Regulation of Estradiol Synthesis by Aromatase Interacting Partner in Breast (AIPB).

Estradiol is essential for the development of female sex characteristics and fertility. Postmenopausal women and breast cancer patients have high levels of estradiol. Aromatase catalyzes estradiol synthesis; however, the factors regulating aromatase activity are unknown. We identified a new 22-kDa protein, aromatase interacting partner in breast (AIPB), from the endoplasmic reticulum of human breast tissue. AIPB expression is reduced in tumorigenic breast and further reduced in triple-negative tumors. Like that of aromatase, AIPB expression is induced by nonsteroidal estrogen. We found that AIPB and aromatase interact in nontumorigenic and tumorigenic breast tissues and cells. In tumorigenic cells, conditional AIPB overexpression decreased estradiol, and blocking AIPB availability with an AIPB-binding antibody increased estradiol. Estradiol synthesis is highly increased in AIPB knockdown cells, suggesting that the newly identified AIPB protein is important for aromatase activity and a key modulator of estradiol synthesis. Thus, a change in AIPB protein expression may represent an early event in tumorigenesis and be predictive of an increased risk of developing breast cancer.

Trends and Characteristics of CDC Global Rapid Response Team Deployments-A 6-Month Report, October 2018-March 2019.

The Centers for Disease Control and Prevention (CDC) Global Rapid Response Team (GRRT) was launched in June 2015 to strengthen the capacity for international response and to provide an agency-wide roster of qualified surge-staff members who can deploy on short notice and for long durations. To assess GRRT performance and inform future needs for CDC and partners using rapid response teams, we analyzed trends and characteristics of GRRT responses and responders, for deployments of at least 1 day during October 1, 2018, through March 31, 2019. One hundred twenty deployments occurred during the study period, corresponding to 2645 person-days. The median deployment duration was 19 days (interquartile range, 5-30 days). Most deployments were related to emergency response (n = 2367 person-days, 90%); outbreaks of disease accounted for almost all deployment time (n = 2419 person-days, 99%). Most deployments were to Africa (n = 1417 person-days, 54%), and epidemiologists were the most commonly deployed technical advisors (n = 1217 person-days, 46%). This case study provides useful information for assessing program performance, prioritizing resource allocation, informing future needs, and sharing lessons learned with other programs managing rapid response teams. GRRT has an important role in advancing the global health security agenda and should continuously be assessed and adjusted to new needs.

The effect of obesity on the rate of heparin-induced thrombocytopenia.

: Heparin-induced thrombocytopenia (HIT) occurs in patients receiving heparin-containing products due to the formation of platelet-activating antibodies to heparin and platelet factor 4. Diagnosis includes utilization of a scoring system known as the 4-T score, and HIT laboratory assays. Recently, obesity was identified as a potential factor associated with the development of HIT. The objective of this study was to evaluate the association of HIT with obesity in ICU and general medicine patients. We performed a chart review of adult patients within the Methodist Healthcare System, and included patients who had an ELISA and serotonin release assay laboratory tests reported within same hospital admission in which they also had documented receipt of heparin. Obese patients were compared with nonobese patients (BMI < 30) for the primary outcome of HIT occurrence, and secondary outcomes including rate of thrombosis, 4-T scores, and ELISA optical density values. We also generated a 5-T score by including one additional point for those with a BMI of 30 or more to determine the predictive value of this score in identifying HIT. Obesity was confirmed to be a risk factor for HIT, and the 5-T score model was also predictive of the development of HIT. However, the 5-T score was not statistically more predictive of HIT than the 4-T score. Predicting HIT remains challenging and novel markers of HIT are needed to improve HIT recognition. Although obesity did not improve the 4-T score, it may improve the predictability of other scoring systems, and further investigation is warranted.

Electrocardiographic artifact potentially misleading to the wrong management.

Atrial flutter (AF) is the second most common supraventricular tachyarrhythmia following atrial fibrillation. We present an interesting case of a diagnostic challenge manifested as an electrocardiogram (ECG) recording mimicking AF in a patient with Parkinson's disease (PD). A 72-year-old African-American female with history of PD presented to our Emergency Department with a one day history of chest pain. Her vital signs were within normal limits. Physical exam was remarkable for bilateral resting hand tremors at a frequency of 6-8 hertz and mild cogwheel rigidity in both upper extremities. Initial ECG was interpreted as AF prompting admission. After careful review of her ECG by a cardiologist, several features such as, sharply contoured upright p waves in all leads, different flutter wave morphologies in the same leads, more prominence of "pseudo-flutter" waves in the limb leads compared to the precordial leads, and return to isoelectric baseline after sharp peaked p waves, questioned the diagnosis of AF. A repeat 12 lead ECG clearly demonstrated normal sinus rhythm, and the patient remained completely asymptomatic throughout the stay. A 48-hour Holter monitoring in the clinic later confirmed consistent sinus rhythm with no evidence of any arrhythmias Tremor induced artifacts can be mistaken for arrhythmias. Correct and accurate diagnosis is critically important, in order to avoid wrong treatment and unnecessary interventions. Our case illustrates the importance of recognizing artifact related ECG changes to prevent unnecessary treatment and hospital admissions.

