Women's Understanding of Windows of Susceptibility and the Role of the Environment in Breast Cancer Risk.

Emerging evidence suggests women who are exposed to harmful environmental exposures, especially during certain critical periods across the lifespan, may increase their breast cancer risk. Such windows of susceptibility (WoS) occur throughout a woman's lifetime, during which she is especially vulnerable to the effects of harmful environmental exposures. This interaction makes the reduction of harmful environmental toxicants during those time periods a priority for community health promotion. Communicating about environmental exposures and their impact on women's health requires an assessment of sense-making around, and understanding of, the link between breast cancer and the environment. To that end, focus groups were conducted to assess the themes that emerge when women make sense of (a) their own breast cancer risk, (b) the environment-cancer connection, and (c) WoS. Results provide insight into how women understand these issues which can inform messaging strategies focused on reducing harmful environmental exposures. Implications are discussed within the context of communication efforts tailored to educate women, particularly mothers with daughters in the prepubertal and pubertal WoS who are particularly vulnerable to harmful environmental exposures.

Severe opioid withdrawal precipitated by Vivitrol®.

The risk of severe precipitated opioid withdrawal (POW) is amplified when precipitated by a long-acting opioid antagonist. IM extended release naltrexone (XRNTX;Vivitrol®) is an FDA approved therapy to prevent relapse of opioid and alcohol abuse. Two cases of precipitated opioid withdrawal from XRNTX are presented that illustrate different patient reactions to POW. A 56-year-old woman developed a hypertensive emergency and required continuous intravenous vasodilator, clonidine, and intensive care monitoring after re-initiation of XRNTX following opioid relapse. A 25-year-old man developed agitation and altered mental status after receipt of XRNTX at the conclusion of a twelve-day detoxification program during which he continued surreptitious use of heroin. The patient received benzodiazepines and haloperidol without adequate affect, and required intubation with propofol, lorazepam, and dexmedetomidine infusions. Management of POW from XRNTX is a challenge to emergency providers and protocols to guide management do not exist. Recommended therapies include intravenous fluids, anti-emetics, clonidine, or benzodiazepines as well as therapy tailored to the organ system affected. To minimize risk of POW it is important for providers instituting XRNTX to adhere to the manufacturers warnings and clinic protocols including a naloxone challenge and ensure an adequate opioid free period prior to administration of XRNTX.

Something wicked this way comes: What health care providers need to know about Candida auris.

Candida auris is a fungal pathogen that recently emerged and rapidly spread around the globe. It is now in Canada. C. auris can cause invasive disease with high mortality rates, is frequently resistant to one or more classes of antifungals, and can be difficult to identify in some clinical microbiology laboratories. C. auris can also involve prolonged colonization of patients' skin and contamination of surrounding environments, resulting in nosocomial outbreaks in hospitals and long-term care facilities. Clinicians, infection prevention and control practitioners and public health officials should be aware of how to mitigate the threat posed by this pathogen. Index cases of C. auris should be suspected in patients with invasive candidiasis and recent hospitalization in global regions where C. auris is prevalent, as well as in patients who fail to respond to empiric antifungal therapy and from whom unidentified or unusual Candida species have been isolated. If a case of C. auris infection or colonization is identified or suspected, the following should take place: notification of local public health authorities and infection prevention and control practitioners; placement of colonized or infected patients in single rooms with routine contact precautions; daily and terminal environmental disinfection with a sporicidal agent; contact tracing and screening for C. auris transmission; and referral of suspicious or confirmed isolates to provincial laboratories. Patients with symptomatic disease should be treated with an echinocandin pending the results of antifungal susceptibility testing, preferably in consultation with an infectious disease specialist. Through the vigilance of front-line health care workers and microbiologists, robust infection prevention and control practices, and local and national surveillance efforts, C. auris can be detected quickly, infections managed and transmissions prevented to protect patients in our health care system.

Compressed sodium chloride as a fast-acting antimicrobial surface: results of a pilot study.

Antimicrobial surfaces are currently being studied as an aid to reduce transmission of pathogens leading to healthcare-associated infections (HAIs). Among the most harmful and costly pathogens that cause HAIs is meticillin-resistant Staphylococcus aureus (MRSA). Currently available and previously investigated antimicrobial surface technologies that are effective against MRSA (e.g. copper alloy surfaces) take 30min to several hours to achieve significant reduction. This article presents a new antimicrobial surface technology made of compressed sodium chloride that reduces MRSA 20-30 times faster than copper alloy surfaces.

Epidemiology and risk factors for nosocomial bloodstream infections in solid organ transplants over a 10-year period.

