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Hypertrophic cardiomyopathy is an inherited disorder due to mutations in contractile proteins that results in a stiff, hypercontractile myocardium. To understand the role of cardiac stiffness in disease progression, here we create an in vitro model of hypertrophic cardiomyopathy utilizing hydrogel technology. Culturing wild-type cardiac myocytes on hydrogels with a Young’s Moduli (stiffness) mimicking hypertrophic cardiomyopathy myocardium is sufficient to induce a hypermetabolic mitochondrial state versus myocytes plated on hydrogels simulating healthy myocardium. Significantly, these data mirror that of myocytes isolated from a murine model of human hypertrophic cardiomyopathy (cTnI-G203S). Conversely, cTnI-G203S myocyte mitochondrial function is completely restored when plated on hydrogels mimicking healthy myocardium. We identify a mechanosensing feedback mechanism between the extracellular matrix and cytoskeletal network that regulates mitochondrial function under healthy conditions, but participates in the progression of hypertrophic cardiomyopathy pathophysiology resulting from sarcomeric gene mutations. Importantly, we pinpoint key ‘linker’ sites in this schema that may represent potential therapeutic targets.

BackgroundCardiovascular disease is the leading cause of death in Australia. Investment in research solutions has been demonstrated to yield health and a 9.8-fold return economic benefit. The sector, however, is severely challenged with success rates of traditional peer-reviewed funding in decline. Here, we aimed to understand the perceived challenges faced by the cardiovascular workforce in Australia prior to the COVID-19 pandemic.MethodsWe used an online survey distributed across Australian cardiovascular societies/councils, universities and research institutes over a period of 6 months during 2019, with 548 completed responses. Inclusion criteria included being an Australian resident or an Australian citizen who lived overseas, and a current or past student or employee in the field of cardiovascular research.ResultsThe mean age of respondents was 42±13 years, 47% were male, 85% had a full-time position, and 40% were a group leader or laboratory head. Twenty-three per cent (23%) had permanent employment, and 82% of full-time workers regularly worked >40 hours/week. Sixty-eight per cent (68%) said they had previously considered leaving the cardiovascular research sector. If their position could not be funded in the next few years, a staggering 91% of respondents would leave the sector. Compared to PhD- and age-matched men, women were less likely to be a laboratory head and to feel they had a long-term career path as a cardiovascular researcher, while more women were unsure about future employment and had considered leaving the sector (all pConclusionStrategic solutions, such as diversification of career pathways and funding sources, and moving from a competitive to a collaborative culture, need to be a priority to decrease reliance on government funding and allow cardiovascular researchers to thrive.

Significance Hypertrophic cardiomyopathy affects 1:500 of the general population. Current drug therapy is used to manage symptoms in patients. There is an unmet need for treatments that can prevent the cardiomyopathy. Here we identify biomarkers of hypertrophic cardiomyopathy resulting from causing cardiac troponin I mutation Gly203Ser, and present a safe, nontoxic, preventative approach for the treatment of associated cardiomyopathy., Currently there is an unmet need for treatments that can prevent hypertrophic cardiomyopathy (HCM). Using a murine model we previously identified that HCM causing cardiac troponin I mutation Gly203Ser (cTnI-G203S) is associated with increased mitochondrial metabolic activity, consistent with the human condition. These alterations precede development of the cardiomyopathy. Here we examine the efficacy of in vivo treatment of cTnI-G203S mice with a peptide derived against the α-interaction domain of the cardiac L-type calcium channel (AID-TAT) on restoring mitochondrial metabolic activity, and preventing HCM. cTnI-G203S or age-matched wt mice were treated with active or inactive AID-TAT. Following treatment, targeted metabolomics was utilized to evaluate myocardial substrate metabolism. Cardiac myocyte mitochondrial metabolic activity was assessed as alterations in mitochondrial membrane potential and flavoprotein oxidation. Cardiac morphology and function were examined using echocardiography. Cardiac uptake was assessed using an in vivo multispectral imaging system. We identified alterations in six biochemical intermediates in cTnI-G203S hearts consistent with increased anaplerosis. We also reveal that AID-TAT treatment of precardiomyopathic cTnI-G203S mice, but not mice with established cardiomyopathy, restored cardiac myocyte mitochondrial membrane potential and flavoprotein oxidation, and prevented myocardial hypertrophy. Importantly, AID-TAT was rapidly targeted to the heart, and not retained by the liver or kidneys. Overall, we identify biomarkers of HCM resulting from the cTnI mutation Gly203Ser, and present a safe, preventative therapy for associated cardiomyopathy. Utilizing AID-TAT to modulate cardiac metabolic activity may be beneficial in preventing HCM in “at risk” patients with identified Gly203Ser gene mutations.

Nowadays nanoparticles are increasingly investigated for the targeted and controlled delivery of therapeutics, as suggested by the high number of research articles (2400 in 2000 vs 8500 in 2020). Among them, almost 2% investigated nanogels in 2020. Nanogels or nanohydrogels (NGs) are nanoparticles formed by a swollen three-dimensional network of synthetic polymers or natural macromolecules such as polysaccharides. NGs represent a highly versatile nanocarrier, able to deliver a number of therapeutics. Currently, NGs are undergoing clinical trials for the delivery of anti-cancer vaccines. Herein, the strategies to load low molecular weight drugs, (poly)peptides and genetic material into polysaccharide NGs as well as to formulate NGs-based vaccines are summarized, with a focus on the microfluidics approach., Carbohydrate Polymers, 266

The proper functioning of central lines is imperative for the management of patients with cancer or on hemodialysis. However, these lifelines can become infected and can malfunction.Chelators such as citrate and EDTA have been widely studied alone or in combination with other antimicrobial agents in catheter lock solutions to prevent catheter-related bloodstream infections and to maintain catheter patency. Given their anticoagulation, antiplatelet aggregation, antibiofilm, antimicrobial activity, safety profile, as well as their low cost, chelators have long been considered alternatives to heparin and a vital component of catheter lock solutions. In this review, we present a detailed summary of the properties of chelators and in vitro and in vivo studies of chelator-containing lock solutions.

