, chemoradiation for 20, and radiotherapy for 1. Patients demographics, treatment data, tumor features, and outcomes were collected.nnnRESULTSnIn this cohort of patients who received multimodal therapy, including neoadjuvant CT and en bloc resection, there was no postoperative mortality. Eight patients (27%) experienced postoperative complications. Resection included at least one rib (nxa0= 27) and the sternum (nxa0= 1) or the spine (nxa0= 8). Negative and microscopic disease resections were achieved in 28 and 2 patients, respectively. Tumor viability (TV) was ≤5% in 18 patients (60%). In patients with TV >5% at definitive histologic examination, adjuvant chemoradiation was associated with a better long-term outcome than was treatment with adjuvant CT alone. The 5-year overall survival and disease-free survival rates were 60.7% and 41.0%, respectively, with a median survival of 87 months. By univariate analysis, TV >5% and pleural extension at diagnosis were associated with poorer long-term survival (p < 0.05).nnnCONCLUSIONSnMultimodality treatment of ESCW, including neoadjuvant CT followed by en bloc resection and adjuvant CT or chemoradiation, is associated with excellent long-term outcomes.