Crossroads between immune responses and physiological regulation: Metabolic control of resistance versus tolerance against disease.

If a threat cannot be avoided, the organism has two defense options: it can try to eliminate the threatening agent or boost physiological mechanisms to tolerate the challenge and its consequences. Both strategies can be (and usually are) used at the same time. Fighting an infection, for instance, requires mounting immune responses to control pathogen burden as well as physiologic adaptations to tolerate stress and damage. Thus, the two strategies are connected and interdependent. We are starting to understand how the regulation of host metabolic physiology during disease impacts both the ability to resist pathogens' burden and tolerate parenchymal tissue functional damage. Here, we review a number of recent publications that have begun to shed light on the physiological and immunological mechanisms that coordinate host defense and metabolic processes. In particular, we will cover the areas of energetic control, substrates utilization, and the regulatory signals that promote infectious disease tolerance.

Mast cells control the expansion and differentiation of IL-10-competent B cells.

The discovery of B cell subsets with regulatory properties, dependent on IL-10 production, has expanded our view on the mechanisms that control inflammation. Regulatory B cells acquire the ability to produce IL-10 in a stepwise process: first, they become IL-10 competent, a poised state in which B cells are sensitive to trigger signals but do not actually express the Il-10 gene; then, when exposed to appropriate stimuli, they start producing IL-10. Even if the existence of IL-10-competent B cells is now well established, it is not yet known how different immune cell types cross talk with B cells and affect IL-10-competent B cell differentiation and expansion. Mast cells (MCs) contribute to the differentiation and influence the effector functions of various immune cells, including B lymphocytes. In this study, we explored whether MCs could play a role in the expansion of IL-10-competent B cells and addressed the in vivo relevance of MC deficiency on the generation of these cells. We show that MCs can expand IL-10-competent B cells, but they do not directly induce IL-10 production; moreover, the absence of MCs negatively affects IL-10-competent B cell differentiation. Noteworthy, our findings reveal that the CD40L/CD40 axis plays a significant role in MC-driven expansion of IL-10-competent B cells in vitro and highlight the importance of MC CD40L signaling in the colon.

Endograft connector technique to treat popliteal artery aneurysm in a morbid obese patient.

Surgical repair of popliteal artery aneurysm in morbid obese patients poses additional challenges. We report a morbid obese patient who had a 59 mm right popliteal artery aneurysm which was successfully treated with the endograft connector technique. This technique was used to perform the distal anastomosis of the below-knee femoro-popliteal bypass. A 10 mm Dacron graft was used as a main graft bypass and an 11 mm/10 cm stentgraft as endograft connector. Following the respective tunnel of the Dacron graft, an end-to-side proximal anastomosis was performed at distal femoral artery. The aneurysm exclusion was obtained through a proximal and a distal ligation. Postoperative duplex showed adequate bypass patency. Knee x-rays demonstrated no signs of stent kinking/fractures. The postoperative course was uneventful and the patient was discharged home on fourth day post operative. The six-month computed tomography scan and the 12-month duplex control showed a patent bypass with no signs of stenosis.

A popliteal artery aneurysm presenting with ab extrinseco popliteal vein occlusion and compartment syndrome: a case report.

INTRODUCTION: Aneurysms of popliteal artery are the most frequently reported aneurysm after abdominal aorta. An unusual presentation is compression to adjacent structure. CASE PRESENTATION: A 67 years old caucasian man presenting deep vein thrombosis signs to the right leg including functional impotence was admitted in emergency setting to Vascular Surgery Unit. A pulsing mass was present in the popliteal cave at inspection. The computed tomography angiography demonstrated a 53.2 mm popliteal artery aneurysm causing an ab extrinseco compression of the popliteal vein and a dislocation of popliteal nerve. A surgical open reconstruction with a reinforced Dacron graft was performed via a posterior approach. Patient was discharged on the fourth postoperative day with no functional impotence. At three and six months Doppler ultrasound followup both popliteal arterial graft and popliteal vein were patent. CONCLUSION: An unusual presentation of a popliteal artery aneurysm can be a popliteal compartment syndrome, especially in large aneurysms. Deep popliteal vein compression and/or popliteal nerve dislocation signs can rarely represent the clinical symptoms. The popliteal artery aneurysm repair is generally required to avoid a distal embolization and rupture. Through a surgical open repair was possible to achieve both popliteal cave decompression and the popliteal artery aneurysm repair.