The enhanced recovery after surgery (ERAS) is nowadays a widely accepted multimodal programme of care in colorectal surgery, but still there is some reluctance in its application to very elderly patients. The aim of this study is to investigate short-term outcomes of laparoscopic resection for colorectal cancer in octogenarian patients within the ERAS programme. Data on 162 consecutive patients aged ≥ 80 years receiving elective minimally invasive colorectal resections within ERAS programme were collected in a multicentre, retrospective database in the period 2008–2017 in Italy. Univariate and multivariate analyses were performed to assess possible risk factors for poor clinical outcomes. The postoperative minor morbidity rate (Clavien–Dindo 1 and 2) was 25.9%. The incidence of postoperative major morbidity rate (severe medical and surgical complications defined as Clavien–Dindo 3 and 4) accounted 6.1% and only 1.8% had an anastomotic leakage. Reoperation rate was 5.5%, perioperative 30-day mortality was 1.8%, and 30-day readmission rate was 6.8%. On average, patients were released after 6 days. A univariate analysis showed that possible risk factors for severe medical complications were: low preoperative albumin level, high Charlson Age Comorbidity Index Score and number of days in the intensive care unit (ICU); risk factors for severe surgical complications were: low preoperative albumin level; risk factors for late hospital discharge were: multivisceral resections, number of days in ICU and body mass index (BMI) > 25 kg/m2. The multivariate analysis confirmed a low level of preoperative albumin and a longer ICU stay as independent risk factors for both postoperative severe surgical complications and late hospital discharge. The minimal invasive nature of the laparoscopic approach together with a multimodal analgesia therapy, the early resumption to oral diet and mobilisation could minimize the surgical stress and play an essential role in order to reduce medical morbidity in high-risk patients. Colorectal surgery within ERAS programme in octogenarians is a safe and flexible treatment in high-volume centres.

Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high‐fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error‐prone (Mrps12ep / ep ) or hyper‐accurate (Mrps12ha / ha ) mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high‐fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue‐specific manner. In two distinct organs that are commonly affected by the metabolic disease, the heart and the liver, Mrps12ep / ep mice were protected against heart defects but sensitive towards lipid accumulation in the liver, activating genes involved in steroid and amino acid metabolism. In contrast, enhanced translational accuracy in Mrps12ha / ha mice protected the liver from a high‐fat diet through activation of liver proliferation programs, but enhanced the development of severe hypertrophic cardiomyopathy and led to reduced lifespan. These findings reflect the complex transcriptional and cell signalling responses that differ between post‐mitotic (heart) and highly proliferative (liver) tissues. We show trade‐offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue‐specific outcomes due to commonly encountered stressful environmental conditions or aging., This work reveals how trade‐offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue‐specific outcomes to metabolic stress or aging. Error‐prone protein synthesis enhanced the rate of translation, protecting against heart defects but stimulated lipid accumulation in the liver. Enhanced translational accuracy protected liver function through activation of proliferation programs, but resulted in severe hypertrophic cardiomyopathy and reduced lifespan.

The development of disseminated cryptococcosis has historically occurred in patients living with advanced human immunodeficiency virus or other immunosuppressive conditions affecting T-cell function. Recently, patients with anti-cytokine neutralising autoantibodies have been recognised to be at risk for disseminated infections by opportunistic intracellular pathogens, including Cryptococcus species. Herein, we present a previously healthy 26-year-old man who was evaluated with disseminated cryptococcosis involving the bone, lung, mediastinum and brain. The patient's serum cryptococcal antigen titres were >1:1,100,000, and evaluation for an underlying immunodeficiency revealed high titres for anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. We also review the literature of all published cases of disseminated cryptococcosis associated with the presence of anti-GM-CSF autoantibodies. Clinicians should have a heightened awareness of anti-cytokine autoantibodies in patients without a known immunodeficiency and development disseminated infections by opportunistic intracellular pathogens.

Sarcomeric gene mutations are associated with the development of hypertrophic cardiomyopathy (HCM). Current drug therapeutics for HCM patients are effective in relieving symptoms, but do not prevent or reverse disease progression. Moreover, due to heterogeneity in the clinical manifestations of the disease, patients experience variable outcomes in response to therapeutics. Mechanistically, alterations in calcium handling, sarcomeric disorganization, energy metabolism and contractility participate in HCM disease progression. While some similarities exist, each mutation appears to lead to mutation‐specific pathophysiology. Furthermore, these alterations may precede or proceed development of the pathology. This review assesses the efficacy of HCM therapeutics from studies performed in animal models of HCM and human clinical trials. Evidence suggests that a preventative rather than corrective therapeutic approach may be more efficacious in the treatment of HCM. In addition, a clear understanding of mutation‐specific mechanisms may assist in informing the most effective therapeutic mode of action., Sarcomeric gene mutations are associated with the development of hypertrophic cardiomyopathy (HCM). Mechanistically, alterations in calcium handling, sarcomeric disorganization, energy metabolism and contractility participate in HCM disease progression. These alterations may precede or proceed development of the pathology. This review assesses the efficacy of preventative versus corrective HCM therapeutics from studies performed in animal models of HCM and human clinical trials.

The insulin/insulin-like growth factor signalling axis is an evolutionary ancient and highly conserved hormonal system involved in the regulation of metabolism, growth and lifespan in animals. Human insulin is stored in the pancreas, while insulin-like growth factor-1 (IGF-1) is maintained in blood in complexes with IGF-binding proteins (IGFBP1–6). Insect insulin-like polypeptide binding proteins (IBPs) have been considered as IGFBP-like structural and functional homologues. Here, we report structures of the Drosophila IBP Imp-L2 in its free form and bound to Drosophila insulin-like peptide 5 and human IGF-1. Imp-L2 contains two immunoglobulin-like fold domains and its architecture is unrelated to human IGFBPs, suggesting a distinct strategy for bioavailability regulation of insulin-like hormones. Similar hormone binding modes may exist in other insect vectors, as the IBP sequences are highly conserved. Therefore, these findings may open research routes towards a rational interference of transmission of diseases such as malaria, dengue and yellow fevers.

© 2017 American Chemical Society. Fibrotic diseases are among the most serious health issues with severe burdens due to their chronic nature and a large number of patients suffering from the debilitating effects and long-term sequelae. Collagenase treatment is a nonsurgical option but has limited results. To date, there is no potent noninvasive solution for fibrosis. Part of the reason for this is the lack of appropriate in vitro live cell screening tools to assess the efficacy of new therapeutical agents. Here, we demonstrate the utility of a cell-based electrochemical impedance biosensor platform to screen the efficacy of potential antifibrotic compounds. The platform employs a label-free and noninvasive strategy to detect the progression of fibrosis and the potency of the antifibrotic molecules in real-time. The fundamental principle that governs this novel system is that dynamic changes in cell shape and adhesion during fibrosis can be measured accurately by monitoring the changes in the impedance. This is achieved by growing the cells on a transparent interdigitated indium tin oxide (ITO) electrodes. It was demonstrated by monitoring the efficacy of a model antifibrotic compound, PXS64, on cells collected from patients with Dupuytren's contracture. We confirmed the validity of the developed biochemical impedance biosensor as an tool for in vitro screening of antifibrotic compounds and provided quantitative information on subcellular influences of the examined chemical molecules using correlative microscopy analyses that monitor the average cell area, cell morphology, and the amount and directionality of the deposited extracellular matrix protein collagen and measurement of cytosolic Ca2+ changes.

