Review: Protein misfolding diseases - the rare case of Marinesco-Sjögren syndrome.

Secretory and cell membrane proteins are synthesized in the endoplasmic reticulum (ER), where a network of molecular chaperones and folding factors ensure correct protein folding and export to post-ER compartments. Failure of this process leads to accumulation of unfolded/misfolded proteins, ER stress, and activation of the unfolded protein response (UPR), a complex signalling pathway aimed at restoring ER homeostasis, whose failure eventually leads to cell death. Suppressor of Ire1/Lhs1 double mutant (SIL1) is a nucleotide exchange factor for immunoglobulin binding protein, the main ER chaperone and primary sensor of ER stress. Loss of SIL1 function causes Marinesco-Sjögren syndrome (MSS), a rare multisystem disease of early infancy for which there is no cure. This review, examines the current understanding of SIL1 activities in the ER, and reviews experimental data describing the consequences of SIL1 deficiency in cell and animal models. We discuss the evidence supporting a role of the UPR - particularly the protein kinase RNA-like endoplasmic reticulum kinase branch - in the pathogenesis of MSS, and how this may be pharmacologically manipulated for treatment.

Review: PrP 106-126 - 25 years after.

A quarter of a century ago, we proposed an innovative approach to study the pathogenesis of prion disease, one of the most intriguing biomedical problems that remains unresolved. The synthesis of a peptide homologous to residues 106-126 of the human prion protein (PrP106-126), a sequence present in the PrP amyloid protein of Gerstmann-Sträussler-Scheinker syndrome patients, provided a tractable tool for investigating the mechanisms of neurotoxicity. Together with several other discoveries at the beginning of the 1990s, PrP106-126 contributed to underpin the role of amyloid in the pathogenesis of protein-misfolding neurodegenerative disorders. Later, the role of oligomers on one hand and of prion-like spreading of pathology on the other further clarified mechanisms shared by different neurodegenerative conditions. Our original report on PrP106-126 neurotoxicity also highlighted a role for programmed cell death in CNS diseases. In this review, we analyse the prion research context in which PrP106-126 first appeared and the advances in our understanding of prion disease pathogenesis and therapeutic perspectives 25 years later.

Bactericidal activity of gallium-doped chitosan coatings against staphylococcal infection.

AIMS: The aim of this study was to develop a new class of gallium (Ga)-doped chitosan (CS) coatings fabricated by electrophoretic deposition (EPD) in staphylococcal infection therapy. METHODS AND RESULTS: Biofilm formation on EPD CS/Ga coatings by Staphylococcus epidermidis and Staphylococcus aureus, which are the main strains involved in postarthroplasty infections, was assessed. The codeposition of an antibacterial agent was effective; Ga loaded into CS matrix reduces biofilm viability by up to 86% and 80% for S. epidermidis and S. aureus strains respectively. Lastly, the influence of pulsed electromagnetic field (PEMF) on the bactericidal activity of CS/Ga coatings was investigated in vitro. To this end, the coatings were incubated with S. epidermidis and S. aureus and exposed to the PEMF using two different frequencies and times. Biofilm viability for S. epidermidis was decreased by 35-40% in the presence of low-frequency (LF) and high-frequency (HF) PEMF respectively. Biofilm viability by S. aureus was not further reduced in the presence of LF PEMF, but decreased by 38% at HF PEMF. CONCLUSIONS: This study has established that a combination of PEMFs with the antibacterial agent improves bactericidal activity of Ga against S. epidermidis strain 14990 and S. aureus strain 12600. SIGNIFICANCE AND IMPACT OF THE STUDY: This new integrated approach could reduce the incidence of infection in orthopaedic implant applications. It also clearly demonstrates that the combination of Ga treatment with PEMF could aid biofilm-associated infection therapy due to improved Ga efficiency.

Definition of criteria and indicators for the prevention of Healthcare-Associated Infections (HAIs) in hospitals for the purposes of Italian institutional accreditation and performance monitoring.