BACKGROUND: Bloodstream infections (BSIs) are a leading cause of morbidity and mortality in solid organ transplantation (SOT). We sought to determine the types of nosocomial BSIs and risk factors for them in SOT. METHODS: Prospectively collected databases of all SOT and nosocomial BSIs occurring at our institution for a 10-year period were reviewed. RESULTS: From 2003-2012, we observed 157 nosocomial BSI episodes in 2257 SOTs, the majority of which were caused by staphylococci and enterococci (67.5%). The most common sources of BSI were central line, organ space, respiratory, and gastrointestinal. Kidney transplant patients had the lowest risk of acquiring a BSI compared with other SOT types. Lung transplant patients were at increased risk of methicillin-resistant Staphylococcus aureus BSI and heart transplant patients were at increased risk of a Candida albicans BSI, when compared to other organ transplant types. When coagulase-negative Staphylococcus (CoNS) or C. albicans was isolated, the central line was most often the source. The implementation of central-line bundles during the study period correlated temporally with a decreased rate of CoNS BSI. Over the 10-year period, vancomycin-resistant enterococci became the most common enterococcal BSI. Donor-positive cytomegalovirus status was associated with an increased risk of BSI, when compared to donor-negative patients. CONCLUSIONS: This study demonstrates the common sources, risk factors, and causative organisms of BSI, which can guide empiric antibiotic choices, and highlights areas where preventative interventions could be targeted to prevent nosocomial BSI in SOT.

Carbon monoxide exposures in New York City following Hurricane Sandy in 2012.

CONTEXT: On October 29, 2012, Hurricane Sandy made landfall and devastated New York's metropolitan area, causing widespread damage to homes and the utility infrastructure. Eight days later, snow and freezing temperatures from a nor'easter storm delayed utility restoration. OBJECTIVE: To examine carbon monoxide (CO) exposures in the 2 weeks following Hurricane Sandy. Methods. This was a retrospective review of prospectively collected, standardized, and de-identified data sets. CO exposures and poisonings identified from two electronic surveillance systems, the New York City Poison Control Center (NYCPCC) and New York City's Syndromic Surveillance Unit, were compared with CO exposures from identical dates in 2008-2011. Data collected from the poison center included exposure type, CO source, poisoning type, treatment, and outcomes. Data collected from the Syndromic Surveillance Unit cases, which were identified by CO-related chief complaints presenting to NYC hospitals, included visit date and time, and patient demographics. RESULTS: Four hundred thirty-seven CO exposures were reported to the NYCPCC, 355 from NYC callers, and the remainder from surrounding counties, which represented a significant increase when compared with CO exposures from identical dates in the preceding 4 years (p < 0.001). The total cases that were reported to the NYCPCC in 2008, 2009, 2010, and 2011 were 18, 13, 24, and 61, respectively. Excluding a single apartment fire that occurred (n = 311), the more common sources of CO were grilling indoors (26.2%) and generators (17.5%). Syndromic surveillance captured 70 cases; 6 cases were captured by both data sets. CONCLUSIONS: CO exposures following weather-related disasters are a significant public health concern, and the use of fuel-burning equipment is a clear source of storm-related morbidity and mortality. Multiple real-time epidemiologic surveillance tools are useful in estimating the prevalence of CO exposure and poisoning and are necessary to assist public health efforts to prevent CO poisoning during and after disasters.

Kidney pericytes: a novel therapeutic target in interstitial fibrosis.

Chronic Kidney Disease affects approximately 8% of the population and contributes considerably to premature morbidity and mortality. Recently reported studies have highlighted an important role for resident microvascular pericytes in the pathogenesis of kidney fibrosis. Pericytes are emerging as the predominant source of the activated, matrix depositing, stromal cell population seen in progressive fibrosis. Further, pericyte activation leads to their detachment from the vasculature, triggers unstable microvasculature and leads to rarefaction. Strategies to modulate pericyte function in these processes are therefore therapeutically attractive. In this review we will first describe our current understanding of the structure and function of the pericyte and the role these cells play in angiogenesis and the pathogenesis of renal fibrosis. Novel therapeutic approaches targeting pericytes in murine models of renal disease will then be considered.

TGFß modulates cell-to-cell communication in early epithelial-to-mesenchymal transition.

