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.

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.

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.

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.

Cytoplasmic free Ca2+ in human platelets: Ca2+ thresholds and Ca-independent activation for shape-change and secretion.

Cytoplasmic free [Ca2+], [Ca2+]i, was measured in human platelets using the intracellularly-trapped, fluorescent indicator quin2. Basal [Ca2+]i with the Ca2+ -ionophore ionomycin revealed apparent thresholds for shape-change, 5-HT release and aggregation of approx. 0.5 microM, 0.8 microM and 2 microM. Thrombin raised [Ca2+]i to 3 microM fast enough for the Ca2+ to have triggered the cell activation. However, thrombin released more 5-HT than ionomycin could, and in Ca2+ -free medium thrombin evoked shape-change and secretion even when [Ca2+]i remained near basal levels throughout, suggesting the existence of alternative triggers for shape-change and secretory exocytosis.

Phase II trial evaluating triplet chemotherapy using gemcitabine, paclitaxel, and carboplatin in the treatment of patients with advanced non-small cell lung cancer.

The purpose of this study was to evaluate the combination of gemcitabine, paclitaxel, and carboplatin in patients with advanced non-small cell lung cancer. Previously untreated patients with stage IIIB or IV non-small cell lung cancer were enrolled into this trial. Sixty-nine patients from the phase II portion and eight patients from the phase I portion were treated with gemcitabine 1,000 mg/m2 intravenously on days I and 8, paclitaxel 200 mg/m2 as a 1-hour infusion on day 1, and carboplatin at an area under the curve of 5.0 intravenously on day 1. Treatment courses were repeated every 21 days. The phase II component of the study was completed at 13 community-based practices in the Minnie Pearl Cancer Research Network. Thirty-four of 71 fully evaluable patients had an objective response (48%, two complete and 32 partial responses). Twenty-five patients (35%) were stable and 12 (17%) progressed. The median response duration was 6 months (range, 3 to 14 months) and the median survival was 9.9 months, with 1- and 2-year survival rates of 47% and 21%, respectively. The combination of gemcitabine, paclitaxel, and carboplatin has been shown to be safe and effective; thus, this three-drug regimen will be compared with a standard two-drug regimen, paclitaxel/carboplatin, in a phase III study.

Studies on acid lipase, and E 600-resistant acid esterase activities in human tissue homogenates.

Detailed comparison of acid lipase and acid esterase activities of human spleen, liver and kidney homogenates has been carried out by means of the following substrates: 14C-tripalmitin, alpha-naphthyl acetate, alpha-naphthyl butyrate, alpha-naphthyl laurate, p-nitro-phenyl acetate, butyrate and laurate. In addition, homogenates of the three tissues were subjected to isoelectric focusing in polyacrylamide gels and histochemical staining with the above mentioned naphthyl substrates in the presence and absence of the organophosphate esterase inhibitor diethyl-p-nitrophenyl phosphate (E 600). These studies provide extensive support for the proposal that E 600-resistant acid naphthyl butyryl and lauryl esterase activities in human tissues derive largely from the enzyme acid lipase. The studies suggest that the most specific chromogenic substrate for this enzyme at a biochemical and histochemical level is alpha-napthyl laurate in the presence of E600 (3 X 10(-6) M).

Influence of restraint on plasma prolactin and corticosterone in female rats.

The effect of restraint on plasma prolactin and corticosterone concentrations was investigated in chronically catheterized, ovariectomized (OVX) or ovariectomized, oestrogen-treated (OVX-PEP) rats. Restraint was induced by tying the hind legs together. In OVX rats, prolactin levels were unchanged following restraint, either during the morning (10.00 h) or afternoon (14.00 h). Prolactin levels increased in OVX-PEP animals when restraint was initiated in the morning; when restraint was initiated in the afternoon the prolactin response depended upon the level of prolactin before restraint. If levels were low (pre-surge) the response to restraint was similar to that observed in the morning; if prolactin levels were high (surge) the response to restraint was reversed and the prolactin level declined. The morning prolactin response to restraint was significantly inhibited and the afternoon surge was retarded in adrenalectomized OVX-PEP (OVX-PEP-ADX) rats; however, in OVX-PEP animals maintained on 0-9% NaCl drinking solution, the morning prolactin response to restraint was also blunted, although the afternoon surge was normal. In OVX-PEP-ADX animals injected with either vehicle alone, or 2 or 4 mg corticosterone for 4 days, and sampled on the morning of day 5, the prolactin response to restraint was absent. Furthermore, when OVX-PEP animals were injected daily with either vehicle or 4 mg corticosterone/day, they showed no increase in prolactin in response to restraint when values were compared with those of uninjected animals. Corticosterone levels after restraint were higher than initial values in all of the above experimental conditions.