BACKGROUND: Healthcare-associated infections (HAIs) are an important issue in terms of quality of care. HAIs impact patient safety by contributing to higher rates of preventable mortality and prolonged hospitalizations. In Italy, analysis of the currently available accreditation systems shows a substantial heterogeneity of approaches for the prevention and surveillance of HAIs in hospitals. The aim of the present study is to develop and propose the use of a synthetic assessment tool that could be implemented homogenously throughout the nation. METHODS: An analysis of nine international and of the 21 Italian regional accreditation systems was conducted in order to identify requirements and indicators implemented for HAI prevention and control. Two relevant reviews on this topic were further analyzed to identify additional evidence-based criteria. The project team evaluated all the requirements and indicators with consensus meeting methodology, then those applicable to the Italian context were grouped into a set of "focus areas". RESULTS: The analysis of international systems and Italian regional accreditation manuals led to the identification respectively of 19 and 14 main requirements, with relevant heterogeneity in their application. Additional evidence-based criteria were included from the reviews analysis. From the consensus among the project team members all the standards were compared and 20 different thematic areas were identified, with a total of 96 requirements and indicators for preventing and monitoring HAIs. CONCLUSIONS: The study reveals a great heterogeneity in the definition of accreditation criteria between the Italian regions. The introduction of a uniform, synthetic assessment instrument, based on the review of national and international standards, may serve as a self-assessment tool to evaluate the achievement of a minimum standards set for HAIs prevention and control in healthcare facilities. This may be used as an assessment tool by the Italian institutional accreditation system, also useful to reduce regional disparities.

Predicting the Need for Intra-operative Large Volume Blood Transfusions During Thoraco-abdominal Aortic Aneurysm Repair.

OBJECTIVE: Thoraco-abdominal aortic aneurysm (TAAA) repair is a complex procedure performed in patients at high cardiovascular risk. High volume intra-operative bleeding is often recorded, and the amount of intra-operative blood product transfusion is associated with relevant morbidity and mortality. The aim of the study was to identify pre-operative predictors of intra-operative large volume blood transfusions (LVBT) to stratify patients pre-operatively. METHODS: This was a retrospective analysis of prospectively collected data of all patients who underwent open TAAA surgery at San Raffaele Scientific Institute from January 2009 to December 2015. Intra-operative red blood cell (RBC) transfusions were administered to maintain a hematocrit of at least 30%. A LVBT was defined as a transfusion of at least four RBC units, corresponding to 1000 mL. RESULTS: The study population included 428 patients: 260 (61%) received fewer than 4 RBC units, and 168 (39%) were transfused with at least 4 RBC units. In patients who underwent LVBT, higher mortality was observed after surgery (p=.003), longer intensive care unit admission (p=.004), and longer mechanical ventilation compared with less transfused patients (p=.0002). The patients who received fewer units were administered a higher dose of heparin during the surgical operation compared with patients of the LVBT group: 3400±1100 vs. 2900±1300 IU (international units) (p=.0004). Pre-operative chronic renal failure (OR 1.8), the pre-operative haemoglobin value (OR 0.8), and the need for urgent or emergent surgery (OR 3.15) were independent predictors of LVBT on multivariate analysis. CONCLUSIONS: The identification of patients at risk of intra-operative LVBT during TAAA surgery is critical as these patients experience a worse outcome. Nevertheless, only few independent predictors are available for clinical practice.

Data in support of Gallium (Ga(3+)) antibacterial activities to counteract E. coli and S. epidermidis biofilm formation onto pro-osteointegrative titanium surfaces.

This paper contains original data supporting the antibacterial activities of Gallium (Ga(3+))-doped pro-osteointegrative titanium alloys, obtained via Anodic Spark Deposition (ASD), as described in "The effect of silver or gallium doped titanium against the multidrug resistant Acinetobacter baumannii" (Cochis et al. 2016) [1]. In this article we included an indirect cytocompatibility evaluation towards Saos2 human osteoblasts and extended the microbial evaluation of the Ga(3+) enriched titanium surfaces against the biofilm former Escherichia coli and Staphylococcus epidermidis strains. Cell viability was assayed by the Alamar Blue test, while bacterial viability was evaluated by the metabolic colorimetric 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Finally biofilm morphology was analyzed by Scanning Electron Microscopy (SEM). Data regarding Ga(3+) activity were compared to Silver.

