A new method for studying human polycystic kidney disease epithelia in culture

A new method for studying human polycystic kidney disease epithelia in culture. Human polycystic kidney disease (PKD) epithelia were successfully grown in culture and expressed abnormal characteristics. Cysts lining epithelia of superficial and deep cysts were microdissected and compared to individual normal human proximal straight tubules (PST) and cortical collecting tubules (CCT) grown in defined media. PKD cyst epithelia differed from normal renal tubular epithelia in growth patterns and structural and functional properties. PKD epithelia grew more rapidly and showed cyst–like areas in otherwise confluent monolayers. Polygonal and elongate cells contained an epithelial–specific cytokeratin antigen and had polarized morphology. An extremely abnormal basement membrane morphology was seen and consisted of some banded collagen and numerous unique blebs or spheroids. These blebs were apparently extruded from intracellular vacuoles and stained with ruthenium red, suggesting a proteoglycan component. Cytochemistry of marker enzymes demonstrated the presence of NaK-ATPase and alkaline phosphatase, but a lack of γ-glutamyl transpeptidase. The response of adenylate cyclase activity to vasopressin, parathyroid hormone, and forskolin was significantly diminished in PKD cells as compared to PST and CCT. These studies suggest a defect in cell growth and basement membrane synthesis in human PKD. Cultured PKD epithelia provide a new tool for the study of the pathogenesis of this disease

Carboxy terminal tail of polycystin-1 regulates localization of TSC2 to repress mTOR.

Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited renal disorder caused by defects in the PKD1 or PKD2 genes. ADPKD is associated with significant morbidity, and is a major underlying cause of end-stage renal failure (ESRF). Commonly, treatment options are limited to the management of hypertension, cardiovascular risk factors, dialysis, and transplantation when ESRF develops, although several new pharmacotherapies, including rapamycin, have shown early promise in animal and human studies. Evidence implicates polycystin-1 (PC-1), the gene product of the PKD1 gene, in regulation of the mTOR pathway. Here we demonstrate a mechanism by which the intracellular, carboxy-terminal tail of polycystin-1 (CP1) regulates mTOR signaling by altering the subcellular localization of the tuberous sclerosis complex 2 (TSC2) tumor suppressor, a gatekeeper for mTOR activity. Phosphorylation of TSC2 at S939 by AKT causes partitioning of TSC2 away from the membrane, its GAP target Rheb, and its activating partner TSC1 to the cytosol via 14-3-3 protein binding. We found that TSC2 and a C-terminal polycystin-1 peptide (CP1) directly interact and that a membrane-tethered CP1 protects TSC2 from AKT phosphorylation at S939, retaining TSC2 at the membrane to inhibit the mTOR pathway. CP1 decreased binding of 14-3-3 proteins to TSC2 and increased the interaction between TSC2 and its activating partner TSC1. Interestingly, while membrane tethering of CP1 was required to activate TSC2 and repress mTOR, the ability of CP1 to inhibit mTOR signaling did not require primary cilia and was independent of AMPK activation. These data identify a unique mechanism for modulation of TSC2 repression of mTOR signaling via membrane retention of this tumor suppressor, and identify PC-1 as a regulator of this downstream component of the PI3K signaling cascade

Synthesis Of Novel 2-aryl-3-(2-morpholinoethyl)-1,3-thiazinan-4-ones Via Ultrasound Irradiation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)This study describes the synthesis of fourteen thiazinanones from a multicomponent reaction of 2-morpholinoehtylamine (as primary amine), arenealdehydes (as carbonyl compound) and the mercaptopropionic acid using both conventional (thermal heating) and ultrasound methodologies. Through thermal heating methodology, the thiazinanones were obtained in 49 to 97% yields for 16 hours and through sonochemistry methodology, the reaction time was reduced for 25 minutes with yields 41 to 88%. The full identification and characterization of unpublished heterocycles were achieved by proton (H-1) and carbon 13 (C-13) nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and infrared. Some of them were also characterized by elemental analysis.27611091115UFPelFAPERGS [11/2068-7]FAPESP [2013/18203-5]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Surgical versus balloon therapy for aortic coarctation in infants ≤ 3 months old

AbstractObjectives. This study compared the efficacy and safety of balloon angioplasty with surgical correction of native aortic coarctation in infants ≤3 months old.Background. There is a controversy with regard to the role of balloon angioplasty in the treatment of aortic coarctation, especially in young infants.Methods. Data from 29 infants ≤3 months old undergoing therapy for aortic coarctation during the decade ending 1992 were analyzed. Fourteen infants underwent surgery, and 15 had balloon angioplasty. The sole criterion for allotment to the balloon group was the availability of an interventional cardiologist at the time of presentation of the infant.Results. The surgical and balloon groups were comparable (p > 0.1) with regard to age (27 ± 35 [mean ± SD] vs. 29 ± 27 days), weight (3.5 ± 0.9 vs. 3.8 ± 1.0 kg) and prevalence (7 of 14 vs. 8 of 15) and type of associated defects. Operative (1 of 14 vs. 1 of 15) and late (3 of 13 vs. 3 of 14) mortality, immediate gradient relief (36 ± 25 to 10 ± 9 mm Hg vs. 41 ± 14 to 6 ± 6 mm Hg) and follow-up gradient (27 ± 27 vs. 24 ± 19 mm Hg) were similar (p > 0.1). Infants with a gradient > 20 mm Hg at follow-up (6 of 13 vs. 7 of 14) and need for reintervention (6 of 13 vs. 7 of 14) were also similar (p > 0.1) in both groups. Duration of hospital stay during the first intervention was higher (p < 0.05) in the surgical (32 ± 37 days) than the balloon (7 ± 6 days) group. Similarly, duration of endotracheal intubation and mechanical ventilation was longer (p < 0.05) in the surgical (12 ± 16 days) than the balloon (2 ± 3 days) group. Complications after surgical intervention (0.86 events/patient) were higher (p < 0.01) than those seen after balloon angioplasty (0.27 events/patient). However, the lack of significant differences observed for mortality rates and residual gradients may be due to low statistical power to detect differences (16% to 49%), implying that this may be due to either actual lack of statistical difference or small sample size.Conclusions. The data indicate that the degree of relief from aortic coarctation and the frequency with which reintervention is needed are similar in both groups. However, the morbidity and complication rates are lower with balloon than with surgical therapy. These data suggest that balloon angioplasty may be an acceptable alternative to surgical correction in the treatment of symptomatic aortic coarctation in infants ≤3 months old

