Src Dependent Pancreatic Acinar Injury Can Be Initiated Independent of an Increase in Cytosolic Calcium

Several deleterious intra-acinar phenomena are simultaneously triggered on initiating acute pancreatitis. These culminate in acinar injury or inflammatory mediator generation in vitro and parenchymal damage in vivo. Supraphysiologic caerulein is one such initiator which simultaneously activates numerous signaling pathways including non-receptor tyrosine kinases such as of the Src family. It also causes a sustained increase in cytosolic calcium- a player thought to be crucial in regulating deleterious phenomena. We have shown Src to be involved in caerulein induced actin remodeling, and caerulein induced changes in the Golgi and post-Golgi trafficking to be involved in trypsinogen activation, which initiates acinar cell injury. However, it remains unclear whether an increase in cytosolic calcium is necessary to initiate acinar injury or if injury can be initiated at basal cytosolic calcium levels by an alternate pathway. To study the interplay between tyrosine kinase signaling and calcium, we treated mouse pancreatic acinar cells with the tyrosine phosphatase inhibitor pervanadate. We studied the effect of the clinically used Src inhibitor Dasatinib (BMS-354825) on pervanadate or caerulein induced changes in Src activation, trypsinogen activation, cell injury, upstream cytosolic calcium, actin and Golgi morphology. Pervanadate, like supraphysiologic caerulein, induced Src activation, redistribution of the F-actin from its normal location in the sub-apical area to the basolateral areas, and caused antegrade fragmentation of the Golgi. These changes, like those induced by supraphysiologic caerulein, were associated with trypsinogen activation and acinar injury, all of which were prevented by Dasatinib. Interestingly, however, pervanadate did not cause an increase in cytosolic calcium, and the caerulein induced increase in cytosolic calcium was not affected by Dasatinib. These findings suggest that intra-acinar deleterious phenomena may be initiated independent of an increase in cytosolic calcium. Other players resulting in acinar injury along with the Src family of tyrosine kinases remain to be explored. © 2013 Mishra et al

Understanding older women's decision making and coping in the context of breast cancer treatment

Background: Primary endocrine therapy (PET) is a recognised alternative to surgery followed by endocrine therapy for a subset of older, frailer women with breast cancer. Choice of treatment is preference-sensitive and may require decision support. Older patients are often conceptualised as passive decision-makers. The present study used the Coping in Deliberation (CODE) framework to gain insight into decision making and coping processes in a group of older women who have faced breast cancer treatment decisions, and to inform the development of a decision support intervention (DSI). Methods: Semi-structured interviews were carried out with older women who had been offered a choice of PET or surgery from five UK hospital clinics. Women's information and support needs, their breast cancer diagnosis and treatment decisions were explored. A secondary analysis of these interviews was conducted using the CODE framework to examine women's appraisals of health threat and coping throughout the deliberation process. Results: Interviews with 35 women aged 75-98 years were analysed. Appraisals of breast cancer and treatment options were sometimes only partial, with most women forming a preference for treatment relatively quickly. However, a number of considerations which women made throughout the deliberation process were identified, including: past experiences of cancer and its treatment; scope for choice; risks, benefits and consequences of treatment; instincts about treatment choice; and healthcare professionals' recommendations. Women also described various strategies to cope with breast cancer and their treatment decisions. These included seeking information, obtaining practical and emotional support from healthcare professionals, friends and relatives, and relying on personal faith. Based on these findings, key questions were identified that women may ask during deliberation. Conclusions: Many older women with breast cancer may be considered involved rather than passive decision-makers, and may benefit from DSIs designed to support decision making and coping within and beyond the clinic setting

Pesticides and Parkinson’s Disease—Is There a Link?

Parkinson’s disease (PD) is an idiopathic disease of the nervous system characterized by progressive tremor, bradykinesia, rigidity, and postural instability. It has been postulated that exogenous toxicants, including pesticides, might be involved in the etiology of PD. In this article we present a comprehensive review of the published epidemiologic and toxicologic literature and critically evaluate whether a relationship exists between pesticide exposure and PD. From the epidemiologic literature, there does appear to be a relatively consistent relationship between pesticide exposure and PD. This relationship appears strongest for exposure to herbicides and insecticides, and after long durations of exposure. Toxicologic data suggest that paraquat and rotenone may have neurotoxic actions that potentially play a role in the development of PD, with limited data for other pesticides. However, both the epidemiology and toxicology studies were limited by methodologic weaknesses. Particular issues of current and future interest include multiple exposures (both pesticides and other exogenous toxicants), developmental exposures, and gene–environment interactions. At present, the weight of evidence is sufficient to conclude that a generic association between pesticide exposure and PD exists but is insufficient for concluding that this is a causal relationship or that such a relationship exists for any particular pesticide compound or combined pesticide and other exogenous toxicant exposure