Vascular catheters are critical tools in modern healthcare yet present substantial risks of serious bloodstream infections that exact significant health and economic burdens. Drug-eluting antimicrobial vascular catheters have become important tools in preventing catheter-related bloodstream infections and their importance is expected to increase as significant initiatives are expanded to eliminate and make the occurrence of these infections unacceptable. Here we review clinically significant and emerging drug-eluting antimicrobial catheters within the categories of antibiotic, antiseptic, novel bioactive agents and energy-enhanced drug eluting antimicrobial catheters. Important representatives of each category are reviewed from the standpoints of mechanisms of action, physical–chemical properties, safety, in vitro and clinical effectiveness.

BackgroundCheckpoint inhibitor (CPI) immunotherapy has revolutionized cancer treatment. However, immune-related adverse events and the risk of infections are not well studied. To assess the infectious risk of CPIs, we evaluated the incidence of infections in lung cancer patients treated with CPIs plus conventional chemotherapy (CC) vs CC alone.MethodsWe performed a retrospective comparative study of patients with advanced non–small cell lung cancer who received CPIs combined with CC and those treated with CC alone at our institution during January 2016 to February 2019. We compared clinical characteristics, treatments, and outcomes including infection rate and mortality between the groups.ResultsWe identified 123 patients for the CPI group and 147 patients for the control (CC) group. Eighteen patients (15%) in the CPI group and 33 patients (22%) in the control group developed infections (P = .1). Pneumonia was the most common infection encountered in both groups. Urinary tract infection was higher in the CC group (40%) than in the CPI group (9%) (P = .01). On multivariable analysis, chronic obstructive pulmonary disease (P = .024), prior use of corticosteroids (P = .021), and neutropenia (P ConclusionsLung cancer patients treated with CPIs combined with CC have a comparable risk of infection to those treated with CC alone, although there is a trend towards fewer infections in those given CPIs, particularly when it comes to urinary tract infections.

In cancer patients with long-term central venous catheters (CVC), removal and reinsertion of a new CVC at a different site might be difficult because of the unavailability of accessible vascular sites. In vitro and animal studies showed that a minocycline-EDTA-ethanol (M-EDTA-EtOH) lock solution may eradicate microbial organisms in biofilms, hence enabling the treatment of central line-associated bloodstream infections (CLABSI) while retaining the catheter in situ . Between April 2013 and July 2014, we enrolled 30 patients with CLABSI in a prospective study and compared them to a historical group of 60 patients with CLABSI who had their CVC removed and a new CVC inserted. Each catheter lumen was locked with an M-EDTA-EtOH solution for 2 h administered once daily, for a total of 7 doses. Patients who received locks had clinical characteristics that were comparable to those of the control group. The times to fever resolution and microbiological eradication were similar in the two groups. Patients with the lock intervention received a shorter duration of systemic antibiotic therapy than that of the control patients (median, 11 days versus 16 days, respectively; P < 0.0001), and they were able to retain their CVCs for a median of 74 days after the onset of bacteremia. The M-EDTA-EtOH lock was associated with a significantly decreased rate of mechanical and infectious complications compared to that of the CVC removal/reinsertion group, who received a longer duration of systemic antimicrobial therapy. (This study has been registered at ClinicalTrials.gov under registration no. NCT01539343.)

Therapeutic approaches for myocardial ischemia–reperfusion injury (MI) have been ineffective due to limited bioavailability and poor specificity. We have previously shown that a peptide that targets the α-interaction domain of the cardiac L-type calcium channel (AID-peptide) attenuates MI when tethered to transactivator of transcription sequence (TAT) or spherical nanoparticles. However some reservations remain regarding use of these delivery platforms due to the relationship with human immunodeficiency virus, off-target effects and toxicity. Here we investigate the use of linear dendronized polymers (denpols) to deliver AID-peptide as a potential MI therapy using in vitro, ex vivo and in vivo models. Optimized denpol-complexed AID-peptide facilitated in vitro cardiac uptake of AID-peptide, and reduced MI. Maximal in vivo cardiac uptake was achieved within the 2 h therapeutic time window for acute myocardial infarction. Importantly, optimized denpol-complexed AID-peptide was not toxic. This platform may represent an alternative therapeutic approach for the prevention of MI.

Myoglobin, encoded by MB, is a small cytoplasmic globular hemoprotein highly expressed in cardiac myocytes and oxidative skeletal myofibers. Myoglobin binds O-2, facilitates its intracellular transport and serves as a controller of nitric oxide and reactive oxygen species. Here, we identify a recurrent c.292C>T ( p.His98Tyr) substitution in MB in fourteen members of six European families suffering from an autosomal dominant progressive myopathy with highly characteristic sarcoplasmic inclusions in skeletal and cardiac muscle. Myoglobinopathy manifests in adulthood with proximal and axial weakness that progresses to involve distal muscles and causes respiratory and cardiac failure. Biochemical characterization reveals that the mutant myoglobin has altered O-2 binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin. Preliminary studies show that mutant myoglobin may result in elevated superoxide levels at the cellular level. These data define a recognizable muscle disease associated with MB mutation., We thank the patients and their families for their collaboration. This study has been funded by Instituto de Salud Carlos III through the project PI14/00738 (co-funded by European Regional Development Fund. ERDF, a way to build Europe) and from a grant from Genzyme Foundation to MO. We thank CERCA Programme/Generalitat de Catalunya for institutional support. GR, NGL, and ARRF are supported by Australian National Health and Medical Research Council Fellowships APP1002147, APP1035955, APP1154524, and Project Grants APP1080587 and APP1146321. ARRF was also supported by a Senior Research Fellowship from the Cancer Research Trust, the MACA Ride to Conquer Cancer and an Australian Research Council Discovery Project Grant (DP160101960). MC is supported by ISCIII (JR15/00042). AWr is a Ragnar Soderberg Fellow in Medicine (M77/13) and is supported by the Swedish Research Council (AW (VR2016-02179). AWe is supported by the Swedish Research Council (2016-01082), Stockholm County Council (20170022), the Swedish Brain Foundation (FO2015-0146), and the Knut & Alice Wallenberg Foundation (KAW 2013.0026 and KAW 2014.0293). KGC is supported by the KOOR, UZ Leuven, Belgium. AG is supported by the Research Council KU Leuven (C24/16/045). JK is a recipient of the Royal Society Wolfson Research Merit Award. TS is supported by Stockholm County Council (20170831), Stiftelsen Frimurare Foundation, and Promobilia. LH is supported by an Australian National Health and Medical Research Council Fellowship (APP1117366). HV is supported by a National Heart Foundation of Australia Fellowship (101930). mu FTIR microscope analysis was performed at MIRAS beamline at ALBA Synchrotron with the collaboration of ALBA staff. We thank professor Josep Garcia Valero from the University of Barcelona for helpful comments on the ultrastructural features. We thank Dolores Moreno, Susana Arnedo, Guy Brochier, and Benjamin Torrejon-Escribano for excellent technical assistance and to the Audiovisual Department from Hospital Universitari de Bellvitge for their help with the preparation of the figures. KCG wants to thank Klara Mallants for technical support and to Dr. Sjoerd G. van Duinen (Leiden), and professsor Joachim Weis (Aachen). Muscle sample and associated data from Family 5 were obtained from Cardiobiotec Biobank (CRB-HCL Hospices Civils de Lyon BB-0033-00046).

