Increased Expression of Interleukin-6 Family Members and Receptors in Urinary Bladder with Cyclophosphamide-Induced Bladder Inflammation in Female Rats

Recent studies suggest that janus-activated kinases–signal transducer and activator of transcription signaling pathways contribute to increased voiding frequency and referred pain of cyclophosphamide (CYP)-induced cystitis in rats. Potential upstream chemical mediator(s) that may be activated by CYP-induced cystitis to stimulate JAK/STAT signaling are not known in detail. In these studies, members of the interleukin (IL)-6 family of cytokines including, leukemia inhibitory factor (LIF), IL-6, and ciliary neurotrophic factor (CNTF) and associated receptors, IL-6 receptor (R) α, LIFR, and gp130 were examined in the urinary bladder in control and CYP-treated rats. Cytokine and receptor transcript and protein expression and distribution were determined in urinary bladder after CYP-induced cystitis using quantitative, real-time polymerase chain reaction (Q-PCR), western blotting, and immunohistochemistry. Acute (4 h; 150 mg/kg; i.p.), intermediate (48 h; 150 mg/kg; i.p.), or chronic (75 mg/kg; i.p., once every 3 days for 10 days) cystitis was induced in adult, female Wistar rats with CYP treatment. Q-PCR analyses revealed significant (p ≤ 0.01) CYP duration- and tissue- (e.g., urothelium, detrusor) dependent increases in LIF, IL-6, IL-6Rα, LIFR, and gp130 mRNA expression. Western blotting demonstrated significant (p ≤ 0.01) increases in IL-6, LIF, and gp130 protein expression in whole urinary bladder with CYP treatment. CYP-induced cystitis significantly (p ≤ 0.01) increased LIF-immunoreactivity (IR) in urothelium, detrusor, and suburothelial plexus whereas increased gp130-IR was only observed in urothelium and detrusor. These studies suggest that IL-6 and LIF may be potential upstream chemical mediators that activate JAK/STAT signaling in urinary bladder pathways

The Ursinus Weekly, May 21, 1909

Brotherhood of St. Paul fletcherizes • Buffalo Bill in Philadelphia • Malcolm Shackelford entertains audience • Glee club • Lecture • Baseball • Ursinus Union • Tennis tournament • Society notes • Alumni notes • Personals • Field house fund • Literary Supplement: A day in May; The power of sentiment; A generation of vipers; Literary criticism on Tolstoy; The power of ideas; Money and hypocrisyhttps://digitalcommons.ursinus.edu/weekly/2873/thumbnail.jp

The Arp2/3 complex is essential for the actin-based motility of Listeria monocytogenes

AbstractActin polymerisation is thought to drive the movement of eukaryotic cells and some intracellular pathogens such as Listeria monocytogenes. The Listeria surface protein ActA synergises with recruited host proteins to induce actin polymerisation, propelling the bacterium through the host cytoplasm [1]. The Arp2/3 complex is one recruited host factor [2,3]; it is also believed to regulate actin dynamics in lamellipodia [4,5]. The Arp2/3 complex promotes actin filament nucleation in vitro, which is further enhanced by ActA [6,7]. The Arp2/3 complex also interacts with members of the Wiskott–Aldrich syndrome protein (WASP) [8] family – Scar1 [9,10] and WASP itself [11]. We interfered with the targeting of the Arp2/3 complex to Listeria by using carboxy-terminal fragments of Scar1 that bind the Arp2/3 complex [11]. These fragments completely blocked actin tail formation and motility of Listeria, both in mouse brain extract and in Ptk2 cells overexpressing Scar1 constructs. In both systems, Listeria could initiate actin cloud formation, but tail formation was blocked. Full motility in vitro was restored by adding purified Arp2/3 complex. We conclude that the Arp2/3 complex is a host-cell factor essential for the actin-based motility of L. monocytogenes, suggesting that it plays a pivotal role in regulating the actin cytoskeleton

Joint MiRNA/mRNA expression profiling reveals rhanges consistent with development of dysfunctional corpus luteum after weight gain

