Long-term limb salvage and functional outcomes for patients undergoing partial calcanectomy.

INTRODUCTION: Partial calcanectomy (PC) can be performed to treat chronic heel ulcers in patients with calcaneal osteomyelitis. Patients undergoing PC often have multiple comorbidities, limited mobility, and face high risk of major limb amputation. This study examined the extent of vascular diagnostic testing and interventions as well as long-term outcomes in patients undergoing PC. METHODS: A retrospective analysis was performed on patients who underwent PC for non-healing calcaneal ulcer over a ten-year period. Demographics, comorbidities, vascular testing, and procedural data were recorded. Additional subgroup analysis was performed according to presence or absence of peripheral arterial disease (PAD). Primary outcomes were major limb amputation (above or below the knee) and mortality. Secondary outcomes included successful wound healing, time to complete wound healing, re-interventions, and change in ambulatory status. RESULTS: A total of 157 patients underwent partial calcanectomies on 162 limbs. 78.3% of patients had diabetes mellitus and 47.8% were diagnosed with PAD. Ankle brachial index with pulse volume recording (ABI/PVR) was performed for 46.5% (73/157) of patients, arterial duplex in 44.6% (70/157), and 19.7% (31/157) had a computed tomography angiogram. Lower extremity revascularization was performed in 28.4% of limbs (46/162). Independent ambulatory status was reported in 40.1% prior to PC and decreased to 17.9% by the time of last recorded follow-up (p < .00001). Long-term amputation-free survival was significantly higher in patients without PAD at 7 years (78.4% vs 57.1%, p = .02). Multivariate logistic regression analysis demonstrated that PAD and end-stage renal disease (ESRD) increased the odds of major limb amputation (OR 3.5 and 2.8, respectively), whereas ESRD and adjuvant podiatric procedures were associated with increased mortality (OR 4.8 and 4.8, respectively). CONCLUSION: Non-invasive vascular testing should be obtained in all patients undergoing PC, in order to stratify risk of amputation and identify candidates for revascularization. Over the long-term, patients undergoing PC face significant risk of prolonged wound healing, decline in ambulatory status, and major limb amputation.

The development of a novel endovascular grasper for challenging inferior vena cava filter retrieval.

OBJECTIVE: Although inferior vena cava (IVC) filters are commonly retrieved using a snare, lateral tilt and fibrosis around struts can complicate the procedure and sometimes require the use of off-label devices. We describe the development of a novel articulating endovascular grasper designed to remove permanent and retrievable IVC filters in any configuration. METHODS: For in vitro testing, the IVC filters were anchored to the inner wall of a flexible tube in a centered or tilted configuration. A high-contrast backlit camera view simulated the two-dimensional fluoroscopy projection during retrieval. The time from the retrieval device introduction into the camera field to complete filter retrieval was measured in seconds. The control experiment involved temporary IVC filter retrieval with a snare. There were four comparative groups: (1) retrievable filter in centered configuration; (2) retrievable filter in tilted configuration; (3) permanent filter in centered configuration; and (4) permanent filter in tilted configuration. Every experiment was repeated five times, with median retrieval time compared with the control group. For in vivo testing in a porcine model, six tilted infrarenal IVC filters were retrieved with grasper via right jugular approach. Comparison analysis between animal and patient procedures was performed for the following variables: total procedure time, the retrieval time, and fluoroscopy time. RESULTS: The in vitro experiments showed comparable retrieval times between the experimental groups 1, 2, and 4 and the control. However, grasper removal of a centered permanent filter (group 3) required significantly less time than in the control (29 vs 79 seconds; P = .009). In the animal model, all IVC filters were retrieved using the grasper with no adverse events. The total procedure time (21.2 vs 43.5 minutes; P = .01) and the fluoroscopy time (4.3 vs 10 minutes; P = .044) were significantly shorter in the animal model compared with the patient group. Moreover, in the patient group, 16.7% of retrievals required advanced endovascular techniques, and one IVC filter could not be retrieved (success rate = 91.7%), whereas all the IVC filters were successfully retrieved in the animal model without the use of additional tools. CONCLUSIONS: The novel endovascular grasper is effective in retrieving different types of IVC filters in different configurations and compared favorably with the snare in the in vitro model. In vivo experiments demonstrated more effective retrieval when compared with matched patient retrievals.