The oligomeric state of the storage form of human insulin in pancreas, which may be affected by several endogenous components of beta-cells storage granules such as arginine, is not known. Here, the effect of arginine on insulin oligomerisation is investigated independently by protein crystallography, molecular dynamics simulations and capillary electrophoresis. The combined results point to a strong effect of ionic strength on insulin assembly. Molecular simulations and electrophoretic measurements at low/mM salt concentrations show no significant effect of arginine on insulin aggregation. In contrast, crystallographic data at high/molar ionic strength indicate inhibition of insulin hexamerization by arginine due to its binding at site relevant for intermolecular contacts, which was also observed in MD simulations. Our results thus bracket the in vivo situation in pancreatic beta-cells storage granules, where the ionic strength is estimated to be in the hundreds of millimolar to sub-molar range. The present findings add to molecular understanding of in vivo insulin oligomerization and storage, with additional implications for insulin stability in arginine-rich injections.

Cell penetrating peptides (CPPs) offer great potential to deliver therapeutic molecules to previously inaccessible intracellular targets. However, many CPPs are inefficient and often leave their attached cargo stranded in the cell’s endosome. We report a versatile platform for the isolation of peptides delivering a wide range of cargos into the cytoplasm of cells. We used this screening platform to identify multiple “Phylomer” CPPs, derived from bacterial and viral genomes. These peptides are amenable to conventional sequence optimization and engineering approaches for cell targeting and half-life extension. We demonstrate potent, functional delivery of protein, peptide, and nucleic acid analog cargos into cells using Phylomer CPPs. We validate in vivo activity in the cytoplasm, through successful transport of an oligonucleotide therapeutic fused to a Phylomer CPP in a disease model for Duchenne’s muscular dystrophy. This report thus establishes a discovery platform for identifying novel, functional CPPs to expand the delivery landscape of druggable intracellular targets for biological therapeutics.

Advancements in immunotherapy have opened a new era in oncology, to include genetic modification of human T-cells to express a chimeric antigen receptor (CAR) that enables targeted tumor recognition (Kochenderfer et al., 2015; Lee et al., 2015; Maus and Levine 2016; Rosenberg et al., 2008). Herein, we report a false-positive HIV testing in a patient who had undergone CAR T-cell therapy created with a lentiviral vector.

HNPCC is an autosomal inherited cancer syndrome characterized by germinal and somatic mutations of DNA mismatch repair (MMR) genes. The inherited mutation in one allele together with an acquired defect in the other allele of an MMR gene leads to accelerate tumor progression.In this study we analyzed a cohort of 11 subjects belonging to four Sicilian families with HNPCC suspected by molecular analysis of coding regions of hMSH2 (NC_000002) and hMLH1 (NC_000003) genes.Molecular analysis has detected the presence of two mutations in gene MSH2 and one mutation in MHL1 gene. In addition, we found a novel mutation consisting in a G deletion at 914 codon of the exon 16 in the MSH2 gene. This deletion leads to a stop codon due to a frame-shift, resulting in a truncated protein.We extended genetic analysis to the other family members and the same mutation was detected in three sisters and in one of the two healthy daughters.This mutation is correlated with clinical findings revealed in genealogic tree and it represents a novel mutation responsible of HNPCC.

Maintenance of cellular calcium homeostasis is critical to regulating mitochondrial ATP production and cardiac contraction. The ion channel known as the L-type calcium channel is the main route for calcium entry into cardiac myocytes. The channel associates with cytoskeletal proteins that assist with the communication of signals from the plasma membrane to intracellular organelles, including mitochondria. This article explores the roles of calcium and the cytoskeleton in regulation of mitochondrial function in response to alterations in L-type calcium channel activity. Direct activation of the L-type calcium channel results in an increase in intracellular calcium and increased mitochondrial calcium uptake. As a result, mitochondrial NADH production, oxygen consumption and reactive oxygen species production increase. In addition the L-type calcium channel is able to regulate mitochondrial membrane potential via cytoskeletal proteins when conformational changes in the channel occur during activation and inactivation. Since the L-type calcium channel is the initiator of contraction, a functional coupling between the channel and mitochondria via the cytoskeleton may represent a synchronised process by which mitochondrial function is regulated in addition to calcium influx to meet myocardial energy demand on a beat to beat basis.

Summary Objectives As infection is a severe complication of Ommaya reservoirs (OR), and existing data is limited, herein we describe the largest study of the clinical manifestations and treatment outcomes of Ommaya reservoir-related infections (ORRI). Methods We retrospectively reviewed the records of all patients at our institution who had an OR placed, and developed a definite device-related infection between 2001 and 2011. Results Among 501 OR placements, 40 patients (8%) developed an ORRI. These presented with meningitis and/or meningoencephalitis (60%), cellulitis (20%), or a combination thereof (20%). Approximately 40% occurred ≤30 days of OR placement, while 60% occurred ≤10 days after the device was last accessed. Only 20% presented with leukocytosis, while another 18% had a normal cerebrospinal fluid (CSF). Gram-positive skin flora accounted >80% of the pathogens. The median hospital stay and duration of antibiotics were 13 and 24 days, respectively. Although mortality rates (≈10%) were similar among all treatment groups ( p > 0.99), shorter hospitalization and antimicrobial treatment durations were obtained with early versus late device removal ( p Conclusions As clinical symptoms can be non-specific and CSF parameters may be within normal limits, a high suspicion for infection is required. The shortest hospitalization and treatment course was achieved with early device removal.