<div><p>Obese women exhibit decreased fertility, high miscarriage rates and dysfunctional corpus luteum (CL), but molecular mechanisms are poorly defined. We hypothesized that weight gain induces alterations in CL gene expression. RNA sequencing was used to identify changes in the CL transcriptome in the vervet monkey (<i>Chlorocebus aethiops</i>) during weight gain. 10 months of high-fat, high-fructose diet (HFHF) resulted in a 20% weight gain for HFHF animals vs. 2% for controls (p = 0.03) and a 66% increase in percent fat mass for HFHF group. Ovulation was confirmed at baseline and after intervention in all animals. CL were collected on luteal day 7–9 based on follicular phase estradiol peak. 432 mRNAs and 9 miRNAs were differentially expressed in response to HFHF diet. Specifically, miR-28, miR-26, and let-7b previously shown to inhibit sex steroid production in human granulosa cells, were up-regulated. Using integrated miRNA and gene expression analysis, we demonstrated changes in 52 coordinately regulated mRNA targets corresponding to opposite changes in miRNA. Specifically, 2 targets of miR-28 and 10 targets of miR-26 were down-regulated, including genes linked to follicular development, steroidogenesis, granulosa cell proliferation and survival. To the best of our knowledge, this is the first report of dietary-induced responses of the ovulating ovary to developing adiposity. The observed HFHF diet-induced changes were consistent with development of a dysfunctional CL and provide new mechanistic insights for decreased sex steroid production characteristic of obese women. MiRNAs may represent novel biomarkers of obesity-related subfertility and potential new avenues for therapeutic intervention.</p></div

Census 2010 Demographic Profile: Jefferson County

This demographic profile describes characteristics of the local and state population based on results from the 2010 Census. The decennial census is an official enumeration, or count, of all residents on April 1st of the census year. The results of the census provide us with information about basic demographic characteristics of the population, including age, race, ethnicity, household composition, housing occupancy, and housing tenure

A coronary heart disease risk model for predicting the effect of potent antiretroviral therapy in HIV-1 infected men

Background Many HIV-infected patients on highly active antiretroviral therapy (HAART) experience metabolic complications including dyslipidaemia and insulin resistance, which may increase their coronary heart disease (CHD) risk. We developed a prognostic model for CHD tailored to the changes in risk factors observed in patients starting HAART. Methods Data from five cohort studies (British Regional Heart Study, Caerphilly and Speedwell Studies, Framingham Offspring Study, Whitehall II) on 13 100 men aged 40-70 and 114 443 years of follow up were used. CHD was defined as myocardial infarction or death from CHD. Model fit was assessed using the Akaike Information Criterion; generalizability across cohorts was examined using internal-external cross-validation. Results A parametric model based on the Gompertz distribution generalized best. Variables included in the model were systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, triglyceride, glucose, diabetes mellitus, body mass index and smoking status. Compared with patients not on HAART, the estimated CHD hazard ratio (HR) for patients on HAART was 1.46 (95% CI 1.15-1.86) for moderate and 2.48 (95% CI 1.76-3.51) for severe metabolic complications. Conclusions The change in the risk of CHD in HIV-infected men starting HAART can be estimated based on typical changes in risk factors, assuming that HRs estimated using data from non-infected men are applicable to HIV-infected men. Based on this model the risk of CHD is likely to increase, but increases may often be modest, and could be offset by lifestyle change

Mortality According to CD4 Count at Start of Combination Antiretroviral Therapy Among HIV-infected Patients Followed for up to 15 Years After Start of Treatment: Collaborative Cohort Study.

BACKGROUND: CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. METHODS: We estimated mortality rates (MRs) by time since start of ART (&lt;0.5, 0.5-0.9, 1-2.9, 3-4.9, 5-9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996-2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996-1997, 1998-1999, 2000-2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0-49, 50-99, 100-199, 200-349, 350-499, ≥500 cells/µL) overall and separately according to time since start of ART. RESULTS: A total of 6344 of 37 496 patients died during 359 219 years of follow-up. The MR per 1000 person-years was 32.8 (95% confidence interval [CI], 30.2-35.5) during the first 6 months, declining to 16.0 (95% CI, 15.4-16.8) during 5-9.9 years and 14.2 (95% CI, 13.3-15.1) after 10 years' duration of ART. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. The adjusted MRR per CD4 group was 0.97 (95% CI, .94-1.00; P = .054) and 1.02 (95% CI, .98-1.07; P = .32) among patients followed for 5-9.9 and ≥10 years, respectively. CONCLUSIONS: After surviving 5 years of ART, the mortality of patients who started ART with low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts

Comparative Prognostic Utility of Indexes of Microvascular Function Alone or in Combination in Patients with an Acute ST-Segment-Elevation Myocardial Infarction