Hybrid Revision of Dysfunctional Aneurysmal Arteriovenous Fistulas.

Endovascular therapy has become the first-line treatment for failing hemodialysis arteriovenous fistulas (AVFs). However, open revision remains an important modality for vascular access maintenance and the recommended approach for AVF aneurysms. This case series describes a hybrid approach for aneurysmal access revision. Three patients were referred for second opinion after failure of endovascular therapy to establish a functioning access. The medical history is briefly described to highlight the limitations of endovascular therapy and the technical advantages of the hybrid approach in these clinical scenarios.

Effect of Doxycycline on Progression of Arterial Calcification in the Noninvasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA(3)CT).

BACKGROUND: Doxycycline has been shown to prevent arterial calcification via attenuation of matrix metalloproteinases (MMP) in preclinical models. We assessed the effects of doxycycline on progression of arterial calcification in patients enrolled in the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT). METHODS: Two hundred and sixty-one patients were randomized to 100 mg doxycycline twice daily or placebo. Arterial calcification was measured in abdominal vessels on noncontrast computed tomography scans. Patients with baseline computed tomography scan and 1 or more follow-up scans within the 2-year study were included for analysis. For individual arteries, mean change in iliofemoral artery calcification over time was calculated via linear regression. Serum MMP-3 and MMP-9 levels were measured at baseline and 6 months. RESULTS: Sixty-five patients in the doxycycline and 66 in the placebo arm were included in this analysis. Baseline characteristics between the groups were similar. The unadjusted mean change in iliofemoral calcium score per year trended toward higher values in patients treated with doxycycline compared with placebo (322 ± 399 units/year vs. 217 ± 307 units/year, P = 0.09). After 6 months, changes in serum MMP-3 and MMP-9 levels were not significantly different between study arms. CONCLUSIONS: In patients with small aortic aneurysm, treatment with doxycycline 100 mg twice daily did not decrease circulating levels of the matrix degrading enzymes MMP-3 and 9 or alter the progression of arterial calcification.

Effect of inferior vena cava filter placement position on device complications.

BACKGROUND: Indwelling inferior vena cava (IVC) filters can cause complications, including penetration into surrounding structures, migration, and thrombosis of the vena cava. Computational fluid dynamics suggests juxtarenal placement of IVC filters decreases the risk of thrombosis; however, this has not been explored clinically. The present study examines the effect of filter placement position on long-term device complications with an emphasis on IVC thrombosis. We hypothesized that IVC filters placed further caudal to the renal veins were more likely to develop long-term thrombosis. METHODS: A retrospective review of the medical records of patients receiving IVC filters at a single tertiary center between 2008 and 2016 was performed. Patients missing follow-up or procedural imaging data were excluded. The placement procedure venograms were reviewed, and the distance from the filter apex to the more inferior renal vein was measured using reported IVC filter lengths for calibration. The patients were divided into three groups according to the tip position relative to the more inferior renal vein: at or superior (group A), 1 to 20 mm inferior (group B), and >20 mm inferior (group C). The patient and procedural characteristics and outcomes were compared between the three groups. The primary end points were IVC thrombosis and device-related mortality. RESULTS: Of 1497 eligible patients, 267 (17.8%) were excluded. The most common placement position was group B (64.0%). The mean age was lowest in group C, followed by groups A and B (age, 59.5 years, 64.6 years, and 62.2 years, respectively; P = .003). No statistically significant differences were found in the distribution of sex or the measured comorbidities. Group C was the most likely to receive jugular access (group C, 71.7%; group A, 48.3%; group B, 62.4%; P < .001) and received more first-generation filters (group C, 58.5%; group A, 46.6%; group B, 52.5%; P = .045). The short-term (<30-day) and long-term (≥30-day) outcomes, including access site hematoma, deep vein thrombosis, and pulmonary embolism, were uncommon, with no differences between the groups. Cases of symptomatic filter penetration, migration, and fracture were rare (one, one, and three cases, respectively). Although a pattern of increasing thrombosis with more inferior placement was found, the difference between groups was not statistically significant (group A, 1.5%; group B, 1.8%; group C, 2.5%; P = .638). No cases of device-related mortality occurred. All-cause mortality after a mean follow-up of 2.6 ± 2.3 years was 41.3% and did not vary significantly between the groups (P = .051). Multivariate logistic regression revealed that placement position did not predict for short- or long-term deep vein thrombosis, pulmonary embolism, IVC thrombosis, or all-cause mortality after adjustment for the baseline patient characteristics. CONCLUSIONS: IVC filters have low rates of short- and long-term complications, including IVC thrombosis. The placement position did not affect the occurrence of device complications in this study.

Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR.

Transitioning from pluripotency to differentiated cell fates is fundamental to both embryonic development and adult tissue homeostasis. Improving our understanding of this transition would facilitate our ability to manipulate pluripotent cells into tissues for therapeutic use. Here, we show that membrane voltage (Vm) regulates the exit from pluripotency and the onset of germ layer differentiation in the embryo, a process that affects both gastrulation and left-right patterning. By examining candidate genes of congenital heart disease and heterotaxy, we identify KCNH6, a member of the ether-a-go-go class of potassium channels that hyperpolarizes the Vm and thus limits the activation of voltage gated calcium channels, lowering intracellular calcium. In pluripotent embryonic cells, depletion of kcnh6 leads to membrane depolarization, elevation of intracellular calcium levels, and the maintenance of a pluripotent state at the expense of differentiation into ectodermal and myogenic lineages. Using high-resolution temporal transcriptome analysis, we identify the gene regulatory networks downstream of membrane depolarization and calcium signaling and discover that inhibition of the mTOR pathway transitions the pluripotent cell to a differentiated fate. By manipulating Vm using a suite of tools, we establish a bioelectric pathway that regulates pluripotency in vertebrates, including human embryonic stem cells.

Kap-ß2/Transportin mediates ß-catenin nuclear transport in Wnt signaling.

Wnt signaling is essential for many aspects of embryonic development including the formation of the primary embryonic axis. In addition, excessive Wnt signaling drives multiple diseases including cancer, highlighting its importance for disease pathogenesis. ß-catenin is a key effector in this pathway that translocates into the nucleus and activates Wnt responsive genes. However, due to our lack of understanding of ß-catenin nuclear transport, therapeutic modulation of Wnt signaling has been challenging. Here, we took an unconventional approach to address this long-standing question by exploiting a heterologous model system, the budding yeast Saccharomyces cerevisiae, which contains a conserved nuclear transport machinery. In contrast to prior work, we demonstrate that ß-catenin accumulates in the nucleus in a Ran-dependent manner, suggesting the use of a nuclear transport receptor (NTR). Indeed, a systematic and conditional inhibition of NTRs revealed that only Kap104, the ortholog of Kap-ß2/Transportin-1 (TNPO1), was required for ß-catenin nuclear import. We further demonstrate direct binding between TNPO1 and ß-catenin that is mediated by a conserved PY-NLS. Finally, using Xenopus secondary axis and TCF/LEF (T Cell factor/lymphoid enhancer factor family) reporter assays, we demonstrate that our results in yeast can be directly translated to vertebrates. By elucidating the nuclear localization signal in ß-catenin and its cognate NTR, our study suggests new therapeutic targets for a host of human diseases caused by excessive Wnt signaling. Indeed, we demonstrate that a small chimeric peptide designed to target TNPO1 can reduce Wnt signaling as a first step toward therapeutics.

Endovascular aneurysm repair with inferior mesenteric artery chimney in a high-risk patient with abdominal aortic aneurysm and iliac occlusion.