For long-term central lines (CL), the lumen is the major source of central line-associated bloodstream infections (CLABSI). The current standard of care for maintaining catheter patency includes flushing the CL with saline or heparin. Neither agent has any antimicrobial activity. Furthermore, heparin may enhance staphylococcal biofilm formation. We evaluated the safety and efficacy of a novel nonantibiotic catheter lock solution for the prevention of CLABSI. Between November 2015 and February 2016, we enrolled 60 patients with hematologic malignancies who had peripherally inserted central catheters (PICC) to receive the study lock solution. The study lock consisted of 15 or 30 μg/ml of nitroglycerin in combination with 4% sodium citrate and 22% ethanol. Each lumen was locked for at least 2 h once daily prior to being flushed. After enrollment of 10 patients at the lower nitroglycerin dose without evidence of toxicity, the dose was escalated to the higher dose (30 μg/ml). There were no serious related adverse events or episodes of hypotension with lock administration. Two patients experienced mild transient adverse events (one headache and one rash) possibly related to the lock and that resolved without residual effect. The CLABSI rate was 0 on lock days versus 1.6/1,000 catheter days (CD) off lock prophylaxis, compared with a rate of 1.9/1,000 CD at the institution in the same patient population. In conclusion, the nitroglycerin-based lock prophylaxis is safe and well tolerated. It may prevent CLABSI when given daily to cancer patients. Large, prospective, randomized clinical trials are needed to validate these findings. (This study has been registered at ClinicalTrials.gov under identifier NCT02577718.)

Resistance to chemotherapy occurs in various diseases (i.e., cancer and infection), and for this reason, both are very difficult to treat. Therefore, novel antimicrobial and chemotherapic drugs are needed for effective antibiotic therapy. The aim of the present study was to assess the antimicrobial and anti-proliferative effects of skin mucus derived from Dasyatis pastinaca (Linnaeus, 1758). Our results showed that skin mucus exhibited a significant and specific antibacterial activity against Gram-negative bacteria but not against Gram-positive bacteria. Furthermore, we also observed a significant antifungal activity against some strains of Candida spp. Concerning anti-proliferative activity, we showed that fish mucus was specifically toxic for acute leukemia cells (HL60) with an inhibition of proliferation in a dose dependent manner (about 52% at 1000 μg/mL of fish skin mucous, FSM). Moreover, we did not observe effects in healthy cells, in neuroblastoma cells (SH-SY5Y), and multiple myeloma cell lines (MM1, U266). Finally, it exhibited strong expression and activity of chitinase which may be responsible, at least in part, for the aforementioned results.

Implant-associated surgical-site infections can have significant clinical consequences. Previously we reported a method for prophylactically disinfecting implant surfaces in surgical pockets, where an antibiotic solution containing minocycline (M) and rifampin (R) was applied as a solid film in a crosslinked biopolymer matrix that partially liquefied in situ to provide extended prophylaxis. Here we studied the effect of adding sodium 2-mercaptoethane sulfonate (MeSNA) on durability of prophylaxis in anin vitromodel of implant-associated surgical-site infection. Adding MeSNA to the M/R biopolymer, antimicrobial film extended the duration for which biofilm formation by multidrug-resistantPseudomonas aeruginosa(MDR-PA) was prevented on silicone surfaces in the model. M/R films with and without MeSNA were effective in preventing colonization by methicillin-resistantStaphylococcus aureus. Independent experiments revealed that MeSNA directly inhibited proteolytic digestion of the biopolymer film and synergistically enhanced antimicrobial potency of M/R against MDR-PA. Incubation of the MeSNA containing films with L929 fibroblasts revealed no impairment of cellular metabolic activity or viability.

The heart is able to respond acutely to changes in oxygen tension. Since ion channels can respond rapidly to stimuli, the "ion channel oxygen sensing hypothesis" has been proposed to explain acute adaptation of cells to changes in oxygen demand. However the exact mechanism for oxygen sensing continues to be debated. Mitochondria consume the lion's share of oxygen in the heart, fuelling the production of ATP that drives excitation and contraction. Mitochondria also produce reactive oxygen species that are capable of altering the redox state of proteins. The cardiac L-type calcium channel is responsible for maintaining excitation and contraction. Recently, the reactive cysteine on the cardiac L-type calcium channel was identified. These data clarified that the channel does not respond directly to changes in oxygen tension, but rather responds to cellular redox state. This leads to acute alterations in cell signalling responsible for the development of arrhythmias and pathology.

Background The most common conditions leading to death after simultaneous pancreas-kidney transplantations (SPKs) are cardiovascular diseases. The aim of this study was to test the platelet aggregation inhibitor acetylsalicylic acid (ASA) resistance in patients after SPKs, including investigations into the triggering factors. Methods Thirty-two patients (22 men, 10 women; overall age, 47.4 ± 8.6 years) were involved in our study and took 100 mg ASA per day. We used optical platelet aggregometry to detect resistance. Results Resistance occurred in 40.6% of the study group. However, with the use of logistic regression analysis, the examined 24 factors did not show any significant correspondence with resistance. Conclusions The incidence of ASA resistance seems to be higher compared with other groups, but the triggering effect is still unproved. Clarifying this question should be important regarding the mortality- and morbidity-reducing capacity of antiplatelet drugs in the management of cardiovascular conditions.

Severe burn injury significantly affects cardiovascular function for up to 3 years. However, whether this leads to long-term pathology is unknown. The impact of non-severe burn injury, which accounts for over 80% of admissions in developed countries, has not been investigated. Using a rodent model of non-severe burn injury with subsequent echocardiography we showed significantly increased left ventricular end systolic diameter (LVESD) and ventricular wall thickness at up to 3 months post-injury. Use of propranolol abrogated the changes in cardiac measures observed. Subsequently we investigated changes in a patient cohort with non-severe injury. Echocardiography measured at baseline and at 3 months post-injury showed increased LVESD at 3 months and significantly decreased posterior wall diameter. Finally, 32 years of Western Australian hospital records were used to investigate the incidence of cardiovascular disease admissions after burn injury. People who had experienced a burn had increased hospital admissions and length of stay for cardiovascular diseases when compared to a matched uninjured cohort. This study presents animal, patient and population data that strongly suggest non-severe burn injury has significant effects on cardiovascular function and long-term morbidity in some burn patients. Identification of patients at risk will promote better intervention and outcomes for burn patients.

A double-blind randomized controlled trial with a paired split-scar design compared verapamil, an L-type Ca2+ channel antagonist, and triamcinolone for prevention of keloid recurrence after excision. Ca2+ channel blocking activity of verapamil in keloid cells was explored. One keloid was excised per subject and each wound half randomized to receive intralesional injections of triamcinolone (10 mg/ml) or verapamil (2.5 mg/ml) at monthly intervals (4 doses). Interim analysis was performed after 14 subjects were completed. Survival analysis demonstrated significantly higher keloid recurrence with verapamil compared to triamcinolone 12 months post-surgery (log-rank test, p = 0.01) and higher overall risk of recurrence with verapamil (hazard ratio 8.44, 95% CI 1.62-44.05). The study was terminated early according to the stopping guideline (p

Rapidly growing mycobacteria (RGM) are environmental organisms capable of causing a wide spectrum of diseases. We identified 116 cancer patients with RGM. Mycobacterium mucogenicum was the leading cause of disease. Removal of the catheter correlated with significant decrease in the bacteremia relapse rate (P = .007). A median duration of 4 weeks of therapy produced a good outcome.