Anion gap, anion gap corrected for albumin, base deficit and unmeasured anions in critically ill patients: implications on the assessment of metabolic acidosis and the diagnosis of hyperlactatemia

Abstract Background Base deficit (BD), anion gap (AG), and albumin corrected anion gap (ACAG) are used by clinicians to assess the presence or absence of hyperlactatemia (HL). We set out to determine if these tools can diagnose the presence of HL using cotemporaneous samples. Methods We conducted a chart review of ICU patients who had cotemporaneous arterial blood gas, serum chemistry, serum albumin (Alb) and lactate(Lac) levels measured from the same sample. We assessed the capacity of AG, BD, and ACAG to diagnose HL and severe hyperlactatemia (SHL). HL was defined as Lac > 2.5 mmol/L. SHL was defined as a Lac of > 4.0 mmol/L. Results From 143 patients we identified 497 series of lab values that met our study criteria. Mean age was 62.2 ± 15.7 years. Mean Lac was 2.11 ± 2.6 mmol/L, mean AG was 9.0 ± 5.1, mean ACAG was 14.1 ± 3.8, mean BD was 1.50 ± 5.4. The area under the curve for the ROC for BD, AG, and ACAG to diagnose HL were 0.79, 0.70, and 0.72, respectively. Conclusion AG and BD failed to reliably detect the presence of clinically significant hyperlactatemia. Under idealized conditions, ACAG has the capacity to rule out the presence of hyperlactatemia. Lac levels should be obtained routinely in all patients admitted to the ICU in whom the possibility of shock/hypoperfusion is being considered. If an AG assessment is required in the ICU, it must be corrected for albumin for there to be sufficient diagnostic utility.</p

Global analysis of gene expression in response to L-Cysteine deprivation in the anaerobic protozoan parasite Entamoeba histolytica

<p>Abstract</p> <p>Background</p> <p><it>Entamoeba histolytica</it>, an enteric protozoan parasite, causes amebic colitis and extra intestinal abscesses in millions of inhabitants of endemic areas. <it>E. histolytica </it>completely lacks glutathione metabolism but possesses L-cysteine as the principle low molecular weight thiol. L-Cysteine is essential for the structure, stability, and various protein functions, including catalysis, electron transfer, redox regulation, nitrogen fixation, and sensing for regulatory processes. Recently, we demonstrated that in <it>E. histolytica</it>, L-cysteine regulates various metabolic pathways including energy, amino acid, and phospholipid metabolism.</p> <p>Results</p> <p>In this study, employing custom-made Affymetrix microarrays, we performed time course (3, 6, 12, 24, and 48 h) gene expression analysis upon L-cysteine deprivation. We identified that out of 9,327 genes represented on the array, 290 genes encoding proteins with functions in metabolism, signalling, DNA/RNA regulation, electron transport, stress response, membrane transport, vesicular trafficking/secretion, and cytoskeleton were differentially expressed (≥3 fold) at one or more time points upon L-cysteine deprivation. Approximately 60% of these modulated genes encoded proteins of no known function and annotated as hypothetical proteins. We also attempted further functional analysis of some of the most highly modulated genes by L-cysteine depletion.</p> <p>Conclusions</p> <p>To our surprise, L-cysteine depletion caused only limited changes in the expression of genes involved in sulfur-containing amino acid metabolism and oxidative stress defense. In contrast, we observed significant changes in the expression of several genes encoding iron sulfur flavoproteins, a major facilitator super-family transporter, regulator of nonsense transcripts, NADPH-dependent oxido-reductase, short chain dehydrogenase, acetyltransferases, and various other genes involved in diverse cellular functions. This study represents the first genome-wide analysis of transcriptional changes induced by L-cysteine deprivation in protozoan parasites, and in eukaryotic organisms where L-cysteine represents the major intracellular thiol.</p

Repeatability of short-duration transient visual evoked potentials in normal subjects