Osteogenic response and osteoprotective effects in vivo of a nanostructured titanium surface with antibacterial properties.

In implantology, as an alternative approach to the use of antibiotics, direct surface modifications of the implant addressed to inhibit bacterial adhesion and to limit bacterial proliferation are a promising tactic. The present study evaluates in an in vivo normal model the osteogenic response and the osteointegration of an anodic spark deposition nanostructured titanium surface doped with gallium (ASD + Ga) in comparison with two other surface treatments of titanium: an anodic spark deposition treatment without gallium (ASD) and an acid etching treatment (CTR). Moreover the study assesses the osteoprotective potential and the antibacterial effect of the previously mentioned surface treatments in an experimentally-induced peri-implantitis model. The obtained data points out a more rapid primary fixation in ASD and ASD + Ga implants, compared with CTR surface. Regarding the antibacterial properties, the ASD + Ga surface shows osteoprotective action on bone peri-implant tissue in vivo as well as an antibacterial effect within the first considered time point.

The effect of silver or gallium doped titanium against the multidrug resistant Acinetobacter baumannii.

Implant-related infection of biomaterials is one of the main causes of arthroplasty and osteosynthesis failure. Bacteria, such as the rapidly-emerging Multi Drug Resistant (MDR) pathogen Acinetobacter Baumannii, initiate the infection by adhering to biomaterials and forming a biofilm. Since the implant surface plays a crucial role in early bacterial adhesion phases, titanium was electrochemically modified by an Anodic Spark Deposition (ASD) treatment, developed previously and thought to provide osseo-integrative properties. In this study, the treatment was modified to insert gallium or silver onto the titanium surface, to provide antibacterial properties. The material was characterized morphologically, chemically, and mechanically; biological properties were investigated by direct cytocompatibility assay, Alkaline Phosphatase (ALP) activity, Scanning Electron Microscopy (SEM), and Immunofluorescent (IF) analysis; antibacterial activity was determined by counting Colony Forming Units, and viability assay. The various ASD-treated surfaces showed similar morphology, micrometric pore size, and uniform pore distribution. Of the treatments studied, gallium-doped specimens showed the best ALP synthesis and antibacterial properties. This study demonstrates the possibility of successfully doping the surface of titanium with gallium or silver, using the ASD technique; this approach can provide antibacterial properties and maintain high osseo-integrative potential.

Hemothorax Management After Endovascular Treatment For Thoracic Aortic Rupture.

OBJECTIVES: The aim was to describe and analyze the management of hemothorax (HTX) and the occurrence of respiratory complications after endovascular repair of thoracic aortic rupture (TEVAR). METHODS: This was a multicenter study with retrospective analysis. Between November 2000 and December 2012, all patients with confirmed HTX due to rupture of the descending thoracic aorta treated with TEVAR were included. Respiratory function (acid base status, Pao2, Paco2, lactate, and respiratory index) was monitored throughout hospitalization. Primary endpoints were survival and post-operative respiratory complications. RESULTS: Fifty-six patients were treated. The mean age was 62 ± 21 years (range 18-92 years). Etiology included traumatic rupture (n = 23, 41%), atherosclerotic aneurysm (n = 20, 36%), Debakey type IIIa dissection (n = 8, 14%), and penetrating aortic ulcer (n = 5, 9%). The primary technical success of TEVAR was 100%. The in hospital mortality rate was 12.5% (n = 7). Hemothorax was drained in 21 (37.5%) cases. In hospital respiratory complications occurred in 23 (41%) patients who required a longer intensive care unit stay (days 2.3 ± 0.7 vs. 1.9 ± 0.8, p = .017), and hospitalization (26 ± 17 vs. 19 ± 17, p = .021). Those who developed post-operative respiratory complications had lower pre-operative PO2 values (mmHg, 80 ± 24 vs. 91 ± 21, p = .012). Respiratory complications and in hospital mortality did not differ among aortic pathologies (p = .269 and p = 1.0, respectively), nor did in hospital mortality differ between patients with and without respiratory complications (13% vs. 12%; p = .990). CONCLUSIONS: Thoracic aortic rupture still has a high mortality rate. Respiratory complications have not been eliminated by endovascular repair. HTX evacuation may have had a positive influence on the survival in these patients. Although traumatic and degenerative ruptures are two significantly different scenarios, survival and respiratory outcomes were similar and were not affected by the underlying aortic disease.