Infections of cardiac implantable electronic devices (CIED) can cause significant morbidity, mortality, and financial burden. Although staphylococcal organisms account for most infections of these cardiac devices, approximately 20% of all CIED-related infections are caused by non-Staphylococcus species. Herein we describe and compare the demographics, clinical presentation, and outcomes of Staphylococcus aureus and non-staphylococcal infections of CIED.We performed a retrospective, multicenter, observational study of patients from 4 academic hospitals in Houston between 2002 and 2009. All 80 identified non-staphylococcal CIED-related infections were matched, at a 1:1 ratio, to S. aureus infections.Although the demographics and general comorbidities in the 2 study groups were relatively similar, the S. aureus group had a higher proportion of patients with coronary artery disease, diabetes mellitus, and end-stage renal disease. Additionally, 81% of S. aureus compared with only 48.5% of the non-staphylococcal CIED-related infections were health care-associated (p < 0.001). Furthermore, when compared to non-staphylococcal infections, the S. aureus group had more indwelling intravascular foreign material (p < 0.001), more rapid clinical progression (p < 0.001), and overall worse clinical presentation (p < 0.001). However, after stratifying by clinical presentation, the mortality rates in the 2 groups were similar (p = 0.45).Since approximately one-fifth of all CIED-related infections are caused by non-staphylococcal organisms, and untimely antibiotic treatment can result in serious complications, it may be prudent to broaden empiric antimicrobial therapy to cover both Gram-positive and -negative bacteria, until the causative organism is identified.

The sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) plays a critical role in Ca(2+) homeostasis via sequestration of this ion in the sarco/endoplasmic reticulum. The activity of this pump is inhibited by oxidants and impaired in aging tissues and cardiovascular disease. We have shown previously that the myeloperoxidase (MPO)-derived oxidants HOCl and HOSCN target thiols and mediate cellular dysfunction. As SERCA contains Cys residues critical to ATPase activity, we hypothesized that HOCl and HOSCN might inhibit SERCA activity, via thiol oxidation, and increase cytosolic Ca(2+) levels in human coronary artery endothelial cells (HCAEC). Exposure of sarcoplasmic reticulum vesicles to preformed or enzymatically generated HOCl and HOSCN resulted in a concentration-dependent decrease in ATPase activity; this was also inhibited by the SERCA inhibitor thapsigargin. Decomposed HOSCN and incomplete MPO enzyme systems did not decrease activity. Loss of ATPase activity occurred concurrent with oxidation of SERCA Cys residues and protein modification. Exposure of HCAEC, with or without external Ca(2+), to HOSCN or HOCl resulted in a time- and concentration-dependent increase in intracellular Ca(2+) under conditions that did not result in immediate loss of cell viability. Thapsigargin, but not inhibitors of plasma membrane or mitochondrial Ca(2+) pumps/channels, completely attenuated the increase in intracellular Ca(2+) consistent with a critical role for SERCA in maintaining endothelial cell Ca(2+) homeostasis. Angiotensin II pretreatment potentiated the effect of HOSCN at low concentrations. MPO-mediated modulation of intracellular Ca(2+) levels may exacerbate endothelial dysfunction, a key early event in atherosclerosis, and be more marked in smokers because of their higher SCN(-) levels.

Infectious and non-infectious diarrhea is a common occurrence in the immunosuppressed population. We present a 43-year-old individual with large-volume stool output Norovirus acute gastroenteritis in the setting of relapsed refractory acute myelogenous leukemia, hematopoietic stem cell transplantation, and biopsy-proven cutaneous and pulmonary graft-versus-host disease. Therapeutic options such as intravenous immunoglobulin or reduction of oral immunosuppressants were not a feasible choice. A prompt clinical cure was achieved with nitazoxanide, a broad spectrum antimicrobial agent. Nitazoxanide may be a safe therapeutic alternative, in which a reduction in immunosuppression is not a viable option.

Calcium is a key determinant of cardiac excitation, contraction and relaxation. Cardiac excitation and contraction is powered by ATP that is synthesized within mitochondria via a calcium-dependent process known as oxidative phosphorylation. During this process oxygen molecules within the mitochondria are converted to superoxide. Under physiological conditions, low levels of ROS are required to maintain normal cellular function. This is achieved as a result of a balance between ROS formation and amelioration by antioxidants. Uninhibited increases in ROS production lead to oxidative stress. Large increases in ROS are associated with damage to mitochondria, DNA, proteins and lipids. In the heart this ultimately leads to apoptosis and loss of myocytes. However sub-lethal increases in ROS can activate hypertrophic signaling kinases and transcription factors including NFAT, CaMK and serine-threonine and tyrosine kinases. Calcium is also an important signaling molecule and a mediator of hypertrophic signaling pathways. ROS and calcium appear to participate as partners in pathological remodeling but their interaction and early mechanisms associated with the development of cardiac hypertrophy are poorly understood. An increase in cytoplasmic calcium can potentiate cellular oxidative stress via effects on mitochondrial metabolism. In addition oxidative stress can regulate the function of calcium channels and transporters. We discuss the evidence for calcium transporting proteins and the mitochondria in oxidative stress responses and propose sites to target in the prevention of cardiac hypertrophy.

Cerebrovascular complications have been reported to occur in patients with neurocysticercosis (NCC). We report a patient who presented with relapsed subarachnoid hemorrhage possibly linked to NCC. In addition, we performed a literature review of all of the reported cases of aneurysmal and non-aneurysmal hemorrhagic cerebrovascular events associated with NCC. We identified 11 such cases. The majority of the individuals were young males (mean: 38 years; 70% males). Four cases (36%) had aneurysms. Four (36%) others had negative cerebral angiograms and therefore classified as non-aneurysmal, while the remaining three (28%) did not report sufficient information to classify them. All cases with aneurysmal hemorrhage underwent successful surgical repair of the aneurysms. Seven patients received albendazole (including three who had had surgery). Three patients died; all three presented in the pre-albendazole era. In summary, neurocysticercosis should be considered in the differential diagnosis of hemorrhagic cerebrovascular events in young patients without classical vascular risk factors who have lived or visited NCC-endemic areas.

Post-transplant lymphoproliferative disorder (PTLD) is generally caused by an uncontrolled B-cell proliferation induced by Epstein-Barr virus (EBV) in the setting of impaired EBV-specific T-cell immunity. PTLD has been described in allogeneic hematopoietic stem cell transplant (HSCT) and rarely in autologous HSCT. Anti-thymocyte globulin (ATG) is being increasingly utilized for acute rejection in organ transplantation, severe autoimmune diseases and aplastic anemia. Mainly, the use of rabbit ATG has been associated with PTLD, which is considered to be more immunosuppressive than equine ATG. The sole administration of equine ATG has rarely been associated with PTLD. Due to the increased use of these potent and novel immunosuppressive agents, it is paramount to be aware of these complications. We present a 55-year-old man with an autologous HSCT who presented with an unusual case of monoclonal plasmacytic PTLD. His lymphoproliferative disorder occurred 3 years after his HSCT and 1 month after the use of equine ATG administered for severe aplastic anemia. We review current concepts of EBV-PTLD, including risk factors, the potential for preemptive therapy and various management strategies.

