A PINK1 input threshold arises from positive feedback in the PINK1/Parkin mitophagy decision circuit.

Mechanisms that prevent accidental activation of the PINK1/Parkin mitophagy circuit on healthy mitochondria are poorly understood. On the surface of damaged mitochondria, PINK1 accumulates and acts as the input signal to a positive feedback loop of Parkin recruitment, which in turn promotes mitochondrial degradation via mitophagy. However, PINK1 is also present on healthy mitochondria, where it could errantly recruit Parkin and thereby activate this positive feedback loop. Here, we explore emergent properties of the PINK1/Parkin circuit by quantifying the relationship between mitochondrial PINK1 concentrations and Parkin recruitment dynamics. We find that Parkin is recruited to mitochondria only if PINK1 levels exceed a threshold and then only after a delay that is inversely proportional to PINK1 levels. Furthermore, these two regulatory properties arise from the input-coupled positive feedback topology of the PINK1/Parkin circuit. These results outline an intrinsic mechanism by which the PINK1/Parkin circuit can avoid errant activation on healthy mitochondria.

Outcomes of Anterior Exposure for Spinal Surgery at an Independent Academic Medical Center.

INTRODUCTION: Anterior exposure for spinal surgery has expanded and is used for common spinal procedures, including anterior lumbar interbody fusion, disc replacement, and vertebral corpectomy. With this approach, vascular injuries have been reported ranging from 1% to 25%. The impact of resident participation on intraoperative and postoperative outcomes within an independent academic medical center has not been widely reported. The objective of this study was to determine the incidence of complications during anterior exposure spinal surgery at an independent academic medical center. METHODS: After institutional review board approval, we conducted a retrospective review of medical records of patients who underwent elective anterior exposure for spinal surgery from 2000 through 2014. RESULTS: The study included 335 patients; 60.3% were female. Thirty-day postoperative complications included surgical site infection (4.2%), urinary tract infection (2.7%), need for blood transfusion (2.1%), retrograde ejaculation (1.2%), and deep vein thrombosis (0.9%). There were 12 vascular injuries overall (3.6%); 2.7% were major vascular injuries. Surgery residents participated in 34% of cases. Resident involvement increased over the course of the study. There was no difference in operative time or complications with resident involvement. CONCLUSIONS: The overall incidence of major vascular injury was 2.7%. Levels of exposure and blood loss were associated with vascular injury. Overall postoperative complication rates as well as major vascular injury rates compared favorably to published benchmarks. Complication rates were unaffected by surgical resident involvement.

Membrane tension maintains cell polarity by confining signals to the leading edge during neutrophil migration.

Little is known about how neutrophils and other cells establish a single zone of actin assembly during migration. A widespread assumption is that the leading edge prevents formation of additional fronts by generating long-range diffusible inhibitors or by sequestering essential polarity components. We use morphological perturbations, cell-severing experiments, and computational simulations to show that diffusion-based mechanisms are not sufficient for long-range inhibition by the pseudopod. Instead, plasma membrane tension could serve as a long-range inhibitor in neutrophils. We find that membrane tension doubles during leading-edge protrusion, and increasing tension is sufficient for long-range inhibition of actin assembly and Rac activation. Furthermore, reducing membrane tension causes uniform actin assembly. We suggest that tension, rather than diffusible molecules generated or sequestered at the leading edge, is the dominant source of long-range inhibition that constrains the spread of the existing front and prevents the formation of secondary fronts.

A density-dependent switch drives stochastic clustering and polarization of signaling molecules.

Positive feedback plays a key role in the ability of signaling molecules to form highly localized clusters in the membrane or cytosol of cells. Such clustering can occur in the absence of localizing mechanisms such as pre-existing spatial cues, diffusional barriers, or molecular cross-linking. What prevents positive feedback from amplifying inevitable biological noise when an un-clustered "off" state is desired? And, what limits the spread of clusters when an "on" state is desired? Here, we show that a minimal positive feedback circuit provides the general principle for both suppressing and amplifying noise: below a critical density of signaling molecules, clustering switches off; above this threshold, highly localized clusters are recurrently generated. Clustering occurs only in the stochastic regime, suggesting that finite sizes of molecular populations cannot be ignored in signal transduction networks. The emergence of a dominant cluster for finite numbers of molecules is partly a phenomenon of random sampling, analogous to the fixation or loss of neutral mutations in finite populations. We refer to our model as the "neutral drift polarity model." Regulating the density of signaling molecules provides a simple mechanism for a positive feedback circuit to robustly switch between clustered and un-clustered states. The intrinsic ability of positive feedback both to create and suppress clustering is a general mechanism that could operate within diverse biological networks to create dynamic spatial organization.

