tbuckley/cabot-search huggingface dataset:
Prevalence and Risk Factors for Urinary Incontinence in Women With Type 2 Diabetes and Impaired Fasting Glucose
Authors: Jeanette S. Brown, Eric Vittinghoff, Feng Lin, Leroy M. Nyberg, John W. Kusek, Alka M. Kanaya
Journal: Diabetes Care (2006)

Diabetes is associated with increased risk of urinary incontinence. It is unknown whether women with pre-diabetes, or impaired fasting glucose (IFG), have increased prevalence of incontinence. We determined the prevalence of, and risk factors for, incontinence among U.S. women with diabetes and IFG.The 2001-2002 National Health and Nutrition Examination Survey measured fasting plasma glucose and obtained information about diabetes and urinary incontinence among 1,461 nonpregnant adult women. Self-reported weekly or more frequent incontinence, both overall and by type (urge and stress), was our outcome.Of the 1,461 women, 17% had diabetes and 11% met criteria for IFG. Prevalence of weekly incontinence was similar among women in these two groups (35.4 and 33.4%, respectively) and significantly higher than among women with normal fasting glucose (16.8%); both urge and stress incontinence were increased. In addition to well-recognized risk factors including age, weight, and oral estrogen use, two microvascular complications caused by diabetes, specifically macroalbuminuria and peripheral neuropathic pain, were associated with incontinence.Physicians should be alert for incontinence, an often unrecognized and therefore undertreated disorder, among women with diabetes and IFG, in particular those with microvascular complications. The additional prospect of improvements in their incontinence may help motivate some high-risk women to undertake difficult lifestyle changes to reduce their more serious risk of diabetes and its sequelae.
Establishment of Axon-Dendrite Polarity in Developing Neurons
Authors: Anthony P. Barnes, Franck Polleux
Journal: Annual Review of Neuroscience (2009)

Neurons are among the most highly polarized cell types in the body, and the polarization of axon and dendrites underlies the ability of neurons to integrate and transmit information in the brain. Significant progress has been made in the identification of the cellular and molecular mechanisms underlying the establishment of neuronal polarity using primarily in vitro approaches such as dissociated culture of rodent hippocampal and cortical neurons. This model has led to the predominant view suggesting that neuronal polarization is specified largely by stochastic, asymmetric activation of intracellular signaling pathways. Recent evidence shows that extracellular cues can play an instructive role during neuronal polarization in vitro and in vivo. In this review, we synthesize the recent data supporting an integrative model whereby extracellular cues orchestrate the intracellular signaling underlying the initial break of neuronal symmetry leading to axon-dendrite polarization.
Response to: "Rescuing the NIH before it is too late"
Authors: D. F. Alexander
Journal: Journal of Clinical Investigation (2006)

We, the directors of the 27 NIH institutes and centers, wanted to respond to the points made by Andrew Marks in his recent editorial. While we appreciate that the scientific community has concerns, the current initiatives and directions of the NIH have been developed through planning processes that reflect openness and continued constituency input, all aimed at assessing scientific opportunities and addressing public health needs.
Phylogenetic Analysis of Gene Structure and Alternative Splicing in -Actinins
Authors: M. Lek, D. G. MacArthur, N. Yang, K. N. North
Journal: Molecular Biology and Evolution (2009)

The alpha-actinins are an important family of actin-binding proteins with the ability to cross-link actin filaments when in dimer form. Members of the alpha-actinin family share a domain topology composed of highly conserved actin-binding and EF-hand domains separated by a rod domain composed of spectrin-like repeats. Functional diversity within this family has arisen through exon duplication and the formation of alternate splice isoforms as well as gene duplications during the evolution of vertebrates. In addition to the known functional domains, alpha-actinins also contain a consensus PDZ-binding site. The completed genome sequence of over 32 invertebrate species has allowed the analysis of gene structure and exon-gene duplication over a diverse range of phyla. Our analysis shows that relative to early branching metazoans, there has been considerable intron loss especially in arthropods with few cases of intron gains. The C-terminal PDZ-binding site is conserved in nearly all invertebrates but is missing in some nematodes and platyhelminths. Alternative splicing in the actin-binding domain is conserved in chordates, arthropods, and some nematodes and platyhelminths. In contrast, alternative splicing of the EF-hand domain is only observed in chordates. Finally, given the prevalence of exon duplications seen in the actin-binding domain, this may act as a significant mechanism in the modification of actin-binding properties.
High Expression of the Very Late Antigen-4 Integrin Independently Predicts Reduced Risk of Relapse and Improved Outcome in Pediatric Acute Myeloid Leukemia: A Report From the Children's Oncology Group
Authors: Roland B. Walter, Todd A. Alonzo, Robert B. Gerbing, Phoenix A. Ho, Franklin O. Smith, Susana C. Raimondi, Betsy A. Hirsch, Alan S. Gamis, Janet L. Franklin, Craig A. Hurwitz, Michael R. Loken, Soheil Meshinchi
Journal: Journal of Clinical Oncology (2010)