We present a case of possible transfusion-transmitted Ehrlichia chaffeensis infection in a heavily transfused cord blood transplant recipient, resulting in severe infection and graft loss. Transfusion-transmitted, vector-borne infections in immunocompromised individuals can have severe consequences, and should be considered in hospitalized patients receiving blood products with unexplained fever or sepsis.

Background— Along with the rising use of cardiac implantable electronic devices (CIEDs), there has been a disproportional increase in the number of infections of such devices. Little is known about nonstaphylococcal CIED-related infections, which make up ≈10% to 30% of all CIED infections. Methods and Results— A retrospective review of hospital records of patients admitted with a CIED-related infection was conducted in 4 academic hospitals in Houston, Tex, between 2002 and 2009. Of the 504 identified patients with CIED-related infection, 80 (16%) had a nonstaphylococcal infection and were the focus of this study. The mean duration of CIED placement before infection was 109±27 weeks, whereas 44% had their device previously manipulated within a mean of 29.5±6 weeks. The mean duration of clinical symptoms before admission was 48±12.8 days. Furthermore, 13 patients (16%) presented with CIED-related endocarditis. Although not described in prior reports, we identified 3 definite and 2 suspected cases of secondary Gram-negative bacteria seeding of the CIED. Inappropriate antimicrobial coverage was provided in ≈50% of the cases with a mean period of 2.1 days. The overall mortality rate was 4%. Conclusions— Nonstaphylococcal CIED-related infections are prevalent and diverse with a relatively low virulence and mortality rate. Because nonstaphylococcal organisms are capable of secondarily seeding the CIED, a high suspicion for CIED-related infection is warranted in patients with bloodstream infection. In patients with suspected CIED infection, adequate Gram-positive and Gram-negative antibacterial coverage should be administered until microbiological data become available.

Gram-positive bacterial infections are an important cause of morbidity and death among cancer patients, despite current therapy. In this case-control study, we evaluated the clinical outcomes and safety of telavancin in cancer patients with uncomplicated Gram-positive bloodstream infections (BSIs). Between March 2011 and May 2013, we enrolled cancer patients with uncomplicated Gram-positive BSIs to receive intravenous telavancin therapy for at least 14 days for Staphylococcus aureus and 7 days for other Gram-positive cocci. Patients with baseline creatinine clearance (CL CR ) values of >50 ml/min received 10 mg/kg/day of telavancin, and those with CL CR values between 30 and 49 ml/min received 7.5 mg/kg/day. Patients were compared with a retrospective cohort of 39 historical patients with Gram-positive BSIs, matched for underlying malignancy, infecting organism, and neutropenia status, who had been treated with vancomycin. A total of 78 patients were analyzed, with 39 in each group. The most common pathogen causing BSIs was S. aureus (51%), followed by alpha-hemolytic streptococci (23%), Enterococcus spp. (15%), coagulase-negative staphylococci (8%), and beta-hemolytic streptococci (3%). Sixty-two percent of patients had hematological malignancies, and 38% had solid tumors; 51% of the patients were neutropenic. The overall response rate determined by clinical outcome and microbiological eradication at 72 h following the initiation of therapy, in the absence of relapse, deep-seated infections, and/or infection-related death, was better with telavancin than with vancomycin (86% versus 61%; P = 0.013). Rates of drug-related adverse events were similar in the two groups (telavancin, 31%; vancomycin, 23%; P = 0.79), with similar rates of renal adverse events. Telavancin may provide a useful alternative to standard vancomycin therapy for Gram-positive BSIs in cancer patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01321879.)

Heparan sulfate (HS) is a glycosaminoglycan that forms a key component of the extracellular matrix (ECM). Breakdown of HS is carried out by heparanase (HPSE), an endo-β-glucuronidase of the glycoside hydrolase 79 (GH79) family. Overexpression of HPSE results in breakdown of extracellular HS and release of stored growth factors and hence is strongly linked to cancer metastasis. Here we present crystal structures of human HPSE at 1.6-A to 1.9-A resolution that reveal how an endo-acting binding cleft is exposed by proteolytic activation of latent proHPSE. We used oligosaccharide complexes to map the substrate-binding and sulfate-recognition motifs. These data shed light on the structure and interactions of a key enzyme involved in ECM maintenance and provide a starting point for the design of HPSE inhibitors for use as biochemical tools and anticancer therapeutics.

The evolutionary divergence of mitochondrial ribosomes from their bacterial and cytoplasmic ancestors has resulted in reduced RNA content and the acquisition of mitochondria-specific proteins. The mitochondrial ribosomal protein of the small subunit 34 (MRPS34) is a mitochondria-specific ribosomal protein found only in chordates, whose function we investigated in mice carrying a homozygous mutation in the nuclear gene encoding this protein. The Mrps34 mutation causes a significant decrease of this protein, which we show is required for the stability of the 12S rRNA, the small ribosomal subunit and actively translating ribosomes. The synthesis of all 13 mitochondrially-encoded polypeptides is compromised in the mutant mice, resulting in reduced levels of mitochondrial proteins and complexes, which leads to decreased oxygen consumption and respiratory complex activity. The Mrps34 mutation causes tissue-specific molecular changes that result in heterogeneous pathology involving alterations in fractional shortening of the heart and pronounced liver dysfunction that is exacerbated with age. The defects in mitochondrial protein synthesis in the mutant mice are caused by destabilization of the small ribosomal subunit that affects the stability of the mitochondrial ribosome with age., Author Summary Mitochondria make most of the energy required by eukaryotic cells and therefore they are essential for their normal function and survival. Mitochondrial function is regulated by both the mitochondrial and nuclear genome. Mutations in nuclear genes encoding mitochondrial proteins lead to mitochondrial dysfunction and consequently diminished energy production, a major symptom of metabolic and mitochondrial diseases. The molecular mechanisms that regulate mitochondrial gene expression and how dysfunction of these processes causes the pathologies observed in these diseases are not well understood. Messenger RNAs encoded by mitochondrial genomes are translated on mitochondrial ribosomes that have unique structure and protein composition. Mitochondrial ribosomes are a patchwork of core proteins that share homology with prokaryotic ribosomal proteins and mitochondria-specific proteins, which can be unique to different organisms. Mitochondria-specific ribosomal proteins have key roles in disease however their functions within mitochondria are not known. Here we show that a point mutation in a mammalian-specific ribosomal protein causes mitochondrial dysfunction, heart abnormalities and progressive liver disease. This mouse provides a valuable model to elucidate the pathogenic mechanisms and progression of metabolic diseases with age, while enabling a more thorough understanding of mitochondrial ribosomes and protein synthesis.