To evaluate the within-session and inter-session repeatability of a new, short-duration transient visual evoked potential (SD-tVEP) device on normal individuals, we tested 30 normal subjects (20/20 visual acuity, normal 24-2 SITA Standard VF) with SD-tVEP. Ten of these subjects had their tests repeated within 1–2 months from the initial visit. Synchronized single-channel EEG was recorded using a modified Diopsys Enfant™ System (Diopsys, Inc., Pine Brook, New Jersey, USA). A checkerboard stimulus was modulated at two reversals per second. Two different contrasts of checkerboard reversal patterns were used: 85% Michelson contrast with a mean luminance of 66.25 cd/m2 and 10% Michelson contrast with a mean luminance of 112 cd/m2. Each test lasted 20 s. Both eyes, independently and together, were tested 10 times (5 times at each contrast level). The following information was identified from the filtered N75-P100-N135 complex: N75 amplitude, N75 latency, P100 amplitude, P100 latency, and Delta Amplitude (N75-P100). The median values for each eye’s five SD-tVEP parameters were calculated and grouped into two data sets based on contrast level. Mean age was 27.3 ± 5.2 years. For OD only, the median (95% confidence intervals) of Delta Amplitude (N75-P100) amplitudes at 10% and 85% contrast were 4.6 uV (4.1–5.9) and 7.1 uV (5.15–9.31). The median P100 latencies were 115.2 ms (112.0–117.7) and 104.0 ms (99.9–106.0). There was little within-session variability for any of these parameters. Intraclass correlation coefficients ranged between 0.64 and 0.98, and within subject coefficients of variation were 3–5% (P100 latency) and 15–30% (Delta Amplitude (N75-P100) amplitude). Bland–Altman plots showed good agreement between the first and fifth test sessions (85% contrast Delta Amplitude (N75-P100) delta amplitude, mean difference, 0.48 mV, 95% CI, −0.18–1.12; 85% contrast P100 latency delay, −0.82 ms, 95% CI, −3.12–1.46; 10% contrast Delta Amplitude (N75-P100) amplitude, 0.58 mV, 95% CI, −0.27–1.45; 10% contrast P100 latency delay, −2.05 mV, 95% CI, −5.12–1.01). The inter-eye correlation and agreement were significant for both SD-tVEP amplitude and P100 latency measurements. For the subset of eyes in which the inter-session repeatability was tested, the intraclass correlation coefficients ranged between 0.71 and 0.86 with good agreement shown on Bland–Altman plots. Short-duration transient VEP technology showed good within-session, inter-session repeatability, and good inter-eye correlation and agreement

Development of a Management Algorithm for Post-operative Pain (MAPP) after total knee and total hip replacement: study rationale and design.

BACKGROUND: Evidence from clinical practice and the extant literature suggests that post-operative pain assessment and treatment is often suboptimal. Poor pain management is likely to persist until pain management practices become consistent with guidelines developed from the best available scientific evidence. This work will address the priority in healthcare of improving the quality of pain management by standardising evidence-based care processes through the incorporation of an algorithm derived from best evidence into clinical practice. In this paper, the methodology for the creation and implementation of such an algorithm that will focus, in the first instance, on patients who have undergone total hip or knee replacement is described. METHODS: In partnership with clinicians, and based on best available evidence, the aim of the Management Algorithm for Post-operative Pain (MAPP) project is to develop, implement, and evaluate an algorithm designed to support pain management decision-making for patients after orthopaedic surgery. The algorithm will provide guidance for the prescription and administration of multimodal analgesics in the post-operative period, and the treatment of breakthrough pain. The MAPP project is a multisite study with one coordinating hospital and two supporting (rollout) hospitals. The design of this project is a pre-implementation-post-implementation evaluation and will be conducted over three phases. The Promoting Action on Research Implementation in Health Services (PARiHS) framework will be used to guide implementation. Outcome measurements will be taken 10 weeks post-implementation of the MAPP. The primary outcomes are: proportion of patients prescribed multimodal analgesics in accordance with the MAPP; and proportion of patients with moderate to severe pain intensity at rest. These data will be compared to the pre-implementation analgesic prescribing practices and pain outcome measures. A secondary outcome, the efficacy of the MAPP, will be measured by comparing pain intensity scores of patients where the MAPP guidelines were or were not followed. DISCUSSION: The outcomes of this study have relevance for nursing and medical professionals as well as informing health service evaluation. In establishing a framework for the sustainable implementation and evaluation of a standardised approach to post-operative pain management, the findings have implications for clinicians and patients within multiple surgical contexts

Older women, breast cancer, and social support

One in ten women over the age of 65 will develop breast cancer. Despite this high incidence of breast cancer among older women, social support for them is often inadequate. This paper describes a qualitative study of the impact of a breast cancer diagnosis on older women from racially/ethnically diverse populations and their subsequent need for social support. Forty-seven older African American, Asian American, Caucasian and Latina women between the ages of 65 to 83 participated in a larger study examining the impact of breast cancer on women from racially/ethnically diverse populations and the meaning and nature of social support. The women completed an in-depth qualitative interview on the psychosocial impact of breast cancer and the meaning and nature of social support. The results indicate that there are variations in reactions to a breast cancer diagnosis among older women, and that these reactions impact their experiences with seeking social support at diagnosis and during treatment. Respondents were concerned about their aging bodies, potential dependency on others, and loss of autonomy. At the same time, the severity of cancer treatment and existing co-morbidities often meant they needed to learn to receive support, and to reach out if they had no support. The implications of these findings underscore the older cancer patient’s need to strengthen her supportive networks at the time of diagnosis, during treatment, and post-treatment