The CD5+ B cell: a B cell lineage with a central role in autoimmune disease?

It is apparent that B cells are heterogeneous with respect to, for example, the antigens they express on their surface, and the stimuli to which they can respond. It is still unclear to what extent these differences relate to the stage of differentiation (eg. virgin B cells differing from activated B cells or memory cells), or whether distinct developmental lineages might exist. It has been proposed by some authors that, in the mouse, B cells expressing the ly-1 antigen constitute a separate lineage. In man also, a minor population of B cells expresses detectable levels of the CD5 antigen, but far less information is available about these cells. Interest in the CD5+ and ly-1+ B cell subpopulations has been further stimulated by the suggestion that these cells might play a special role in autoimmune disease. Although, in mouse, ly-1+ B cells differ in several respects from ly-1- B cells, the main evidence that they form a separate lineage derives from experiments in which ly-1+ B cells could not be reconstituted with adult bone marrow. It should be borne in mind that the situation is quite different in humans where, following bone marrow transplantation, CD5+ B cells are rapidly restored. Moreover, in the irradiated mice, at least in some of the experiments ly-1+ B cells were in fact reconstituted by adult bone marrow. Furthermore, at least in humans, expression of CD5 can sometimes be induced. There is, as yet, no good evidence that human CD5+ B cells form a distinct lineage, and it is possible that CD5 expression depends upon microenvironmental influences acting on the B cell during its differentiation. Several interesting properties have been attributed to ly-1+ B cells, including the ability to provide help to other B cells, and the secretion of autocrine factors. However there is also evidence that these features are not exclusive to B cells expressing ly-1. It has also been suggested that ly-1+ B cells might be long-lived. It is not yet known whether some of the properties of ly-1+ B cells might be a direct result of their expressing this antigen; this may become more clear when the function of CD5 is elucidated. The suggestion that the repertoire of ly-1+ B cells might be biased towards the expression of certain V genes is very interesting. Many of the hybridomas from neonatal mice produce antibodies which are multi-specific, and therefore well suited to form a first line of defence against potential pathogens.(ABSTRACT TRUNCATED AT 400 WORDS)

B cell differentiation and lymphocyte surface phenotype in late onset hypogammaglobulinaemia.

Lymphocyte function and cell surface phenotype were examined in fifteen patients with late onset hypogammaglobulinaemia. The percentage of surface immunoglobulin-positive B cells in fourteen of the fifteen patients was in the normal range. Patients' B cells expressed MHC class II antigens at normal levels. For one patient, there was relatively high sIgD and low sIgM expression on B cells; the rest of the patients did not differ from controls in surface immunoglobulin density. The proportion of B cells positive for CD5 in patients was comparable to normal controls, and considerably less than in cord blood. However, the pattern of immunoglobulin isotype secretion in vitro by patients' B cells closely paralleled responses of cord blood B cells. Spontaneous secretion of IgM and IgG by patients' B cells was very low. Following polyclonal activation in the presence of autologous T cells, cells from thirteen patients secreted IgM within the normal range in response to at least one activator. The response of patients' purified B cells to IL-2 and gamma-IFN was variable. For four of six tested, B cells cultured with IL-2 and gamma-IFN together with polyclonal activators secreted normal levels of IgM. B cells from the other two patients secreted little or no IgM in response to these cytokines. For fourteen patients, IgG secretion following polyclonal activation remained low both when B cells were cultured with T cells or with a combination of IL-2 and gamma-IFN. IgG subclass imbalance was seen in one patient, whose cells secreted an unusually high proportion of IgG3, and undetectable IgG2 and IgG4; this pattern was consistent whether T cell help was provided by autologous or allogeneic T cells. Similarly purified B cells from this patient showed deficient IgG2 and IgG4 production in response to IL-2 and gamma-IFN.

A signal processing model of diagnostic x-ray scatter.