To evaluate the prognostic significance of the integrin cell adhesion molecule very late antigen-4 (VLA-4) in acute myeloid leukemia (AML).We prospectively quantified VLA-4 expression in 216 patients enrolled onto COG-AAML03P1 by flow cytometry and correlated expression levels with disease characteristics and clinical outcome.VLA-4 mean fluorescence intensity (MFI) varied 35-fold (range, 30 to 1,110; median, 219.5). High VLA-4 expression (> median MFI), compared with low expression, was associated with younger age (7.1 v 12.1 years, respectively; P < .001), lower FLT3 internal tandem duplication prevalence (4% v 21%, respectively; P < .001), and higher likelihood of extramedullary disease (16% v 5%, respectively; P = .013). In low- and high-expression groups, rates of remission (89% v 80%, respectively; P = .137) and minimal residual disease (29% v 25%, respectively; P = .700) were similar. Patients with low VLA-4 expression, compared with high expression, had a higher relapse rate (RR; 44% +/- 10% v 24% +/- 9%, respectively; P = .011) and lower disease-free survival (DFS; 48% +/- 11% v 67% +/- 10%, respectively; P = .023) after 3 years. Multivariate analyses showed that low VLA-4 expression was an independent adverse prognostic factor for DFS (hazard ratio [HR] = 1.98; P = .038) and RR (HR = 2.77; P = .009). Subgroup analyses indicated that the prognostic role of VLA-4 expression was most prominent in patients with standard-risk AML, in whom low VLA-4 expression was associated with inferior DFS (34% +/- 16% v 69% +/- 14% for high expression; P = .011) and higher RR (61% +/- 16% v 26% +/- 14% for high expression; P = .009). A similar trend was seen in low-risk but not high-risk patients.High VLA-4 expression is associated with better clinical outcome in pediatric AML and is an independent predictor of relapse that may refine our abilities to stratify patients without identifiable cytogenetic or molecular risk factors.
Implications and Prognostic Value of K-ras Mutation for Early-Stage Lung Cancer in Women
Authors: H. H. Nelson, D. C. Christiani, E. J. Mark, J. K. Wiencke, J. C. Wain, K. T. Kelsey
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Because there is no clear consensus as to the predictive value of K-ras gene mutation for survival in patients with lung cancer, we examined the occurrence of K-ras mutations in a large, prospective case series of non-small-cell lung cancer (NSCLC). Our goals were to define the patient characteristics associated with K-ras mutation and to determine whether mutation of this gene might be a biomarker of patient prognosis. METHODS: Consecutive, newly diagnosed patients with lung cancer treated with potentially curative resection over a 4-year period were recruited for study. The mutation status of K-ras codon 12 in each patient's tumor DNA was determined by means of polymerase chain reaction-restriction fragment length polymorphism analysis of archived pathology specimens. Analyses were restricted to adenocarcinoma. RESULTS: There was a statistically significant association between female sex and K-ras mutation after adjustment for carcinogen exposures (odds ratio = 3.3; 95% confidence interval [CI] = 1.3-7.9); mutations were found only in smokers. Comparison of Kaplan-Meier curves indicated a strong association between K-ras mutation and decreased patient survival (two-sided P = .009); analysis stratified by pathologic staging groups revealed that this association was statistically significant only for stage I tumors (two-sided P = .002). Cox proportional hazards modeling indicated that K-ras codon 12 mutation was a statistically significant predictor of patient survival, after adjustment for the effects of age, sex, and stage (risk ratio = 1.8; 95% CI = 1.1-3.1). CONCLUSIONS: After adjustment for environmental exposures, non-small-cell lung tumors in women appear to be more likely than those in men to harbor K-ras mutations, suggesting a possible role of estrogen exposure in either the initiation or the selection of K-ras mutant clones in adenocarcinoma. In addition, our data suggest that K-ras codon 12 mutation is a marker of aggressive NSCLC, as evidenced by its association with decreased patient survival, particularly for early-stage disease.
Combined Blockade of the Chemokine Receptors CCR1 and CCR5 Attenuates Chronic Rejection
Authors: James J. Yun, David Whiting, Michael P. Fischbein, Anamika Banerji, Yoshihito Irie, Daniel Stein, Michael C. Fishbein, Amanda E.I. Proudfoot, Hillel Laks, Judith A. Berliner, Abbas Ardehali
Journal: Circulation (2004)