Background—Primary percutaneous coronary intervention (PCI) is frequently successful at restoring coronary artery blood flow in patients with acute ST-segment elevation myocardial infarction, however, failed myocardial reperfusion commonly passes undetected in up to half of these patients. The index of microvascular resistance (IMR) is a novel invasive measure of coronary microvascular function. We aimed to investigate the pathological and prognostic significance of an index of microvascular resistance (IMR&gt;40), alone or in combination with a coronary flow reserve (CFR≤2.0), in the culprit artery after emergency PCI for acute STEMI. Methods—Patients with acute STEMI were prospectively enrolled during emergency PCI, and categorized according to IMR (≤40 or &gt;40) and CFR (≤2.0 or &gt;2.0). Cardiac MRI was acquired 2 days and 6 months post-MI. All-cause death or first heart failure hospitalization was a pre-specified outcome (median follow-up duration 845 days). Results—IMR and CFR were measured in the culprit artery at the end of PCI in 283 STEMI patients (mean age 60 (12) years, 73% male). The median [interquartile range] IMR and CFR were 25 [15-48] and 1.6 [1.1-2.1], respectively. An IMR&gt;40 was a multivariable associate of myocardial hemorrhage (odds ratio (OR) (95% confidence interval (CI)) 2.10 (1.03, 4.27); p=0.042. An IMR&gt;40 was closely associated with microvascular obstruction. Symptom to reperfusion time, TIMI blush grade, and no (≤30%) ST segment resolution, were not associated with these pathologies. An IMR&gt;40 was a multivariable associate of the changes in LV ejection fraction (coefficient (95% CI) (-2.12 (-4.02, -0.23); p=0.028) and LV end-diastolic volume (7.85 (0.41, 15.29); p=0.039) at 6 months, independent of infarct size. An IMR&gt;40 (odds ratio 4.36 (95% CI 2.10, 9.06); p&lt;0.001) was a multivariable associate of all-cause death or heart failure. Compared with an IMR&gt;40, the combination of IMR&gt;40 with CFR≤2.0 did not have incremental prognostic value. Conclusions—An IMR&gt;40 is a multivariable associate of LV and clinical outcomes post-STEMI, independent of the size of infarction. Compared with standard clinical measures of the efficacy of myocardial reperfusion, including the ischemic time, ST-segment elevation, the angiographic blush grade and CFR, IMR has superior clinical value for risk stratification and may be considered as a reference test for failed myocardial reperfusion

Coronary thermodilution waveforms after acute reperfused stsegment-elevation myocardial infarction:Relation to microvascular obstruction and prognosis

Background: Invasive measures of microvascular resistance in the culprit coronary artery have potential for risk stratification in acute ST‐segment–elevation myocardial infarction. We aimed to investigate the pathological and prognostic significance of coronary thermodilution waveforms using a diagnostic guidewire. Methods and Results: Coronary thermodilution was measured at the end of percutaneous coronary intervention, (PCI) and contrast‐enhanced cardiac magnetic resonance imaging (MRI) was intended on day 2 and 6 months later to assess left ventricular (LV) function and pathology. All‐cause death or first heart failure hospitalization was a pre‐specified outcome (median follow‐up duration 1469 days). Thermodilution recordings underwent core laboratory assessment. A total of 278 patients with acute ST‐segment elevation myocardial infarction EMI (72% male, 59±11 years) had coronary thermodilution measurements classified as narrow unimodal (n=143 [51%]), wide unimodal (n=100 [36%]), or bimodal (n=35 [13%]). Microvascular obstruction and myocardial hemorrhage were associated with the thermodilution waveform pattern (P=0.007 and 0.011, respectively), and both pathologies were more prevalent in patients with a bimodal morphology. On multivariate analysis with baseline characteristics, thermodilution waveform status was a multivariable associate of microvascular obstruction (odds ratio [95% confidence interval]=5.29 [1.73, 16.22];, P=0.004) and myocardial hemorrhage (3.45 [1.16, 10.26]; P=0.026), but the relationship was not significant when index of microvascular resistance (IMR) &gt;40 or change in index of microvascular resistance (5 per unit) was included. However, a bimodal thermodilution waveform was independently associated with all‐cause death and hospitalization for heart failure (odds ratio [95% confidence interval]=2.70 [1.10, 6.63]; P=0.031), independent of index of microvascular resistance&gt;40, ST‐segment resolution, and TIMI (Thrombolysis in Myocardial Infarction) Myocardial Perfusion Grade. Conclusions: The thermodilution waveform in the culprit coronary artery is a biomarker of prognosis and may be useful for risk stratification immediately after reperfusion therapy