Video. Laparoscopic distal pancreatectomy and splenectomy for splenic artery aneurysm.

BACKGROUND: Large splenic artery aneurysms are rare but comprise 60% of all visceral artery aneurysms. Most are found incidentally and rupture in the nonpregnant patient has an approximate 25 to 36% mortality rate. Historically these have been managed with an open surgical approach for resection. METHODS: We present the case of a 43-year-old man with a recent episode of bacterial endocarditis with an incidental finding of a large 6-cm splenic artery aneurysm. There was noted to be splenic vein occlusion and multiple splenic infarcts versus abscesses on preoperative imaging. There were concerns that this represented a mycotic aneurysm. He underwent laparoscopic en bloc splenic artery aneurysm resection with splenectomy and distal pancreatectomy with preoperative prophylactic balloon catheter placement. RESULTS: His large splenic artery aneurysm was adjacent to the splenic hilum. Due to the splenic vein occlusion, there were large collateral vessels complicating the dissection. Additionally, the aneurysm had dense adhesions to the tail of the pancreas from a desmoplastic reaction. To safely remove the aneurysm, a distal pancreatectomy was included with resection of the spleen. The specimen was successfully removed intact using the laparoscopic approach. The patient had an uneventful recovery and was discharged home on postoperative day 2. Final pathology revealed no evidence of bacterial etiology. CONCLUSIONS: Laparoscopic distal pancreatectomy with splenectomy is an appropriate minimally invasive option for the treatment of splenic artery aneurysms. This video demonstrates the technical challenges and management options for successfully completing a distal pancreatectomy and splenectomy in the face of a splenic artery aneurysm.

Traumatic fracture of polytetrafluoroethylene axillofemoral bypass graft.

We report traumatic disruption of a ringed polytetrafluorethylene (PTFE) axillofemoral bypass (AFB) graft due to a fall. We also review the literature of previously reported blunt traumatic PTFE graft disruptions. A 75-year-old man with previous bilateral AFB grafting presented with a painful left chest wall mass after a fall from standing height. Chest computed tomography (CT) revealed a large chest wall hematoma. The patient underwent evacuation of the hematoma, resection of the fractured graft, and placement of an interposition PTFE graft. Two prior case reports have documented the midportion PTFE graft disruption from blunt trauma. Our case report demonstrates the potential for disruption of the midportion of ringed PTFE AFB grafts with direct blunt trauma. The diagnosis was confirmed by CT scan and the graft was successfully repaired with an interposition graft.

Seconds from disaster: lessons learned from laparoscopic release of the median arcuate ligament.

Median arcuate ligament syndrome (MALS) is a rare entity that manifests as abdominal pain, nausea, vomiting, and diarrhea. The median arcuate ligament is a fibrous band that connects the crura of the diaphragm. In some people, the ligament is positioned in a way that compresses the celiac axis, which in a subset of individuals causes the symptoms associated with MALS. Surgical release of the ligament can relieve these symptoms. After viewing a video that described the laparoscopic median arcuate ligament release technique at the 2006 SAGES meeting and reviewing the online video, we report our experience with two cases and discuss the lessons learned in performing the procedure within a training program. We also discuss the extent to which surgical resident participation contributes to intraoperative complications during a new and complex surgery.

On the spontaneous emergence of cell polarity.

Diverse cell polarity networks require positive feedback for locally amplifying distributions of signalling molecules at the plasma membrane. Additional mechanisms, such as directed transport or coupled inhibitors, have been proposed to be required for reinforcing a unique axis of polarity. Here we analyse a simple model of positive feedback, with strong analogy to the 'stepping stone' model of population genetics, in which a single species of diffusible, membrane-bound signalling molecules can self-recruit from a cytoplasmic pool. We identify an intrinsic stochastic mechanism through which positive feedback alone is sufficient to account for the spontaneous establishment of a single site of polarity. We find that the polarization frequency has an inverse dependence on the number of signalling molecules: the frequency of polarization decreases as the number of molecules becomes large. Experimental observation of polarizing Cdc42 in budding yeast is consistent with this prediction. Our work suggests that positive feedback can work alone or with additional mechanisms to create robust cell polarity.

Delayed neurologic deficit after infrarenal endovascular aortic aneurysm repair.

Spinal cord ischemia is a rare and devastating complication after elective abdominal aortic aneurysm repair. It has recently been reported to occur after endovascular aortic aneurysm repair. We report the first case of delayed neurologic deficit after endovascular aortic aneurysm repair using the Zenith (Cook) device.

Prevalence and prognosis of electrocardiographic left ventricular hypertrophy, ST segment depression and negative T-wave; the Copenhagen City Heart Study.