Breast cancer patient with everolimus-induced angioedema: A rare occurrence with potential for serious consequences.

Background The development of angioedema is a rare yet serious clinical event that may develop due to an adverse drug reaction. Rapid recognition and treatment of this adverse reaction is critical for optimal patient outcomes; however, prevention of this occurrence is preferred. Case report A 59-year-old woman presented to the emergency department with lingual angioedema caused by the addition of everolimus to her medication regimen. The patient improved after withdrawal of the offending agent and standard treatment. Early recognition by healthcare providers and management of everolimus-induced angioedema is vital for successful patient outcomes. This report increases awareness of everolimus as a potentially causative agent for the development of angioedema.

Effectiveness of insecticide-treated bednets in malaria prevention in Haiti: a case-control study.

BACKGROUND: Insecticide-treated bednets (ITNs) are effective in preventing malaria where vectors primarily bite indoors and late at night, but their effectiveness is uncertain where vectors bite outdoors and earlier in the evening. We studied the effectiveness of ITNs following a mass distribution in Haiti from May to September, 2012, where the Anopheles albimanus vector bites primarily outdoors and often when people are awake. METHODS: In this case-control study, we enrolled febrile patients presenting to outpatient departments at 17 health facilities throughout Haiti from Sept 4, 2012, to Feb 27, 2014, who were tested with malaria rapid diagnostic tests (RDTs), and administered questionnaires on ITN use and other risk factors. Cases were defined by positive RDT and controls were febrile patients from the same clinic with a negative RDT. Our primary analysis retrospectively matched cases and controls by age, sex, location, and date, and used conditional logistic regression on the matched sample. A sensitivity analysis used propensity scores to match patients on ITN use propensity and analyse malaria among ITN users and non-users. Additional ITN bioefficacy and entomological data were collected. FINDINGS: We enrolled 9317 patients, including 378 (4%) RDT-positive cases. 1202 (13%) patients reported ITN use. Post-hoc matching of cases and controls yielded 362 cases and 1201 matched controls, 19% (333) of whom reported consistent campaign net use. After using propensity scores to match on consistent campaign ITN use, 2298 patients, including 138 (7%) RDT-positive cases, were included: 1149 consistent campaign ITN users and 1149 non-consistent campaign ITN users. Both analyses revealed that ITNs did not significantly protect against clinical malaria (odds ratio [OR]=0·95, 95% CI 0·68-1·32, p=0·745 for case-control analysis; OR=0·95, 95% CI 0·45-1·97, p=0·884 for propensity score analysis). ITN and entomological data indicated good ITN physical integrity and bioefficacy, and no permethrin resistance among local mosquitoes. INTERPRETATION: We found no evidence that mass ITN campaigns reduce clinical malaria in this observational study in Haiti; alternative malaria control strategies should be prioritised. FUNDING: The Global Fund to Fight AIDS, Tuberculosis, and Malaria, and the US-based Centers for Disease Control and Prevention (CDC).

A multidisciplinary initiative to standardize intensive care to acute care transitions.

QUALITY ISSUE: Transfers from intensive care units to acute care units represent a complex care transition for hospitalized patients. Within our institution, variation in transfer practices resulted in unpredictable processes in which patient safety concerns were raised. INITIAL ASSESSMENT: Key stakeholders were engaged across the institution. Patient safety ('incident') reports and a staff survey identified safety concerns. CHOICE OF A SOLUTION: Using lean methodology, current transfer processes were mapped for the four adult intensive care units and waste was identified. During a summit of key stakeholders an ideal transfer process was conceived and a structured handoff tool (checklist) was developed. A daily management system (DMS) was implemented to monitor adherence. EVALUATION: The primary process outcome was adherence to the standardized workflow. Audits at 4, 8, and 12 months after implementation indicated that the checklist was used for 100% of transfers. Secondary outcomes included the percentage of transfers completed within a pre-specified time window of 120 minutes, provider notification of patient arrival on the acute care unit, and staff survey responses assessing adequacy of transfer communication. LESSONS LEARNED: Prior work has shown that structuring handoffs can improve patient safety, but the novelty of this project was addressing the transfer process in its entirety, across silos of care. Factors leading to the success of this project were the involvement of key stakeholders across the entire institution early in the project development phase, employment of lean methodology, and implementation of tools to guide workflow adherence and track causes of deviation from the workflow.