An anatomical review of spinal cord blood supply.

Knowledge of the spinal cord (SC) vascular supply is important in patients undergoing procedures that involve the thoracic and thoracoabdominal aorta. However, the SC vasculature has a complex anatomy, and teaching is often based only on anatomical sketches with highly variable accuracy; historically, this has required a "leap of faith" on the part of aortic surgeons. Fortunately, this "leap of faith" is no longer necessary given recent breakthroughs in imaging technologies and postprocessing software. Imaging methods have expanded the non-invasive diagnostic ability to determine a patient's SC vascular pattern, particularly in detecting the presence and location of the artery of Adamkiewicz. CT is the imaging modality of choice for most patients with thoracic and thoracoabdominal aortic disease, proving especially useful in the determination of feasibility and planning of endovascular treatment. Thus the data set required for analysis of SC vascular anatomy is usually already available. We have concentrated our efforts on CT angiography, which offers particularly good imaging capabilities with state-of-the-art multidetector scanners. Multidetector row helical CT provides examinations of an extensive range in the craniocaudal direction with thin collimation in a short time interval, giving excellent temporal and spatial resolution. This paper provides examples of the SC vasculature imaging quality that can be obtained with 64 row scanners and appropriate postprocessing. Knowledge of the principal anatomical features of the SC blood supply of individual patients undergoing open or endovascular thoracoabdominal procedures has several potential benefits. For open surgery, analysis of the SC vasculature could tell us the aortic region that feeds the Adamkiewicz artery and thus needs to be reimplanted. For endovascular procedures, we can determine whether the stent-graft will cover the Adamkiewicz artery, thus avoiding unnecessary coverage. CT data can also be used to stratify risk of SC ischemia and guide the selective use of spinal cord injury prevention strategies.

Open treatment of extent IV thoracoabdominal aortic aneurysms.

AIM: Extent IV thoracoabdominal aortic aneurysm (TAAA) open repair is considered relatively safer to repair than other extents of TAAA in terms of both perioperative mortality and spinal cord ischemia. Our purpose is to report our experience and to perform a literature review regarding extent IV TAAA open repair in order to provide an updated benchmark for comparison with any other alternative strategy in this aortic segment. METHODS: From 1993 to 2015 we performed 736 open repairs for TAAA (177 extent I, 196 extent II, 141 extent III, 222 extent IV). In extent IV group there were 164 men (73.9%) and the mean age was 67.4±9.3 years (range 32-84). The aneurysm etiology was degenerative in 198 patients (95.6%). Twelve patients (5.4%) underwent emergent operation. Totally abdominal approach was used in 22.0% of the cases. Until 2006 left heart bypass (LHBP) and cerebrospinal fluid drainage (CSFD) were almost never performed during extent IV repair. Since 2006 we changed our approach with a more aggressive use of LHBP (22.9%) and CSFD (43.4%) in 83 consecutive extent IV. Renal arteries perfusion was performed with 4 °C Ringer's solution until 2009 and with 4 °C Custodiol solution since September 2009 to date. Literature search was performed on several databases (PubMed, BioMedCentral, Embase, and the Cochrane Central Register of clinical trials). Research was updated on March 1th 2015. RESULTS: Perioperative mortality in our overall group of TAAA and in the extents IV was 10.7% and 4.9%, respectively (P=0.01); spinal cord ischemia rate 11.4% and 2.7%, respectively (P=0.0001). In the extents IV treated between 2006 and 2015 we observed a further trend of outcomes improvement with a rate of perioperative mortality and spinal cord ischemia of 1.2%, and 2.4%, respectively. Database searches yielded a total of 767 articles. Excluding non-pertinent titles or abstracts, we retrieved in complete form and assessed 27 studies according to the selection criteria. Nine studies were further excluded because of our prespecified exclusion criteria. The final 18 manuscripts included a total of 2098 patients. In this group median mortality rate was 4.8% (interquartile range 3-6) and the mean incidence of spinal cord ischemia was 1.56±1.54%. CONCLUSION: Perioperative outcomes after extent IV TAAA open repair were significantly better compared to our overall TAAA series. A more aggressive use of CSFD, LHBP and renal perfusion with Custodiol solution allowed a further trend of outcomes improvement in our series of extent IV TAAA open repair. Literature analysis confirmed during extent IV open repair very satisfactory perioperative outcomes with rates of mortality and spinal cord ischemia dropped to under 5% and 2%, respectively.