Chemokine-chemokine receptor interaction and the subsequent recruitment of T-lymphocytes to the graft are early events in the development of chronic rejection of transplanted hearts or cardiac allograft vasculopathy (CAV). In this study, we sought to determine whether blockade of chemokine receptors CCR1 and CCR5 with Met-RANTES affects the development of CAV in a murine model.B6.CH-2(bm12) strain donor hearts were transplanted heterotopically into wild-type C57BL/6 mice (myosin heavy chain II mismatch). Recipients were treated daily with either Met-RANTES or vehicle starting on postoperative day 4 and were euthanized on postoperative days 24 and 56. We found that Met-RANTES significantly reduced intimal thickening in this model of chronic rejection and that Met-RANTES markedly decreased the infiltration of CD4 and CD8 T lymphocytes and MOMA-2+ monocytes/macrophages into transplanted hearts. Met-RANTES also suppressed the ex vivo and in vitro proliferative responses of recipient splenocytes to donor antigens. Finally, Met-RANTES treatment was associated with a marked reduction in RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels in the donor hearts.Antagonism of the chemokine receptors CCR1 and CCR5 with Met-RANTES attenuates CAV development in vivo by reducing mononuclear cell recruitment to the transplanted heart, proliferative responses to donor antigens, and intragraft RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels. These findings suggest that chemokine receptors CCR1 and CCR5 play significant roles in the development of chronic rejection and may serve as potential therapeutic targets.
Long-Acting Injectable Progestin Contraception and Risk of Type 2 Diabetes in Latino Women With Prior Gestational Diabetes Mellitus
Authors: Anny H. Xiang, Miwa Kawakubo, Siri L. Kjos, Thomas A. Buchanan
Journal: Diabetes Care (2006)

OBJECTIVE—To investigate the impact of a long-acting injectable progestin, depo-medroxyprogesterone acetate (DMPA), compared with combination oral contraceptives (COCs) on the risk of diabetes in Latino women with prior gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS—An observational cohort study of 526 Hispanic women with prior GDM who were not diabetic in their postpartum visit during January 1987 to October 1997 and who elected DMPA (n = 96) or COCs (n = 430) as initial contraception were followed for a maximum of 9.2 years with a median follow-up of ∼12 months. Oral glucose tolerance tests were performed and choice of contraception method was recorded at each visit as part of routine clinical care. RESULTS—Annual diabetes incidence rates were 19% in the DMPA group and 12% in the COC group, with an unadjusted hazard ratio (HR) of 1.58 (95% CI 1.00–2.50; P = 0.05) for DMPA compared with COCs. Adjustment for baseline imbalances reduced the HR to 1.18 (0.67–2.28; P = 0.57). Additional adjustment for weight gain during follow-up, which was on average 1.8 kg higher in the DMPA group (P &amp;lt; 0.0001), reduced the HR to 1.07. DMPA interacted with baseline serum triglyceride levels and, separately, with breast-feeding to increase the diabetes risk. CONCLUSIONS—DMPA use was associated with an increased risk of diabetes that appeared to be explained by three factors: 1) use in women with increased baseline diabetes risk, 2) weight gain during use, and 3) use with high baseline triglycerides and/or during breast-feeding.
Primary care trusts should delay treatment to cut deficits
Authors: Rebecca Coombes
Journal: BMJ (2005)

Primary care trusts should tell hospitals to “go slow” and delay inpatient treatments for up to six months in a bid to cut financial deficits to zero before the end of the financial year, the health secretary has said.