TRAF2 and p38 are involved in B cells CD40-mediated APE/Ref-1 nuclear translocation: a novel pathway in B cell activation.

The interaction between CD40 and its ligand CD40L plays a key role in the regulation of B cell proliferation, activation, isotype switching and the humoral memory response. APE/Ref-1 plays a key role in transcriptional responses during CD40-mediated B cell activation. It is demonstrated that CD40 signaling is mediated principally through TRAF adapter proteins. Different TRAFs exhibit specific biological functions and the role of individual TRAFs in the activation of different CD40-dependent signaling pathways has not yet been defined. To better understand the role of these factors in CD40-mediated B cell activation and how they contribute to APE/Ref-1 activity, we investigated the TRAF molecules and the downstream protein kinases directly activated in the pathways triggered by CD40. Here we show that TRAF2 is involved in CD40-mediated induction of APE/Ref-1 nuclear translocation and that the two proteins physically interact in vitro and in vivo. Moreover, treatment with the p38 inhibitor, SB203580 or site directed mutagenesis of the serine 54 (Ser(54)) in the MAP kinase consensus site present in APE/Ref-1 blocks its nuclear translocation caused by CD40-mediated B cell activation and reveals a potential role of p38 in this pathway. These data together uncovers a new signaling pathway regulating APE/Ref-1 nuclear translocation involving CD40-crosslinking, TRAF2 and p38.

Stent-assisted detachable coil embolization of wide-necked renal artery aneurysms.

Renal artery aneurysms (RAAs) are rare with an estimated incidence of 0.1% in the general population, and they represent approximately 25% of all visceral aneurysms. The gold standard of treatment is open surgery, but it is associated with a high risk of nephrectomy, mortality, and morbidity. Less invasive endovascular therapies are becoming increasingly common for the treatment of RAAs. Here, we aimed to report three cases of wide-necked complex renal artery aneurysms treated endovascularly using stent-assisted coil embolization with self-expandable stent nitinol Solitaire AB and Concerto Axium coils. In addition, we describe the use of the waffle-cone technique in a case of wide-necked saccular RAA involving the renal artery bifurcation. Technical success was achieved in all three cases with no early or late complications and no recurrences.

Use of the directional atherectomy for the treatment of femoro-popliteal lesions in patients with critical lower limb ischemia.

Femoro-popliteal PTA for the treatment of critical limb ischemia is frequently associated with unsatisfactory procedural success rates while directional atherectomy (DCA) has improved success rate since claudicant patients undergoing percutaneous treatment of femoro-popliteal obstructive disease. The aim of this prospective study is to evaluate the safety, efficacy and procedural success of DCA, at one year, in the percutaneous treatment of femoro-popliteal obstructive disease in patients with critical limb ischemia. METHODS: From March 2012 to March 2013 18 consecutive patients with critical limb ischemia were treated with DCA (Turbohawk/Covidien-ev3 Endovascular Inc., North Plymouth, Minnesota, USA) for the treatment of femoro-popliteal obstructive disease. Patients were evaluated at 12 months. RESULTS: Technical and procedural success was achieved in every patient. No in-hospital major adverse cardiovascular events occurred. Primary endpoint: freedom from any amputation was obtained in all patients. Secondary endpoints: clinical (Rutherford class improvement) and hemodynamic success (Ankle-brachial index improvement) was achieved in all patients. CONCLUSION: The use of DCA for the treatment of femoro-popliteal obstructive disease is a safe and effective therapeutic strategy for patients with critical limb ischemia. The data included in our study should be considered hypothesis-generating in order to design of a randomized trial comparison with conventional PTA.