A 63-year-old man presented for the treatment of abdominal aortic aneurysm in the setting of bilateral internal iliac artery compromise from prior peripheral arterial disease treatments. The inferior mesenteric artery (IMA) measured 5 mm. Patient underwent coronary artery stenting 6 months prior and experienced left leg claudication. He underwent endovascular aneurysm repair with chimney IMA grafting and a femorofemoral bypass with uneventful recovery. At 1 year, computed tomography angiogram shows no flow in the aneurysm sac, and his left leg claudication resolved. Endovascular aneurysm repair with chimney IMA grafting for colonic perfusion preservation is a reasonable alternative to open surgical repair with IMA reimplantation in high-risk patients.

The wire loop technique for IVC filter removal.

Inferior vena cava (IVC) filters are effective therapy to prevent pulmonary embolism in patients with contraindication to anticoagulation. However, IVC wall penetration by the filter struts is a common complication that can lead to symptoms specially when adjacent organs are impacted. This case report and video describe the wire loop technique for successful endovascular IVC filter retrieval in a patient with lower back pain caused by a spinal strut penetration. The patient's back pain resolved after filter retrieval and he remained stable on anticoagulation with no recurrence of venous thromboembolism.

Common femoral artery erosion as a source of thromboembolic acute limb ischemia.

We have reported a case of delayed hip prosthetic erosion into the common femoral artery (CFA) 3 years after implantation. The patient had initially presented with left lower extremity acute limb ischemia secondary to a popliteal artery embolism. However, the metal artifact around the hip joint prevented CFA evaluation using conventional imaging. Diagnostic angiography with intraoperative intravascular ultrasound revealed CFA dilatation with adherent intraluminal thrombus. Open surgical repair showed hip prosthesis erosion through the posterior wall of the CFA. Our findings emphasize the necessity for a thorough, multimodal embolic workup and the usefulness of intravascular ultrasound as an adjunctive tool for intravascular anatomy evaluation.

Xenopus as a platform for discovery of genes relevant to human disease.

Congenital birth defects result from an abnormal development of an embryo and have detrimental effects on children's health. Specifically, congenital heart malformations are a leading cause of death among pediatric patients and often require surgical interventions within the first year of life. Increased efforts to navigate the human genome provide an opportunity to discover multiple candidate genes in patients suffering from birth defects. These efforts, however, fail to provide an explanation regarding the mechanisms of disease pathogenesis and emphasize the need for an efficient platform to screen candidate genes. Xenopus is a rapid, cost effective, high-throughput vertebrate organism to model the mechanisms behind human disease. This review provides numerous examples describing the successful use of Xenopus to investigate the contribution of patient mutations to complex phenotypes including congenital heart disease and heterotaxy. Moreover, we describe a variety of unique methods that allow us to rapidly recapitulate patients' phenotypes in frogs: gene knockout and knockdown strategies, the use of fate maps for targeted manipulations, and novel imaging modalities. The combination of patient genomics data and the functional studies in Xenopus will provide necessary answers to the patients suffering from birth defects. Furthermore, it will allow for the development of better diagnostic methods to ensure early detection and intervention. Finally, with better understanding of disease pathogenesis, new treatment methods can be tailored specifically to address patient's phenotype and genotype.

Complex endovascular retrieval of an intravascular foreign body.

We report a case of a 54-year-old man who developed bilateral multifocal pneumonia as a result of septic thromboembolization from an ingested ballpoint pen that migrated through the gastrointestinal system and lodged in the inferior vena cava. The ballpoint pen was removed from the inferior vena cava with a complex endovascular approach using internal jugular and common femoral vein access with the combination of a snare device and atraumatic laparoscopic grasper. He was also found to have a duodenal perforation requiring primary repair in a staged fashion after endovascular removal of the ballpoint pen.

Erosion of Common Femoral Artery 3 Years After Total Hip Arthroplasty in a Patient with Marfan Syndrome: A Case Report.