Single-donor granulocyte transfusions for improving the outcome of high-risk pediatric patients with known bacterial and fungal infections undergoing stem cell transplantation: a 10-year single-center experience.

Bacterial and fungal infections remain a significant cause of transplant-related mortality following allogeneic stem cell transplantation (SCT). Granulocyte transfusions (GTs) may reduce the neutropenic period after SCT and prevent further progression of the existing infection (that is, therapeutic GT) in addition to standard antibacterial and antifungal therapy. A retrospective analysis was performed on 28 consecutive pediatric SCT recipients who received at least one dose of GT between March 2003 and November 2013 at a single institution. All donors were conditioned with G-CSF+dexamethasone with harvest performed 12-18 h later. Indications for SCT were acute leukemia in 46% (13/28) and severe aplastic anemia in 21% (6/28). The main indications for GT were invasive fungal disease in 50%, bacterial infection in 21% and co-morbidities with predicted reduced tolerance to sepsis in 18% (5/28). The median number of GT was 6 (range 1-14) with a median dose of 3.56 × 10(10) granulocytes infused. The median increment in ANC was 1.06 × 10(9)/L and correlated with the granulocyte dose infused. Adverse reactions observed were mild and infrequent. Sixty-four percent of patients (18/28) are alive with only 2 of the 10 deaths being related to progression of infection. In addition there was a low overall incidence of grade 3-4 acute mucositis and a very low incidence (7%) of acute GvHD grade 3-4. Single-donor GTs afford protection to children undergoing SCT at additional risk of infection and may reduce the overall incidence of severe GvHD.

Strategies to treat thoracic aortitis and infected aortic grafts.

Infectious thoracic aortitis is a rare disease, especially since the incidence of syphilis and tuberculosis has dropped in western countries. However, the risk to develop an infectious aortitis and subsequent mycotic aneurysm formation is still present, particularly in case of associated endocarditis, sepsis, and in immunosuppressive disorders. Moreover, the number of surgical and endovascular thoracic aortic repairs is continuously increasing, and infective graft complications are observed more frequently. Several etiopathogenetic factors may play a role in thoracic aortic and prosthetic infections, including hematogenous seeding, local bacterial translocation, and iatrogenous contamination. Also, fistulization of the esophagus or the bronchial tree is commonly associated with these diseases, and it represents a critical event requiring a multidisciplinary management. Knowledge on underlying micro-organisms, antibiotic efficacy, risk factors, and prevention strategies has a key role in the management of this spectrum of infectious diseases involving the thoracic aorta. When the diagnosis of a mycotic aneurysm or a prosthetic graft infection is established, treatment is demanding, often including a number of surgical options. Patients are usually severely compromised by sepsis, and in most cases they are considered unfit for surgery for general clinical conditions or local concerns. Thus, results of different therapeutic strategies for infectious diseases of the thoracic aorta are still burdened with very high morbidity and mortality. In this manuscript, we review the literature regarding the main issues related to thoracic infectious aortitis and aortic graft infections, and we report our personal series of patients surgically treated at our institution for these conditions from 1993 to 2014.

Propofol and survival: a meta-analysis of randomized clinical trials.