What the young physician should know about May-Thurner syndrome.

May-Thurner syndrome (MTS) is an anatomically variable condition resulting in compression of the left common iliac vein between the right common iliac artery and the underlying spine with subsequent development of a left deep vein thrombosis (DVT). Although this syndrome is rare, its true prevalence is likely underestimated. Mainly, clinical symptoms and signs include, but are not limited to, pain, swelling, venous stasis ulcers, skin pigmentation changes and post-thrombotic syndrome. Correct treatment is not well established and is based on clinical presentation. Staged thrombolysis with/without prophylactic retrievable inferior vena cava filter placement followed by angioplasty/stenting of the left iliac vein appears to be the best option in MTS patients with extensive DVT. The aim of this review is to present in a simple and didactic form all variable clinical presentations of MTS and to outline possible management within the current guidelines.

Management of finger gangrene caused by steal syndrome in vascular access for hemodialysis Personal experience and a brief review of the literature.

INTRODUCTION: Severe dialysis-associated steal syndrome (DASS) is an uncommon and severe complication after arteriovenous fistula (AVF) creation that can lead to finger gangrene and amputation. As the number of patients on hemodialysis increases in western countries the number of patients at risk for DASS will continue to rise. METHODS: We retrospectively reviewed all patients who underwent a surgical intervention for the management of DASS with finger gangrene from January 2004 to July 2013. Demographic data, pre-operative work-up, procedure details and outcomes were collected. A literature search using MEDLINE's Medical Subject Heading terms was used to identify recent articles. Cross-references from these articles were also used. RESULTS: A total of nine patients were identified. Mean age was 53 years, 67% were women. All patients presented with finger tissue loss or gangrene. Surgical procedures included AVF closure/ligation (5), distal artery ligation (DRAL) (2), distal revascularization with interval ligation (DRIL) (1), banding (1). All patients had improvement of symptoms during follow-up. No major amputation occurred. CONCLUSIONS: Surgical interventions to correct DASS in patients with finger gangrene are mandatory while conservative management is not recommended. The decision for which type of procedure is made individually, according to clinical symptoms, technical findings, and patients' general state of health.

Use of cocultures for the study of cellular interactions influencing B cell regulatory functions.

Many immunological processes are contextually controlled by complex interactions among different cell types. Several studies have shown that B cells produce the immune regulatory cytokine IL-10 in response to different external stimuli but also to immune-mediated signals. Endogenous signals that derive from the cross talk between B lymphocytes and other cells of the immune system can affect IL-10 production by B cells in both physiological and pathological conditions. With the aim to provide a guide for the study of how partner cells can induce IL-10-producing B cells, here we describe the protocols to investigate IL-10 production at a single cell level in a dendritic cell-B cell coculture in vitro system. These methods are a proof of concept that can be easily extrapolated and adapted to the study of the interaction between B cells and other immune cell types.

Accidental Coverage of Both Renal Arteries during Infrarenal Aortic Stent-Graft Implantation: Cause and Treatment.

The purpose of this paper is to report a salvage maneuver for accidental coverage of both renal arteries during endovascular aneurysm repair (EVAR) of an infrarenal abdominal aortic aneurysm (AAA). A 72-year-old female with a 6 cm infrarenal abdominal aortic aneurysm was treated by endovascular means with a standard bifurcated graft. Upon completing an angiogram, both renal arteries were found to be accidentally occluded. Through a left percutaneous brachial approach, the right renal artery was catheterized and a chimney stent was deployed; however this was not possible for the left renal artery. A retroperitoneal surgical approach was therefore carried out with a retrograde chimney stent implanted to restore blood flow. After three months, both renal arteries were patent and renal function was not different from the baseline. Both endovascular with percutaneous access via the brachial artery and open retroperitoneal approaches with retrograde catheterization are feasible rescue techniques to recanalize the accidentally occluded renal arteries during EVAR.

IL-10 production by B cells is differentially regulated by immune-mediated and infectious stimuli and requires p38 activation.