CASE: A patient with congenital hip dysplasia and Marfan syndrome presented 3 years after total hip arthroplasty (THA) with acute ischemia of the left lower extremity secondary to popliteal artery embolism. Intravenous ultrasound revealed common femoral artery (CFA) dilation with an intraluminal thrombus. Open repair showed prosthetic erosion through the CFA despite proper implant positioning and lack of hardware failure. CONCLUSION: This is a rare complication of THA in a patient with impaired vascular integrity secondary to a connective tissue disorder. Similar patients may be at a higher risk for unusual vascular complications, and diagnosis may require atypical imaging modalities.

Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID.

Patients with common variable immunodeficiency associated with autoimmune cytopenia (CVID+AIC) generate few isotype-switched B cells with severely decreased frequencies of somatic hypermutations (SHMs), but their underlying molecular defects remain poorly characterized. We identified a CVID+AIC patient who displays a rare homozygous missense M466V mutation in ß-catenin-like protein 1 (CTNNBL1). Because CTNNBL1 binds activation-induced cytidine deaminase (AID) that catalyzes SHM, we tested AID interactions with the CTNNBL1 M466V variant. We found that the M466V mutation interfered with the association of CTNNBL1 with AID, resulting in decreased AID in the nuclei of patient EBV-transformed B cell lines and of CTNNBL1 466V/V Ramos B cells engineered to express only CTNNBL1 M466V using CRISPR/Cas9 technology. As a consequence, the scarce IgG+ memory B cells from the CTNNBL1 466V/V patient showed a low SHM frequency that averaged 6.7 mutations compared with about 18 mutations per clone in healthy-donor counterparts. In addition, CTNNBL1 466V/V Ramos B cells displayed a decreased incidence of SHM that was reduced by half compared with parental WT Ramos B cells, demonstrating that the CTNNBL1 M466V mutation is responsible for defective SHM induction. We conclude that CTNNBL1 plays an important role in regulating AID-dependent antibody diversification in humans.

The potential and limitations of induced pluripotent stem cells to achieve wound healing.

Wound healing is the physiologic response to a disruption in normal skin architecture and requires both spatial and temporal coordination of multiple cell types and cytokines. This complex process is prone to dysregulation secondary to local and systemic factors such as ischemia and diabetes that frequently lead to chronic wounds. Chronic wounds such as diabetic foot ulcers are epidemic with great cost to the healthcare system as they heal poorly and recur frequently, creating an urgent need for new and advanced therapies. Stem cell therapy is emerging as a potential treatment for chronic wounds, and adult-derived stem cells are currently employed in several commercially available products; however, stem cell therapy is limited by the need for invasive harvesting techniques, immunogenicity, and limited cell survival in vivo. Induced pluripotent stem cells (iPSC) are an exciting cell type with enhanced therapeutic and translational potential. iPSC are derived from adult cells by in vitro induction of pluripotency, obviating the ethical dilemmas surrounding the use of embryonic stem cells; they are harvested non-invasively and can be transplanted autologously, reducing immune rejection; and iPSC are the only cell type capable of being differentiated into all of the cell types in healthy skin. This review focuses on the use of iPSC in animal models of wound healing including limb ischemia, as well as their limitations and methods aimed at improving iPSC safety profile in an effort to hasten translation to human studies.

Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2018 Update and Clinical Implications.

Thoracic aortic aneurysms, with an estimated prevalence in the general population of 1%, are potentially lethal, via rupture or dissection. Over the prior two decades, there has been an exponential increase in our understanding of the genetics of thoracic aortic aneurysm and/or dissection (TAAD). To date, 30 genes have been shown to be associated with the development of TAAD and ∼30% of individuals with nonsyndromic familial TAAD have a pathogenic mutation in one of these genes. This review represents the authors' yearly update summarizing the genes associated with TAAD, including implications for the surgical treatment of TAAD. Molecular genetics will continue to revolutionize the approach to patients afflicted with this devastating disease, permitting the application of genetically personalized aortic care.