BACKGROUND: One of the most commonly used hypnotics is propofol. Several studies performed in cardiac surgery suggested an increased mortality in patients receiving a propofol-based total intravenous anaesthesia. Furthermore, the possibility of infections and the 'propofol syndrome' have suggested that propofol might be dangerous. Nonetheless, propofol is widely used in different settings because of its characteristics: fast induction, rapid elimination, short duration of action, smooth recovery from anaesthesia, few adverse effects, no teratogenic effects, characteristics that have undoubtedly contributed to its popularity. The effect of propofol on survival is unknown. We decided to carry out a meta-analysis of all randomized controlled studies ever performed on propofol vs. any comparator in any clinical setting. METHODS: Pertinent studies were independently searched in BioMedCentral, PubMed, Embase, Clinicaltrial.gov, and Cochrane Central Register of Clinical Trials by expert investigators. The following inclusion criteria were used: random allocation to treatment, comparison between propofol and any comparator in any clinical setting. RESULTS: One hundred thirty-three studies randomizing 14,516 patients were included. No differences in mortality between patients receiving propofol [349/6957 (5.0%)] vs. any comparator [340/7559 (4.5%)] were observed in the overall population [risk ratio = 1.05, 95% confidence interval (0.93 to 1.18), P = 0.5] and in several sub-analyses. CONCLUSION: Inspite of theoretical concerns, propofol has no detrimental effect on survival according to the largest meta-analysis of randomized trials ever performed on hypnotic drug.

Clinical use of extra-large self-expanding stents.

The aim of this study is to describe our clinical experience with an extra-large self-expandable stent specifically designed to treat aortic lesions (E-XL, Jotec GmbH, Hechingen, Germany), now commercially available in Europe. The E-XL was used at our Institution in 14 patients (mean age, 56±12 years; 9 males) with the following indications: improve proximal fixation (4 cases), type I endoleak (2 cases), aortic dissection with static malperfusion (1 case) and dynamic malperfusion (7 cases). Early results have been shown to be safe and effective in different clinical settings, including in emergency cases. This peculiar aortic stent could be useful in the armamentarium of the endovascular surgeon.

Redo surgery in ascending aorta and aortic arch.

AIM: Reinterventions following previous ascending aorta and aortic arch repair are uncommon, but technically challenging and often burdened with high morbidity and mortality. The aim of this article is to present a single-center experience in the treatment of this complex pathology, using different surgical approaches. METHODS: Between 1999 and 2014, 17 patients (14 males, mean age 73±16 years) underwent ascending aorta and aortic arch redo surgery at our Department. A prospectively maintained database including thoracic aortic procedures was reviewed retrospectively to collect data on redo patients. RESULTS: In 13 cases the index procedure was an endovascular or hybrid procedure on the aortic arch performed at our Department, for an in-house reintervention rate of 6.9% (13/188). In 10 cases the cause of reintervention was stent-graft distal migration, treated by means of endovascular relining in all cases, associated with adjunctive supra-aortic trunks debranching via sternotomy in 6 cases. In 5 cases the cause of reintervention was retrograde ascending aortic dissection, in 1 case ascending aortic anastomotic pseudoaneurysm following supra-aortic trunk debranching, and in 1 case mediastinitis following implantation of an endovascular plug previously used to treat an ascending aortic pseudoaneurysm. In these last 7 cases, all patients were treated by means of ascending and arch surgical replacement under deep hypothermic circulatory arrest (DHCA) and antegrade cerebral perfusion (ACP). No 30-day mortality was observed. Major perioperative morbidity included 1 paraplegia, 1 minor stroke, 1 bleeding requiring reintervention, and 3 cases of respiratory failure requiring prolonged intubation (2) or tracheostomy (1). CONCLUSION: In our experience, incidence of serious complications requiring reinterventions following ascending aorta or aortic arch repair is not negligible. Redo surgery in ascending aorta and aortic arch is feasible in high-volume and experienced centers, as it often requires hybrid repair via midline sternotomy, or surgical replacement under DHCA and ACP.