Factors affecting the number and type of student research products for chemistry and physics students at primarily undergraduate institutions: A case study.

For undergraduate students, involvement in authentic research represents scholarship that is consistent with disciplinary quality standards and provides an integrative learning experience. In conjunction with performing research, the communication of the results via presentations or publications is a measure of the level of scientific engagement. The empirical study presented here uses generalized linear mixed models with hierarchical bootstrapping to examine the factors that impact the means of dissemination of undergraduate research results. Focusing on the research experiences in physics and chemistry of undergraduates at four Primarily Undergraduate Institutions (PUIs) from 2004–2013, statistical analysis indicates that the gender of the student does not impact the number and type of research products. However, in chemistry, the rank of the faculty advisor and the venue of the presentation do impact the number of research products by undergraduate student, whereas in physics, gender match between student and advisor has an effect on the number of undergraduate research products. This study provides a baseline for future studies of discipline-based bibliometrics and factors that affect the number of research products of undergraduate students

Reflections and Experiences of a Co-Researcher involved in a Renal Research Study

Background Patient and Public Involvement (PPI) is seen as a prerequisite for health research. However, current Patient and public involvement literature has noted a paucity of recording of patient and public involvement within research studies. There have been calls for more recordings and reflections, specifically on impact. Renal medicine has also had similar criticisms and any reflections on patient and public involvement has usually been from the viewpoint of the researcher. Roles of patient and public involvement can vary greatly from sitting on an Advisory Group to analysing data. Different PPI roles have been described within studies; one being a co-researcher. However, the role of the co-researcher is largely undefined and appears to vary from study to study. Methods The aims of this paper are to share one first time co-researcher's reflections on the impact of PPI within a mixed methods (non-clinical trial) renal research study. A retrospective, reflective approach was taken using data available to the co-researcher as part of the day-to-day research activity. Electronic correspondence and documents such as meeting notes, minutes, interview thematic analysis and comments on documents were re-examined. The co-researcher led on writing this paper. Results This paper offers a broad definition of the role of the co-researcher. The co-researcher reflects on undertaking and leading on the thematic analysis of interview transcripts, something she had not previously done before. The co-researcher identified a number of key themes; the differences in time and responsibility between being a coresearcher and an Advisory Group member; how the role evolved and involvement activities could match the co-researchers strengths (and the need for flexibility); the need for training and support and lastly, the time commitment. It was also noted that it is preferable that a co-researcher needs to be involved from the very beginning of the grant application. Conclusions The reflections, voices and views of those undertaking PPI has been largely underrepresented in the literature. The role of co-researcher was seen to be rewarding but demanding, requiring a large time commitment. It is hoped that the learning from sharing this experience will encourage others to undertake this role, and encourage researchers to reflect on the needs of those involved.Peer reviewedFinal Published versio

Relationship between age at menopause, obesity, and incident heart failure: The Atherosclerosis Risk in Communities Study

Background The mechanisms linking menopausal age and heart failure (HF) incidence are controversial. We investigated for heterogeneity by obesity on the relationship between menopausal age and HF incidence. Methods and Results Using postmenopausal women who attended the Atherosclerosis Risk in Communities Study Visit 4, we estimated hazard ratios of incident HF associated with menopausal age using Cox proportional hazards models, testing for effect modification by obesity and adjusting for HF risk factors. Women were categorized by menopausal age: \u3c45 years, 45 to 49 years, 50 to 54 years, and ≥55 years. Among 4441 postmenopausal women, aged 63.5±5.5 years, there were 903 incident HF events over a mean follow-up of 16.5 years. The attributable risk of generalized and central obesity for HF incidence was greatest among women who experienced menopause at age ≥55 years: 11.09/1000 person-years and 7.38/1000 person-years, respectively. There were significant interactions of menopausal age with body mass index and waist circumference for HF incidence

The health of women and girls determines the health and well-being of our modern world: A White Paper From the International Council on Women's Health Issues

The International Council on Women's Health Issues (ICOWHI) is an international nonprofit association dedicated to the goal of promoting health, health care, and well-being of women and girls throughout the world through participation, empowerment, advocacy, education, and research. We are a multidisciplinary network of women's health providers, planners, and advocates from all over the globe. We constitute an international professional and lay network of those committed to improving women and girl's health and quality of life. This document provides a description of our organization mission, vision, and commitment to improving the health and well-being of women and girls globally