AIMS/HYPOTHESIS: A key pathology in diabetic nephropathy is tubulointerstitial fibrosis. The condition is characterised by increased deposition of the extracellular matrix, fibrotic scar formation and declining renal function, with the prosclerotic cytokine TGF-ß1 mediating many of these catastrophic changes. Here we investigated whether TGF-ß1-induced epithelial-to-mesenchymal transition (EMT) plays a role in alterations in cell adhesion, cell coupling and cell communication in the human renal proximal tubule. METHODS: Whole-cell and cell compartment abundance of E-cadherin, N-cadherin, snail, vimentin, ß-catenin and connexin-43 was determined in human kidney cell line (HK)2 and human proximal tubule cells with or without TGF-ß1, using western blotting and immunocytochemistry, followed by quantification by densitometry. The contribution of connexin-43 in proximal tubule cell communication was quantified using small interfering RNA knockdown, while dye-transfer was used to assess gap junctional intercellular communication (GJIC). Functional tethering was assessed by single-cell force spectroscopy with or without TGF-ß1, or by immunoneutralisation of cadherin ligation. RESULTS: High glucose (25 mmol/l) increased the secretion of TGF-ß1 from HK2 cells. Analysis confirmed early TGF-ß1-induced morphological and phenotypical changes of EMT, with altered levels of adhesion and adherens junction proteins. These changes correlated with impaired cell adhesion and decreased tethering between coupled cells. Impaired E-cadherin-mediated adhesion reduced connexin-43 production and GJIC, these effects being mimicked by neutralisation of E-cadherin ligation. Upregulation of N-cadherin failed to restore adhesion or connexin-43-mediated GJIC. CONCLUSIONS/INTERPRETATION: We provide compelling evidence that TGF-ß1-induced EMT instigates a loss of E-cadherin, cell adhesion and ultimately of connexin-mediated cell communication in the proximal tubule under diabetic conditions; these changes occur ahead of overt signs of renal damage.

ANCA-associated vasculitis is linked to carriage of the Z allele of α1 antitrypsin and its polymers.

BACKGROUND: Small studies have linked α1 antitrypsin (α1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). OBJECTIVE: To test the validity and the mechanism of this association between α1AT and AAV. METHODS: The distribution of α1AT deficiency alleles Z and S was compared between 856 White Europeans with AAV and 1505 geographic and ethnically matched healthy controls. Genotyping was performed by allelic discrimination assay. RESULTS: were compared between cases and controls using χ(2) tests. The serum and renal biopsies for α1AT polymers were compared using the polymer-specific 2C1 antibody. The role of α1AT polymers in promoting inflammation was investigated by examining their ability to prime neutrophils for ANCA activation as assessed by CD62L shedding, superoxide production and myeloperoxidase degranulation. Results The Z but not the S allele was over-represented in the patients compared with controls (HR=2.25, 95% CI 1.60 to 3.19). Higher concentrations of polymers of α1AT were detected in serum from patients carrying the Z allele than in those not carrying the Z allele (median (IQR) 1.40 (0.91-3.32) mg/dl vs 0.17 (0.06-0.28) mg/dl, p<0.001); polymers of α1AT were also seen in the renal biopsy of a patient with vasculitic glomerulonephritis. Polymers of α1AT primed neutrophils with CD62L shedding and increased superoxide production following ANCA activation. Carriage of the Z allele was not associated with disease severity, survival or relapse. CONCLUSIONS: The Z but not the S deficiency allele is associated with AAV. Polymers of α1AT are present in the serum and glomeruli of at least some patients with the Z allele, which may promote inflammation through priming of neutrophils.

3-D ultrasound guidance of surgical robotics using catheter transducers: feasibility study.

The goal of this study was to test the feasibility of using a real-time 3-D (RT3D) ultrasound scanner with matrix array catheter probes to guide a surgical robot. We tested the accuracy of using 3-D catheter transducers with the 3-D measurement software of the scanner to direct automatically a robot arm that touched two needle tips together within a water tank and inside a vascular graft. RMS measurement error ranged from 2.4 to 3.4 mm for two catheter designs.

Real-time three-dimensional transesophageal echocardiography for guiding interventional electrophysiology: feasibility study.

