Functional characterization of tissue inhibitor of metalloproteinase-1 (TIMP-1) N- and C-terminal domains during xenopus laevis development

Extracellular matrix (ECM) remodeling is essential for facilitating developmental processes. ECM remodeling, accomplished by matrix metalloproteinases (MMPs), is regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). While the TIMP N-terminal domain is involved in inhibition of MMP activity, the C-terminal domain exhibits cell-signaling activity, which is TIMP and cell type dependent. We have previously examined the distinct roles of the Xenopus laevis TIMP-2 and -3 C-terminal domains during development and here examined the unique roles of TIMP-1 N- and C-terminal domains in early X. laevis embryos. mRNA microinjection was used to overexpress full-length TIMP-1 or its individual N- or C-terminal domains in embryos. Full-length and C-terminal TIMP-1 resulted in increased lethality compared to N-terminal TIMP-1. Overexpression of C-terminal TIMP-1 resulted in significant decreases in mRNA levels of proteolytic genes including TIMP-2, RECK, MMP-2, and MMP-9, corresponding to decreases in MMP-2 and -9 protein levels, as well as decreased MMP-2 and MMP-9 activities. These trends were not observed with the N-terminus. Our research suggests that the individual domains of TIMP-1 are capable of playing distinct roles in regulating the ECM proteolytic network during development and that the unique functions of these domains are moderated in the endogenous full-length TIMP-1 molecule. © 2014 M. A. Nieuwesteeg et al

Colitis linfoplasmocitaria canina : un hallazgo frecuente en la exploración colonoscópica

En este trabajo se describen los hallazgos clínicos, laboratoriales y colonoscópicos de la colitis linfoplasmocitaria canina, aparte de tratar los aspectos más relevantes sobre su etiopatogenia y diagnóstico, para describir finalmente las pautas de tratamiento del proceso

Stable expression of α1-antitrypsin Portland in MDA-MB-231 cells increased MT1-MMP and MMP-9 levels, but reduced tumour progression.

The membrane bound matrix metalloproteinase MT1-MMP plays roles in modulating cell movement, independent of its abilities to remodel the extracellular matrix. Unlike many MMPs, MT1-MMP is activated in the Golgi prior to secretion by a pro-protein convertase, primarily furin. Regulation of the activation of pro-MT1-MMP has been methodically investigated, as altering the level of the active protein has broad implications in both activating other proMMPs, including pro-MMP-2, and many subsequent remodelling events. Our previous work in MCF-7 cells has demonstrated that modest, and not extremely high, levels of active MT1-MMP manifests into altered cell morphology and movement. At this low but optimal amount of MT1-MMP protein, changes to MT1-MMP levels are always mirrored by MMP-9 and pERK levels, and always opposite to MMP-2 levels. In this study, stable expression of the furin inhibitor α1- antitrypsin Portland (α1-PDX) in MDA-MB-231 cells increased overall MT1-MMP levels, but cells maintained a 21% proportion of pro-MT1-MMP. The increase in MT1- MMP was mirrored by increases in MMP-9 and pERK, but a decrease in MMP-2. These changes were associated with increased NF-κB transcription. In vitro analysis showed that α1-PDX decreased cell protrusions and migration, and this manifested as decreased tumourigenesis when examined in vivo using a chick CAM assay

Cabin-fuselage-wing structural design concept with engine installation

The purpose of this project is to provide a fuselage structural assembly and wing structural design that will be able to withstand the given operational parameters and loads provided by Federal Aviation Regulation Part 23 (FAR 23) and the Statement of Work (SOW). The goal is to provide a durable lightweight structure that will transfer the applied loads through the most efficient load path. Areas of producibility and maintainability of the structure will also be addressed. All of the structural members will also meet or exceed the desired loading criteria, along with providing adequate stiffness, reliability, and fatigue life as stated in the SOW. Considerations need to be made for control system routing and cabin heating/ventilation. The goal of the wing structure and carry through structure is also to provide a simple, lightweight structure that will transfer the aerodynamic forces produced by the wing, tailboom, and landing gear. These forces will be channeled through various internal structures sized for the pre-determined loading criteria. Other considerations were to include space for flaps, ailerons, fuel tanks, and electrical and control system routing. The difficulties encountered in the fuselage design include expanding the fuselage cabin to accept a third occupant in a staggered configuration and providing ample volume for their safety. By adding a third person the CG of aircraft will move forward so the engine needs to be moved aft to compensate for the difference in the moment. This required the provisions of a ring frame structure for the new position of the engine mount. The difficulties encountered in the wing structural design include resizing the wing for the increased capacity and weight, and compensating for a large torsion produced by the tail boom by placing a great number of stiffeners inside the boom, which will result in the relocation of the fuel tank. Finally, an adequate carry through structure for the wing and fuselage interface will be designed to effectively transmit loads through the fuselage

Project Reach: Implementation of Evidence-Based Psychotherapy Within Integrated Healthcare for Hurricane Harvey Affected Individuals

Project Reach was established to deliver evidence-based mental healthcare services to children and adults affected by Hurricane Harvey and its aftermath. Through Project Reach, an innovative multi-component assessment and treatment service is utilized to identify and treat in integrated healthcare settings both children and adults exhibiting significant behavioral health concerns in Houston. The aim is to provide sustainable, integrated mental health services through primary care and school-based settings to post-Harvey affected individuals whose emotional needs remain unmet. This paper describes the design and implementation of Project Reach as well as special considerations for implementation. The overall goal of Project Reach is to form a platform for expanding integrated services for those affected by Harvey that will maximize behavioral health outcomes while reducing cost and improving access