IL-10 is an immune suppressive cytokine with pleiotropic effects on B cell biology. IL-10 production has a pivotal role for the regulatory suppressive functions that B cells exert in many physiological and pathological settings. Several exogenous stimuli and endogenous immune mediators can trigger IL-10-producing B cell maturation. To clarify and gain a better insight into the mechanisms of IL-10 production by B cells, we first compared the effects of LPS, CpG, agonistic CD40 mAb and BAFF on IL-10 production, and then we investigated the signal transduction mechanisms responsible for these responses. While infectious/danger stimuli determine the rapid production and release of IL-10 by B cells, a limited subset of CD40-poised, IL-10-competent B cells produce IL-10 in response to a later antigenic or infectious signal. Although BAFF is able to induce a similar subset of IL-10-competent B cells, these cells do not similarly respond to the same antigenic or infectious signals. Importantly, by using specific inhibitors of the MAP kinase pathways, we found that while il-10 gene expression triggered by the TLR agonists LPS and CpG is strongly dependent on p38 activity, the induction of IL-10 competence in CD40-activated B cells does not depend on ERK1/2, p38 or JNK pathways.

A wire-loop technique for implantation of an iliac branched device in a patient with previous surgery for a ruptured abdominal aortic aneurysm.

We described a modified technique for implanting a bridging stent-graft into an iliac branched device. A 79-year-old male who had received aortobiiliac synthetic graft surgery for a ruptured abdominal aortic aneurysm six months earlier was admitted to our unit for treatment of a left common iliac aneurysm involving the origin of the hypogastric artery. A standard technique was unsuccessful at implanting the bridging stent-graft, and therefore a wire-loop guidewire over the graft bifurcation was used to stabilize the contralateral sheaths and to complete the implantation.

Late, giant brachial artery aneurysm following hemodialysis fistula ligation in a renal transplant patient: case report and literature review.

Brachial artery aneurysm (BAA) following long-standing arteriovenous fistula ligation after renal transplantation is uncommon. Herein, we describe the case of a 64-year-old man who developed a giant symptomatic BAA 21 years after ligation of the fistula. He was submitted to surgical excision of the aneurysm followed by interposition prosthetic graft.

Regulatory B cells: evidence, developmental origin and population diversity.

The adaptive immune system has developed several highly effective mechanisms in order to avoid excessive or unwanted reactions and promote resolution of immune activation. An emerging, significant body of evidence indicates that B cells can actively modulate immune responses by mechanisms that do not directly involve the production of antibodies. B cells appear to have the capacity to both induce and suppress immune effector mechanisms and they exert these functions both by contact-dependent interactions and through the secretion of cytokines. In this review we will focus on the regulatory suppressive function of several recently described B cell populations, functionally defined "regulatory B cells" or Breg cells. We will first outline the evidence that has led to their identification and then we will summarize current hypotheses on their ontogeny and possible lineage relationship.

Retroaortic left renal vein and inflammatory abdominal aortic aneurysm.

The aim of this study was to report successful surgical management of an inflammatory abdominal aortic aneurysm associated with a retroaortic left renal vein. The patient, a 78-year-old man, presented with diffuse abdominal pain, fever, and constipation. Contrast-enhanced computed tomography showed soft tissue surrounding the aneurysm and a left renal vein behind the aorta. Intraoperative findings confirmed the CT images. The patient is alive and well 6 months postoperatively.

Carotid artery stenting with contralateral carotid occlusion in a rare aortic arch configuration.

We present the case of a 47-year-old man admitted to our department with an episode of aphasia. Duplex scan showed an occluded right internal carotid artery and severe left internal carotid artery stenosis. Contrast-enhanced computer tomography demonstrated a common trunk for both common carotid arteries anterior to the trachea and aberrant right subclavian artery posterior to the esophagus. The patient was considered to be a high risk for carotid endarterectomy and, consequently, we performed stenting of the left carotid artery. To our knowledge, this is the first case reporting the combination of these two aortic arch anomalies and the concomitant endovascular treatment of atherosclerotic carotid stenosis.