Patricia Hewitt, under questioning from the parliamentary health select committee last week, said all trusts were expected to balance their books before the end of March, even if that meant deliberately delaying operations. The government's target on waiting times is that by the end of this month no patient should be waiting longer than six months for inpatient treatment.

Ms Hewitt …
Effectiveness of TNF inhibitor treatment with various methotrexate doses in patients with rheumatoid arthritis: results from clinical practice
Authors: Sofie H M Manders, Wietske Kievit, Eddy Adang, Tim J Jansen, Jan N Stolk, Henk Visser, Annemarie M Schilder, Harald E Vonkeman, Mart A F J van de Laar, Piet L C M van Riel
Journal: Annals of the Rheumatic Diseases (2014)

Tumour necrosis factor inhibitor (TNFi) treatment in patients with rheumatoid arthritis is more effective when combined with methotrexate (MTX).1–3 However, little is known about which MTX dose to use. With great interest, we read the article by Burmester et al 4 on the efficacy and safety of ascending MTX doses with adalimumab. This randomised double-blind study showed comparable results for adalimumab with 10 and 20 mg MTX, in MTX naive patients. Because of the potential side effects, it is often preferred to use MTX doses as low as possible. Therefore, the following questions arise: what happens in daily practice with MTX plus adalimumab, where most patients are not MTX naive when starting TNFi, and are the results the same for etanercept and infliximab?

Data were collected within the Dutch RhEumatoid Arthritis …
NOV-002, a Glutathione Disulfide Mimetic, as a Modulator of Cellular Redox Balance
Authors: Danyelle M. Townsend, Lin He, Steven Hutchens, Tracy E. Garrett, Christopher J. Pazoles, Kenneth D. Tew
Journal: Cancer Research (2008)

Abstract NOV-002 is a novel glutathione disulfide mimetic that when administered in combination with standard chemotherapeutic regimens has resulted in increased efficacy (survival, tumor response) and improved tolerance to chemotherapy (e.g., hematologic recovery) in advanced non–small cell lung cancer patients. We show that NOV-002, which is not cytotoxic as a single agent, generated time- and concentration-dependent oxidative signals at the cell surface (reduction in protein thiols) and intracellularly [altered oxidized glutathione (GSSG) and reduced glutathione levels and ratio; increased reactive oxygen species] in the premyeloid HL-60 cell line and that this was associated with an increase in S-glutathionylation of cell proteins, particularly actin. Commensurate with these effects, NOV-002 activated p38, c-Jun-NH2-kinase, and extracellular signal-regulated kinase and caused a dose-dependent increase in phosphorylation of three proteins that have previously been linked with hematopoiesis, AKT, JAK2, and STAT5. The effect of NOV-002 on enzymes involved in glutathione metabolism was evaluated. Relative to oxidized glutathione, NOV-002 was an equivalent substrate for glutathione reductase and was an inhibitor of protein disulfide isomerase, one of the components of the redox-sensitive unfolded protein response pathway. These redox-stimulated cell signaling actions occurred in the context of increased HL-60 cell proliferation after treatment with NOV-002. Overall, the pleiotropic pharmacologic effects of NOV-002 can be attributed to the GSSG component of the drug, and modulation of cellular redox balance is a feature central to the mechanism of action of NOV-002. Such modulation may underlie its clinical actions, including hematologic recovery and immunostimulation in the face of chemosuppression. [Cancer Res 2008;68(8):2870–7]
A PLEA FOR THE EARLIER OPERATIVE TREATMENT OF ACUTE OTITIS MEDIA
Authors: F. H. Diggle
Journal: BMJ (1924)