A model of scatter is developed from a signal processing approach. The scattering process is viewed as a nonlinear filter (NLF), which transforms a two-dimensional signal representing phantom thickness into a two-dimensional signal of scattered radiation. The NLF point spread function (PSF) is derived from a single scattering model, using the principles of Compton scattering and x-ray attenuation. The PSF is characterized by three approximations: a constant geometric shape, a volume that depends on the phantom thickness, and a width that depends on the phantom-to-detector distance. This leads to a closed form expression for the scatter-to-primary ratio as a function of phantom thickness, field size, photon energy, source-to-phantom distance, and phantom-to-detector distance. The NLF model is compared with previously reported measurements using constant thickness phantoms, and discrepancies are discussed. The good agreement found between the NLF model and measured data shows that the functional dependence of scatter on the above parameters, previously only explained in terms of empirical models or Monte Carlo simulations, can be incorporated into a signal processing model.

A contrast-detail analysis of diagnostic ultrasound imaging.

For diagnostic ultrasound imaging, as in computed tomography, a feature of prime importance is the detection of focal lesions of varying size and contrast (echo amplitude) from surrounding tissue. This study describes a new tissue-stimulating phantom which has been used to measure the threshold detection of varying contrast, simulated lesions. The phantom consists of a block of tissue-mimicking gelatin which contains a row of conical targets at a depth of 7 cm. Each cone contains a different tissue-mimicking material so that the echo amplitude of the cones relative to the background material covers a dynamic range of 20 dB. Cross-sectional B-scans, perpendicular to the lengths of the cones, result in images of disks of constant diameter but varying contrast. Parallel cross-sectional scans yield "lesions" varying in diameter from 20 to 1 mm. Relative contrast of the cones vs background tissue is obtained by varying scattering particle sizes from 90 to 300 microns. Ultrasound B-scans of the phantom were examined by medical physicist observers to determine threshold detection of lesions as a function of size and contrast. The results indicate that detection of high contrast targets is limited by the imaging system's spatial resolution. Detection of low contrast targets is limited by the image speckle, i.e., coherent noise.

Reconstruction of blood vessels from x-ray subtraction projections: limited angle geometry.

Several algorithms have been investigated for reconstructing blood vessels from a limited number of x-ray subtraction projections, distributed over a limited range of angles. Both computer simulations and an in vivo animal study were carried out. The best reconstruction performance was achieved using an algorithm that folded in two pieces of a priori knowledge of the vascular density distributions: (1) the object is dilute, consisting mainly of a void; and (2) the density distribution in the reconstructions is most likely to be non-negative. Both the signal-to-noise ratio (SNR) and the signal to out-of-focus blur were quantitated. Compared to tomosynthetic reconstruction (backprojection), the amount of residual blur from out-of-focus planes was significantly reduced with only a small penalty in diminished SNR. The combined effect resulted in significant qualitative image improvement for real arterial distributions as demonstrated in a canine arterial imaging example.

Angular response of miniature ultrasonic hydrophones.

The voltage response of ceramic and polyvinylidene fluoride (PVDF) hydrophones was measured in the receive mode for angles of incidence ranging from 0 degrees to 90 degrees. The measurements were performed at 2.5, 3.5, 5.0, and 8.0 MHz; these frequencies are typical of those used in medical diagnosis. The results are compared to three theoretical models based on diffraction theory; correlation between the measured response and theoretical models is evident for some PVDF hydrophones but not for others, and not for any ceramic hydrophone. The effective radius, as defined in the AIUM-NEMA standard for diagnosis ultrasound, is calculated and compared to the test criteria established in that standard. All of the ceramic hydrophones and two of the five PVDF hydrophones failed to meet the criteria.

Simulation studies of dual-energy x-ray absorptiometry.

Computer simulations were performed to predict the performance characteristics of dual-energy x-ray absorptiometry. K-edge filter techniques were analyzed in detail and compared to 153Gd sources in terms of output intensity, precision, patient dose, image contrast, beam hardening, and marrow fat effects. Similar analyses were performed for two dual-kV techniques that have been reported in the literature. The simulations indicate that K-edge filter techniques, or a dual-kV technique combined with K-edge filtering, can provide performance capabilities that equal or exceed those achievable with 153Gd systems. A (70/140) dual-kV technique with conventional (Al or Cu) filtration also has advantages in terms of source output intensity, but is 2-3 X inferior to the K-edge techniques and 153Gd in terms of patient dose and beam-hardening effects.