AIMS: To evaluate the prevalence and the independent prognosis of electrocardiographic left ventricular hypertrophy by voltage only, ST depression and negative T wave, isolated negative T wave and left ventricular hypertrophy plus ST depression and negative T wave for cardiac morbidity and mortality, without known ischaemic heart disease at baseline. METHODS AND RESULTS: Follow-up data from the Copenhagen City Heart Study were used. Subjects were 5243 men and 6391 women, age range 25-74 years. End-points were (1) myocardial infarction, (2) ischaemic heart disease and (3) cardiovascular disease mortality. Relative risk was age- and sex-adjusted, and multivariately adjusted for known cardiovascular risk factors. During 7 years follow-up, left ventricular hypertrophy plus ST depression and negative T wave had an age-adjusted relative risk of 3.78 (95% confidence interval 2.29-6.25) for myocardial infarction, 4.27 (2.95-6.16) for ischaemic heart disease and 3.75 (2.41-5.85) for cardiovascular disease. A negative T wave, ST depression and negative T wave changes, and left ventricular hypertrophy with negative T wave also carry independent prognostic information for myocardial infarction, ischaemic heart disease and cardiovascular disease. CONCLUSIONS: Electrocardiographic left ventricular hypertrophy with ST depression and negative T wave changes are the electrocardiographic abnormalities with the greatest prognostic information for future cardiac events. Electrocardiographic negative T waves, ST depression and negative T wave abnormalities and left ventricular hypertrophy with negative T waves, also have prognostic information.

[Diagnosis of acute myocardial infarction in Denmark]. / Diagnostik af akut myokardieinfarkt i Danmark.

The introduction of new biochemical markers for myocardial damage in the recent years and different application of these methods in different centres may have an impact on the diagnostic criteria for acute myocardial infarction (AMI). By means of a questionnaire we studied the diagnostic criteria for AMI in relation to the use of different biochemical markers among 78 Danish hospitals. There were large variations with regard to the choice of cardiac markers and diagnostic values for different markers. CK-B is the cardiac marker mostly used followed by CK-MB. Troponin-T test was used by about 20% of the centres. Many centres are planning to use CK-MB and Troponin-T test. A common national and international policy for diagnosis of AMI in relation to different cardiac markers should reduce these improper differences.

Prognostic implications of ventricular ectopy one week, one month, and sixteen months after an acute myocardial infarction. Danish Study Group on Verapamil in Myocardial Infarction.

BACKGROUND: Ventricular ectopy early after an acute myocardial infarction (AMI) has previously been demonstrated to predict mortality. Less information is available about the prognostic implications of ventricular ectopy occurring late after an AMI, and no information is available about the prognostic implication of the development of ventricular ectopy during the first year after an AMI. HYPOTHESIS: The purpose of the present prospectively conducted trial, a part of the Danish Verapamil Infarction Trial II (DAVIT II), was to evaluate the prognostic implication of (1) ventricular premature complexes (VPCs) recorded by 24-h Holter monitoring 1 week, 1 month, and 16 months after an AMI; and (2) development of > 10 VPCs/h or of any complex ventricular ectopy, that is, pairs, more than two types of VPCs, ventricular tachycardia, or > 10 VPCs/h during follow-up after an AMI. METHODS: Patients were monitored 1 week (n = 250), 1 month (n = 210), and 16 months (n = 201) after AMI. RESULTS: Multivariate analyses based on history, clinical findings, and ventricular ectopy showed the following results: After 1 week, > 10 VPCs/h (p = 0.0006) and heart failure (p < 0.007); after 1 month, > 10 VPCs/h (p = 0.003) and resting heart rate (p < 0.02); and after 16 months, ventricular tachycardia (p = 0.002) independently predicted long-term mortality. Mortality was significantly predicted by the development of > 10 VPCs/h from 1 week to 1 month (p = 0.003) and 16 months (p = 0.03), and from 1 to 16 months (p = 0.007) after AMI, as well as by the development of any complex ventricular ectopy from 1 week to 1 month (p = 0.02) and 16 months (p = 0.01), and from 1 to 16 months (p = 0.04) after AMI. CONCLUSION: The present study demonstrated that 1 week and 1 month after an AMI the quantity of VPCs, that is, > 10 VPCs/h, predicted mortality, whereas 16 months after an AMI the quality of VPCs, that is, ventricular tachycardia, predicted mortality.

Treatment with verapamil and trandolapril in patients with congestive heart failure and angina pectoris or myocardial infarction. The DAVIT Study Group. Danish Verapamil Infarction Trial.

In a double-blind, randomized trial in a consecutive group of postinfarct patients in treatment with diuretic agents for congestive heart failure, the 3 month rate of cardiac events (i.e., death, repeat infarction, unstable angina pectoris, or repeat admission because of heart failure) was 14% in patients treated with verapamil and trandolapril and 35% in patients treated with trandolapril (p = 0.01). In another study of patients with angina pectoris and left ventricular ejection fraction less than 40%, trandolapril plus verapamil improved exercise duration and left ventricular ejection fraction. These findings indicate that combined treatment with verapamil and trandolapril may be beneficial in patients with congestive heart failure.