Breast reconstruction surgeries using tissue expanders (TEs) have highly reported infection rates. To decrease this, we developed a method for disinfecting TEs and surgical pockets, where an antimicrobial solution was applied as a solid film at implantation that subsequently liquefied in situ to provide extended prophylaxis. Silicone discs cut from TEs were covered with gelatin-based films containing minocycline (M) and rifampin (R). Discs and films soaked in saline were subsequently challenged with pathogen at days 1, 3, 7, and 10 and quantified for potential biofilm formation. Discs that were not harvested at each specific time points were refreshed with sterile saline. The discs were challenged with clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and multidrug-resistant Pseudomonas aeruginosa (MDR-PA). Recoveries of adherent organisms from uncovered silicone discs and gelatin-wrapped discs without added antimicrobial agents were5 × 10(4) CFU/disc for each organism at each time point. Experimental 0.1%M/0.05%R gelatin films completely inhibited all challenge organisms from attaching to the silicone (p 0.05) at each time point through day 10. Cytotoxicity was assessed by incubating films with HEK-293T human fibroblasts. There were no significant differences in HEK-293T cell survival between controls and any of the antimicrobial films. The in situ liquefying, bioabsorable, antimicrobial wrap prevented biofilm formation by microorganisms on silicone surfaces in vitro with minimal cytotoxicity.

Bovine seminal ribonuclease is a member of the RISBAses (ribonucleases with special biological actions) family. It exerts specific anti-tumor, embryotoxic, aspermatogenic and immunosuppressive activities. The cytotoxic effect of bovine seminal ribonuclease on tumor cells is accompanied by the induction of apoptosis. We provide ultrastructural and flow cytometry evidence of apoptotic death following bovine seminal ribonuclease treatment, in normal cells and phytohemagglutinin-stimulated lymphocytes. Transmission and scanning electron microscopy, which were fully supported by flow cytometry data, showed typical features of apoptosis, such as decreased cell size, chromatin condensation, fragmentation in micronuclei, and the presence of apoptotic bodies.

Objective.The rate of postmastectomy tissue expander (TE) infection remains excessively high, ranging between 2% and 24%. We hypothesized that current perioperative antimicrobial regimens utilized for breast TE reconstruction may be outdated as a result of recent changes in microflora and susceptibility patterns.Design and Methods.We reviewed the records of all patients who had a TE reconstructive procedure and developed a definite breast TE infection between 2003 and 2010 at MD Anderson Cancer Center. Antimicrobials were stratified into 3 groups: systemic perioperative, local irrigation, and oral immediate postoperative antimicrobials. These were considered discordant if they did not target the isolated organisms, while a breakthrough infection was defined as an infection that occurred despite concordant antimicrobial coverage.Results.Overall, 75 patients with a definite TE infection were identified. The most common organisms identified were methicillin-resistant Staphylococcus epidermidis (29%), methicillin-resistant Staphylococcus aureus (15%), and gram-negative rods (26%). The use of systemic perioperative antimicrobials was deemed discordant in 51% of the cases. Although 79% of the patients received broad-spectrum perioperative local antimicrobial irrigation, 63% developed a breakthrough infection. Even though 61% received oral postoperative prophylactic antimicrobials, 63% of the times they were deemed discordant.Conclusions.Contrary to the proven effectiveness of a single dose of perioperative antibiotics, the common use of local antimicrobial irrigation and prolonged postoperative oral antibiotics appears to be an inadequate component of our preventive armamentarium. Also, because methicillin-resistant staphylococcal and pseudomonal infections occurred approximately 60% of the time, at institutions that have observed an increase of these organisms, it may be prudent that perioperative antimicrobials target these microorganisms.

At 30 years into the HIV infection epidemic, the optimal antiretroviral (ARV) regimen for infected patients with cancer remains unknown. We therefore sought to retrospectively study different ARV regimens used in this population. Data from HIV-infected patients seen at The University of Texas MD Anderson Cancer Center in Houston, Texas, USA, from 2001 to 2012 were reviewed. Patients received nucleoside reverse transcriptase inhibitors (NRTIs) plus protease inhibitors (PIs), non-NRTIs (NNRTIs), integrase strand-transfer inhibitors (INSTIs), or combinations of these. A total of 154 patients were studied. Most patients were male (80%), white (51%) and had haematological malignancies (HMs) (58%). NRTIs were combined with PIs (37%), NNRTIs (32%), INSTIs (19%) or combinations of these (11%). INSTIs were the most commonly used in patients with HM and in those receiving high-dose steroids or topoisomerase inhibitors (p

Summary About 20 species of rapidly growing mycobacteria species that are capable of infecting human beings and causing bloodstream infections have been identified. Many more of these species are being discovered worldwide, especially in resource-poor settings. These microorganisms have been known to cause outbreaks and pseudo-outbreaks. Although rapidly growing mycobacteria are not highly virulent or life threatening, they have a high predisposition to create biofilms and to colonise and infect intravascular catheters. Early detection and identification of specific species can help to estimate predictable antimicrobial susceptibility patterns. However, because susceptibility data originate from developed countries, studies in resource-poor settings urgently need to be done. The best outcome of cure without recurrence depends on a combination of at least 4 weeks of treatment with two or more active antimicrobial agents, plus removal of the intravascular catheter. We review and discuss the epidemiology, pathogenesis, diagnosis, management, and outcomes of rapidly growing mycobacterial bloodstream infections.

Implantation of cardiac implantable electronic devices (CIED) has dramatically increased over the past several years. Although several preventive measures have been implemented, there has been a disproportional increase in the number of CIED-related infections. To evaluate the adherence of bacteria to polyurethane and titanium, the 2 surfaces that coat the CIED, we proceeded with an in vitro study using the most common microorganisms responsible for CIED-related infections. Original, unused 1 × 1 centimeter titanium and polyurethane flat plates were incubated with coagulase-negative staphylococci, methicillin-resistant Staphylococcus aureus, and Pseudomonas aeruginosa. Each experiment was repeated 5 times. After incubating the titanium and polyurethane plates for 3, 6, 12, or 24 hours, all 3 organisms displayed a higher grade of bacterial adherence to the polyurethane versus titanium surfaces (p = 0.01). In conclusion, to decrease the rate of bacterial adherence, especially during the immediate postimplantation period when the CIED is at high risk for bacterial adherence, colonization, and infection, it may be prudent to consider constructing CIED surfaces with a higher proportion of titanium over polyurethane. Animal studies are warranted to explore the relevance of these laboratory findings.