At present, there are limited methods of acquiring three-dimensional visualization of cardiac structure and function in real-time during interventional electrophysiology procedures. Images acquired for integration of computerized tomography and magnetic resonance imaging with electroanatomic mapping systems are static and are obtained earlier in time. The purpose of this study was to test the feasibility of real-time three-dimensional transesophageal echocardiography for the guidance of interventional electrophysiological studies. A matrix array transducer with 504 channels operating at 5 MHz in a 1 cm diameter steerable esophageal probe was used in conjunction with a scanner capable of real-time 3D scanning of pyramidal volumes from 65 degrees to 120 degrees at rates up to 30 volumes per second. This device has a spatial resolution of approximately 3 mm at 5 cm depth. The authors acquired real-time three-dimensional images of anatomic landmarks of value for electrophysiological procedures in five closed chest canines. Real-time, three-dimensional ultrasound imaging was also used for visualization and guidance of interventional catheter devices within the canine heart. Real-time three-dimensional images of the atria, pulmonary veins, and coronary sinus were acquired. Real-time 3-D color flow Doppler was employed to confirm patency. Multiple image planes of image volumes and rendered views were used to track catheter position and orientation. Images of left veno-atrial junctions have been confirmed by dissection. This study has demonstrated the feasiblity of using real-time three-dimensional transesophageal echocardiography for guiding interventional electrophysiology. The technology has the potential to fill a niche as an adjunct modality for cost-effective real-time interventional guidance and assessment, providing catheter and pacing lead visualization simultaneously with functional volumetric cardiac imaging.

Integrated endoscope for real-time 3D ultrasound imaging and hyperthermia: feasibility study.

The goal of this research is to determine the feasibility of using a single endoscopic probe for the combined purpose of real-time 3D (RT3D) ultrasound imaging of a target organ and the delivery of ultrasound therapy to facilitate the absorption of compounds for cancer treatment. Recent research in ultrasound therapy has shown that ultrasound-mediated drug delivery improves absorption of treatments for prostate, cervical and esophageal cancer. The ability to combine ultrasound hyperthermia and 3D imaging could improve visualization and targeting of cancerous tissues. In this study, numerical modeling and experimental measurements were developed to determine the feasibility of combined therapy and imaging with a 1 cm diameter endoscopic RT3D probe with 504 transmitters and 252 receive channels. This device operates at 5 MHz and has a 6.3 mm x 6.3 mm aperture to produce real time 3D pyramidal scans of 60-120 degrees incorporating 64 x 64 = 4096 image lines at 30 volumes/sec interleaved with a 3D steerable therapy beam. A finite-element mesh was constructed with over 128,000 elements in LS-DYNA to simulate the induced temperature rise from our transducer with a 3 cm deep focus in tissue. Quarter-symmetry of the transducer was used to reduce mesh size and computation time. Based on intensity values calculated in Field II using the transducer's array geometry, a minimum I(SPTA) of 3.6 W/cm2 is required from our endoscope probe in order to induce a temperature rise of 4 degrees C within five minutes. Experimental measurements of the array's power output capabilities were conducted using a PVDF hydrophone placed 3 cm away from the face of the transducer in a watertank. Using a PDA14 Signatec data acquisition board to capture full volumes of transmitted ultrasound data, it was determined that the probe can presently maintain intensity values up to 2.4 W/cm2 over indefinite times for therapeutic applications combined with intermittent 3D scanning to maintain targeting. These values were acquired using 8 cycle bursts at a prf of 6 kHz. Ex vivo heating experiments of excised pork tissue yielded a maximum temperature rises of 2.3 degrees C over 5 minutes of ultrasound exposure with an average rise of 1.8 +/- 0.2 degrees C over 5 trials. Modifications to the power supply and transducer array may enable us to reach the higher intensities required to facilitate drug delivery therapy.

Real-time 3D transesophageal echocardiography.

Transesophageal echocardiography (TEE) is an essential diagnostic tool in patients with poor transthoracic echocardiographic windows or when detailed imaging of structures distant from the chest wall is necessary. A real-time 3D TEE probe has been fabricated in our laboratory in order to increase the amount of information available during a transesophageal procedure. The 1 cm diameter esophageal probe utilizes a 2-dimensional, 5 MHz array at its tip with a 6.3 mm diameter aperture, including 504 active channels. The array has a periodic vernier geometry with an element pitch of 0.18 mm, built onto a multilayer flexible (MLF) interconnect circuit. In order to accommodate 504 channels within the device, a 1 m long Gore MicroFlat cable was utilized for wiring the MLF to the corresponding system connectors. Pulse-echo tests in a water tank have yielded a -6 dB bandwidth of 25.3%. Fully connected to the system through 3 m of cable, the probe shows an average 50 omega insertion loss of-85 dB with a standard deviation of 4 dB, as determined through pitch-catch measurements for a sampling of 10 elements. Using the completed 3D TEE probe with the Volumetrics Medical Imaging 3D scanner, real-time volumetric images of in vivo canine cardiac anatomy have been acquired, displaying atrial views, mitral valve function and interventional catheter guidance.