Developmentally regulated ceramide synthase 6 increases mitochondrial Ca2+ loading capacity and promotes apoptosis.

Ceramides, which are membrane sphingolipids and key mediators of cell-stress responses, are generated by a family of (dihydro) ceramide synthases (Lass1-6/CerS1-6). Here, we report that brain development features significant increases in sphingomyelin, sphingosine, and most ceramide species. In contrast, C(16:0)-ceramide was gradually reduced and CerS6 was down-regulated in mitochondria, thereby implicating CerS6 as a primary ceramide synthase generating C(16:0)-ceramide. Investigations into the role of CerS6 in mitochondria revealed that ceramide synthase down-regulation is associated with dramatically decreased mitochondrial Ca(2+)-loading capacity, which could be rescued by addition of ceramide. Selective CerS6 complexing with the inner membrane component of the mitochondrial permeability transition pore was detected by immunoprecipitation. This suggests that CerS6-generated ceramide could prevent mitochondrial permeability transition pore opening, leading to increased Ca(2+) accumulation in the mitochondrial matrix. We examined the effect of high CerS6 expression on cell survival in primary oligodendrocyte (OL) precursor cells, which undergo apoptotic cell death during early postnatal brain development. Exposure of OLs to glutamate resulted in apoptosis that was prevented by inhibitors of de novo ceramide biosynthesis, myriocin and fumonisin B1. Knockdown of CerS6 with siRNA reduced glutamate-triggered OL apoptosis, whereas knockdown of CerS5 had no effect: the pro-apoptotic role of CerS6 was not stimulus-specific. Knockdown of CerS6 with siRNA improved cell survival in response to nerve growth factor-induced OL apoptosis. Also, blocking mitochondrial Ca(2+) uptake or decreasing Ca(2+)-dependent protease calpain activity with specific inhibitors prevented OL apoptosis. Finally, knocking down CerS6 decreased calpain activation. Thus, our data suggest a novel role for CerS6 in the regulation of both mitochondrial Ca(2+) homeostasis and calpain, which appears to be important in OL apoptosis during brain development.

Interactive computer-based simulator for training in blade navigation and targeting in myringotomy.

A virtual-reality simulator was developed for the training of Otolaryngology (Ear-Nose-Throat) surgical residents to perform myringotomy, a relatively common surgical procedure in which an incision is made in the eardrum mainly to treat middle-ear infections. The simulator presents the trainee with a three-dimensional (3D) virtual model of the ear that can be viewed through a mock surgical microscope consisting of a stereo visor mounted on a custom-designed stand. The trainee interacts with the virtual ear using a real myringotomy blade, the movements of which are tracked in real time using a stereo optical tracker. Interactions of the blade with virtual tissues are calculated and rendered on the visor using freely available physics and graphics software engines. Six experienced surgical residents and surgeons assessed the effectiveness of the simulator as a viable training tool by completing a questionnaire designed specifically for this study after using the simulator. Surgeons and residents were positively impressed by the simulator as a training tool and would recommend its use as part of training.

Integrin-associated Lyn kinase promotes cell survival by suppressing acid sphingomyelinase activity.

Integrins govern cellular adhesion and transmit signals leading to activation of intracellular signaling pathways aimed to prevent apoptosis. Herein we report that attachment of oligodendrocytes (OLs) to fibronectin via alpha(v)beta(3) integrin receptors rendered the cells more resistant to apoptosis than the cells attached to laminin via alpha(6)beta(1) integrins. Investigation of molecular mechanisms involved in alpha(v)beta(3) integrin-mediated cell survival revealed that ligation of the integrin with fibronectin results in higher expression of activated Lyn kinase. Both in OLs and in the mouse brain, Lyn selectively associates with alpha(v)beta(3) integrin, not with alpha(v)beta(5) integrin, leading to suppression of acid sphingomyelinase activity and preventing ceramide-mediated apoptosis. In OLs, knockdown of Lyn with small interfering RNA resulted in OL apoptosis with concomitant accumulation of C(16)-ceramide due to activation of acid sphingomyelinase (ASMase) and sphingomyelin hydrolysis. Knocking down ASMase partially protected OLs from apoptosis. In the brain, ischemia/reperfusion (IR) triggered rearrangements in the alpha(v)beta(3) integrin-Lyn kinase complex leading to disruption of Lyn kinase-mediated suppression of ASMase activity. Thus, co-immunoprecipitation studies revealed an increased association of alpha(v)beta(3) integrin-Lyn kinase complex with ionotropic glutamate receptor subunits, GluR2 and GluR4, after cerebral IR. Sphingolipid analysis of the brain demonstrated significant accumulation of ceramide and sphingomyelin hydrolysis. The data suggest a novel mechanism for regulation of ASMase activity during cell adhesion in which Lyn acts as a key upstream kinase that may play a critical role in cerebral IR injury.