Treatment with verapamil and trandolapril in patients with congestive heart failure and myocardial infarction. The Danish Verapamil Infarction Trial (DAVIT Study Group).

UNLABELLED: EFFECTS OF VERAPAMIL AND TRANDOLAPRIL: Progression of heart failure, sudden death and death from re-infarction are the major cause of the increased mortality in postinfarct patients with congestive heart failure. Angiotensin converting enzyme (ACE) inhibitors such as trandolapril can prevent the progression of heart failure and thus improve survival. The calcium antagonist verapamil has been shown to prevent sudden death and re-infarction in postinfarct patients without congestive heart failure. HYPOTHESIS: The Danish Verapamil Infarction Trial (DAVIT) study group hypothesized the combined treatment with trandolapril and verapamil might prevent cardiac events in postinfarct patients with coronary heart disease. The first double-blind randomized trial included 100 patients and supported this hypothesis, as the cardiac event rate was significantly lower after 3 months in patients treated with the combination than in those treated with trandolapril alone (14 versus 35%, respectively; P = 0.01, hazard ratio 0.35, 95% confidence interval 0.15-0.85).

Cardiac event rates after acute myocardial infarction in patients treated with verapamil and trandolapril versus trandolapril alone. Danish Verapamil Infarction Trial (DAVIT) Study Group.

Angiotensin-converting enzyme (ACE) inhibitors improve survival in patients with congestive heart failure (CHF) after an acute myocardial infarction (AMI), but mortality may be as high as 10% to 15% after 1 year. Verapamil prevents cardiac events after an AMI in patients without CHF. We hypothesized that in postinfarct patients with CHF already prescribed diuretics and an ACE inhibitor, additional treatment with verapamil may reduce cardiac event rate. In this multicenter, double-blind study, patients with CHF receiving diuretic treatment were consecutively randomized to treatment with trandolapril 1 mg/day for 1 month and 2 mg/day the following 2 months (n = 49), or to trandolapril as mentioned plus verapamil 240 mg/day for 1 month and 360 mg/day for 2 months (n = 51). Trial medication started 3 to 10 days after AMI. All patients were followed for 3 months. End points in the trandolapril/trandolapril-verapamil groups were death 1/1, reinfarction 7/1, unstable angina 9/3, and readmission for CHF 6/2. The 3-month first cardiac event rate was 35% in trandolapril-treated patients and 14% in trandolapril-verapamil-treated patients (hazard ratio 0.35, 95% confidence interval 0.15 to 0.85, p = 0.015). These data suggest that verapamil reduces cardiac event rates in post-AMI patients with CHF when added to an ACE inhibitor and a diuretic.

[Torsade de Pointes tachycardia during sotalol treatment of a patient with normal potassium levels]. / Torsade de pointes-takykardi ved sotalolbehandling af en normokaliaemisk patient.

Proarrhythmia in the form of Torsade de Pointes tachycardia (TdP) is a well-known complication of sotalol treatment. It most often occurs in the setting of sotalol overdosing, renal impairment, bradycardia, hypokalaemia, hypomagnesiaemia or lengthening of the QT-interval due to other drugs. TdP is reported without these predisposing factors. In the described case, TdP might be facilitated by bradycardia and by potassium depletion without concomitant hypokalaemia after diuretic treatment.

Effect of verapamil on the prognosis of patients with early postinfarction electrical or mechanical complications. The Danish Verapamil Infarction Trial II (DAVIT II).

The Danish Verapamil Infarction Trial II (DAVIT II) demonstrated from the second postinfarction week, that long term treatment with verapamil significantly improved reinfarction free survival after an acute myocardial infarction (AMI). The present post hoc analysis of DAVIT II was undertaken with the purpose of evaluating the effect of treatment with verapamil in patients with early electrical complications, i.e. ventricular or atrial fibrillation, ventricular tachycardia, or second or third degree atrioventricular block, with or without mechanical complication, i.e. heart failure, during the first post-AMI week. In the placebo group, the 18-month mortality rate was lowest (9.5%) in patients without electrical or mechanical complications, highest (24.6%) in patients with electrical events only, and in-between (17.5%) in patients with mechanical problems regardless of presence of electrical complications. Verapamil significantly reduced the 18-month mortality rate in patients with early electrical without mechanical complications (60% reduction, P = 0.02), and in patients without mechanical complications (35% reduction, P = 0.02). Verapamil did not change the mortality rate in patients with mechanical complications.