Spontaneous intratumoral bleeding and rupture of giant gastric stromal tumor (> 30 cm) in a young patient

<p>Abstract</p> <p>Background</p> <p>Few cases of GIST bigger than 15 cm have been reported in medical literature, all primarily in elderly patients. We report an unusual case, in which a giant gastric GIST – in a young patient – presented as spontaneous intratumoral bleeding followed by intraluminal rupture.</p> <p>Case presentation</p> <p>A 37-year-old man was admitted with an acute onset of abdominal pain. CT showed a 32 × 25 cm mass with some cystic lesions and areas of calcification. Twelve hours after admission the patient presented with an episode of upper GI bleeding, and a significant decrease of tumor size and hemoglobin level. An upper endoscopy showed a large bulge in the posterior aspect of the gastric wall, and a small ulcer with continuous bleeding coming from a central orifice. A subtotal gastrectomy was carried out. Pathological examination showed a giant gastric GIST measuring 32 × 25 × 21 cm and weighing 3.750 g. Immunohistochemical staining demonstrated positive reactivity to C-kit protein, CD34, and α-smooth muscle actin; but negative reactivity to S-100 protein.</p> <p>Conclusion</p> <p>Intratumoral bleeding is a very rare presentation of GIST; preoperative diagnosis is always made difficult by the absence of pathognomonic signs or symptoms. Emergency local excision with negative margins associated with adjuvant therapy with imatinib mesylate remains the main modality of treatment for high risk GISTs.</p

Levels of insulin and HOMA-IR in adolescents in Saltillo, Coahuila, Mexico

An alarming rise of obesity in adolescents has been observed, placing them at risk of developing resistance to insulin (IR) and its adverse metabolic consequences such as diabetes mellitus type 2 (DM2), metabolic syndrome and cardiovascular disease. Objective: To know the prevalence of obesity, and the levels of glucose, insulin and HOMA-IR and its association with the BMIz, waist circumference and the pubertal stage in a random sample of adolescents. Materials and methods: 292 adolescents between 12 and 15 years (152 female and 140 male), whose anthropometric measurements (weight, height and waist circumference) were taken, body mass index calculated and Z-score determined. Blood glucose and insulin levels were evaluated from a sample of blood and their HOMA-IR was determined. Results: The results showed that 32.5% were obese, 22.3% were overweight and 23.6% showed adolescent central obesity. Glucose levels (p = 0.016), insulin (p = 0.0001) and HOMA-IR (p = 0.0001) showed significant differences in the group with obesity. Values of the three parameters were increased with the stage of puberty. We found significant differences in the levels of glucose (p = 0.0388), insulin (p = 0.0005) and HOMA-IR (p = 0.0001) between the prepubertal and postpubertal stages

Going Beyond Promoting: Preparing Students to Creatively Solve Future Problems

While we cannot know what problems the future will bring, we can be almost certain that solving them will require creativity. In this article we describe how our course, a first-year undergraduate mathematics course, supports creative problem solving. Creative problem solving cannot be learned through a single experience, so we provide our students with a blend of experiences. We discuss how the course structure enables creative problem solving through class instruction, during class activities, during out of class assessments, and during in class assessments. We believe this course structure increases student comfort with solving open-ended and ill-defined problems similar to what they will encounter in the real world

Dose patterns in commercially insured subjects chronically exposed to opioids: a large cohort study in the United States

<p>Abstract</p> <p>Background</p> <p>Little data exist on how opioid doses vary with the length of exposure among chronic opioid users.</p> <p>Methods</p> <p>To characterize the change in the dosage of opioids over time, a retrospective cohort study using the PharMetrics database for the years 1999 through 2008 was conducted. Individuals exposed to opioids in 2000 who had 2 opioid dispensings at least 6 months apart and were opioid naive (did not receive any opioid 6 month before their exposure in 2000) were included. The date of the first dispensing in 2000 was defined as the index date and the dispensing had to be for a strong and full agonist opioid. All opioid doses were converted to oral morphine equivalent doses. Exposure was classified as continuous or intermittent. Mean, median, interquartile range, and 95^thpercentile of opioid dose over 6-month periods, as well as the percentage of subjects who ever received a high or very high opioid dose, were calculated.</p> <p>Results</p> <p>Among the 48,986 subjects, the mean age was 44.5 years and 54.5% were women. Intermittent exposure was observed in 99% of subjects; continuous exposure was observed in 1% of subjects. The mean duration of exposure for the subjects who were continuously exposed to opioids was 477 days. In subjects with no cancer diagnosis who were continuously exposed to opioids, the mean, 25^th, 50^th, and 75^thpercentile of dose was stable during the first 2 years of use, but the 95^thpercentile increased. Seven percent of them were exposed to doses of 180 mg or more of morphine at some point.</p> <p>Conclusions</p> <p>Dose escalation is uncommon in subjects with intermittent exposure to opioids. For subjects with continuous exposure to opioids who have cancer, doses rise substantially with time. For those without cancer, doses remain relatively stable for the first 2 years of use, but subsequently increase. Seven percent of subjects with no cancer diagnosis will be exposed to daily doses of 180 mg or more of morphine equivalent at some point.</p