Behavioral correction of Parkinsonian rats following the transplantation of immortalized fibroblasts genetically modified with TH and GCH genes.

Eukaryotic plasmid vectors encoding the tyrosine hydroxylase (TH) gene and GTP cyclohydrolase-1 (GCH) gene were constructed and introduced into immortalized fibroblasts obtained from SV40 large antigen (LT(AG)) transformed rat primary fibroblasts. TH and GCH positive clones were selected and identified by immunohistochemistry and RT-PCR, respectively. Hemi-parkinsonian rats created using 6-hydroxydopamine (6-OHDA) were used to assess the therapeutic effect created by the co-implantation of immortalized fibroblasts genetically modified by TH or GCH genes. Animal behavior was significantly improved two weeks following implantation and behavioral correction was maintained for over 14 weeks. Behavioral improvement was paralleled by exogenous TH gene expression, identified by TH immunohistochemistry and RT-PCR analyses. The transplanted cells survived for at least 38 weeks as demonstrated by fibronectin immunohistochemical staining. Tumor formation or host reaction was not seen, although TH expression was negative for 20 weeks after the implantation. This work demonstrates that the co-transplantation of immortalized fibroblasts genetically modified by TH and GCH genes may be developed as a valuable approach to the treatment of Parkinson's disease.

Electrostatic micromachine scanning mirror for optical coherence tomography.

Compact electrostatic micromirror structures for use in the scanning arm of an optical coherence tomography (OCT) system are described. These devices consist of millimeter-scale mirrors resting upon micrometer-scale polyimide hinges that are tilted by a linear micromachine actuator, the integrated force array (IFA). The IFA is a network of deformable capacitor cells that electrostatically contract with an applied voltage. The support structures, hinges, and actuators are fabricated by photolithography from polyimide-upon-silicon wafers. These devices were inserted into the scanning arm of an experimental OCT imaging system to produce in vitro and in vivo images at frame rates of 4 to 8 Hz.

Real-time cylindrical curvilinear 3-D ultrasound imaging.

In patients who are obese or exhibit signs of pulmonary disease, standard transthoracic scanning may yield poor quality cardiac images. For these conditions, two-dimensional transesophageal echocardiography (TEE) is established as an essential diagnostic tool. Current techniques in transesophageal scanning, though, are limited by incomplete visualization of cardiac structures in close proximity to the transducer. Thus, we propose a 2D curvilinear array for 3D transesophageal echocardiography in order to widen the field of view and increase visualization close to the transducer face. In this project, a 440 channel 5 MHz two-dimensional array with a 12.6 mm aperture diameter on a flexible interconnect circuit has been molded to a 4 mm radius of curvature. A 75% element yield was achieved during fabrication and an average -6dB bandwidth of 30% was observed in pulse-echo tests. Using this transducer in conjunction with modifications to the beam former delay software and scan converter display software of the our 3D scanner, we obtained cylindrical real-time curvilinear volumetric scans of tissue phantoms, including a field of view of greater than 120 degrees in the curved, azimuth direction and 65 degrees phased array sector scans in the elevation direction. These images were achieved using a stepped subaperture across the cylindrical curvilinear direction of the transducer face and phased array sector scanning in the noncurved plane. In addition, real-time volume rendered images of a tissue mimicking phantom with holes ranging from 1 cm to less than 4 mm have been obtained. 3D color flow Doppler results have also been acquired. This configuration can theoretically achieve volumes displaying 180 degrees by 120 degrees. The transducer is also capable of obtaining images through a curvilinear stepped subaperture in azimuth in conjunction with a rectilinear stepped subaperture in elevation, further increasing the field of view close to the transducer face. Future work includes development of an array for adapting these modifications to a 6 mm diameter endoscope probe.

Real-time three-dimensional intracardiac echocardiography.

Using catheter-mounted 2-D array transducers, we have obtained real-time 3-D intracardiac ultrasound (US) images. We have constructed several transducers with 64 channels inside a 12 French catheter lumen operating at 5 MHz. The transducer configuration may be side-scanning or beveled, with respect to the long axis of the catheter lumen. We have also included six electrodes to acquire simultaneous electrocardiograms. Using an open-chest sheep model, we inserted the catheter into the cardiac chambers to study the utility of in vivo intracardiac 3-D scanning. Images obtained include a cardiac four-chamber view, mitral valve, pulmonic valve, tricuspid valve, interatrial septum, interventricular septum and ventricular volumes. We have also imaged two electrophysiological interventional devices in the right atrium, performed an in vitro ablation study, and viewed the pulmonary veins in vitro.