large pea, was found partly on the surface of one of the lower renal papillae.It arose from one of the intrarenal branches of the renal artery.It is unfortunate that, owing to the pressure of military surgery, the specimen was not preserved.Ane-uryN-sm of the renal artery is very rare.M. J. Conroyl estimated from post-mortein records that only about 1 per cent. of all aneurysms affect this artery.Sir Heniry Morris,2 in 1900, was able to collect the records of only 21 cases, and two-tllirds of these were traumatic in origin; Conroy, in 1923, succeeded in adding 11 cases, but he overlooked 3 cases published by David Newman'making 35 in all.Two of Newman's cases were very like the one recorded here, for they were spontaneous in origin, saccular, and situated within the kidney or its pelvis.One of theseo arose in the relnal artery itself, and the other, like mine, originated in one of the large branches of this artery.It is clear that this type is not easily recognized even wlhen the kidney has been exposed in order to find and stop a painless haematuria which threatens life.It is probable that small aneurysms affecting the branches of the renal artery have been overlooked even after the kidney has been removed, either during life or after deatli.It wouild have been easy to miss the small aneurysm wlich caused so much mischief in my patient.Apart from haenmorrhage, these intrarenal aneurysms cause no symptoms or signs and are only found after deatlh from some other disease. Etiology.We are not concerned here witlh traumatic aneurysms of the renal arteries, which are due to contusions, lacerations, rulpture, wounds, or operations upon the kidney.The causo of spontaneous aneur-ysms is the same here as else- where.Atheroma, syphilis, embolism, or inifection appear to hiave been the causes in the few recorded cases; in my case there was no evidence of any of these.The average age of the seventeen known cases of spontaneous aneurysm was ov-er 40.A little more than half of them arose from br-ancches of the renal artery.Symptoms anid Signs.Spontaneous aneurysms are usually small in size, remain intact, and give no clinical signs, but when they rupture into the pelvis " symptoimiless haematuria," which is gener- ally very profuse and eitlher intermittent or iremittent, occurs.This is in striking contrast to traumatic renal
Coagulation factor VA2440G causes east Texas bleeding disorder via TFPIα
Authors: Lisa M. Vincent, Sinh Tran, Ruzica Livaja, Tracy A. Bensend, Dianna M. Milewicz, Björn Dahlbäck
Journal: Journal of Clinical Investigation (2013)

The autosomal dominantly inherited east Texas bleeding disorder is linked to an A2440G variant in exon 13 of the F5 gene. Affected individuals have normal levels of coagulation factor V (FV) activity, but demonstrate inhibition of global coagulation tests. We demonstrated that the A2440G mutation causes upregulation of an alternatively spliced F5 transcript that results in an in-frame deletion of 702 amino acids of the large activation fragment, the B domain. The approximately 250-kDa FV isoform (FV-short), which can be fully activated by thrombin, is present in all A2440G carriers’ plasma (n = 16). FV-short inhibits coagulation through an indirect mechanism by forming a complex with tissue factor pathway inhibitor-α (TFPIα), resulting in an approximately 10-fold increase in plasma TFPIα, suggesting that the TFPIα:FV-short complexes are retained in circulation. The TFPIα:FV-short complexes efficiently inhibit thrombin generation of both intrinsic and extrinsic coagulation pathways. These data demonstrate that the east Texas bleeding disorder–associated F5A2440G leads to the formation of the TFPIα:FV-short complex, which inhibits activation and propagation of coagulation.
Apoptosis of ventricular and atrial myocytes from pacing-induced canine heart failure
Authors: M Heinke
Journal: Cardiovascular Research (2001)

Objective: Rapid ventricular pacing in dogs results in a low output cardiomyopathic state similar to idiopathic dilated cardiomyopathy in man. Cell death by apoptosis may play an important role in the loss of cardiac function. This study investigates the molecular pathways involved in the regulation of apoptosis in dogs with pacing-induced heart failure. Methods: Apoptosis was identified by terminal transferase nick end-labelling (TUNEL) in the ventricles and atria of dog hearts affected by rapid-ventricular pacing. Western blots were used to determine expression of the components involved in the initiation (Fas, Fas-Ligand, FADD), regulation (Bcl-2, Bax) and execution (caspase-2 and caspase-3) of apoptosis. Results: Pacing-induced heart failure resulted in a significant increase in the number of ventricular and atrial myocyte nuclei undergoing apoptosis as measured by TUNEL. Compared to the samples from control hearts (n = 6) the expression of Bcl-2, an inhibitor of apoptosis, was significantly reduced in ventricles from five dogs with pacing-induced heart failure. No change in the expression of the apoptotic inducer Bax was detected. Fas and FADD were significantly elevated in all paced ventricles, and Fas-L was only detected in the paced hearts. Both caspase-2 and caspase-3 were elevated following ventricular pacing. Conclusions: We have identified components of the signalling pathways along which apoptosis proceeds following the induction of heart failure in dogs. Apoptosis was also detected in the atria raising the possibility that, like human dilated cardiomyopathy, the molecular changes are global.