tbuckley/cabot-search huggingface dataset:
Screening for Albuminuria Identifies Individuals at Increased Renal Risk
Authors: Marije van der Velde, Nynke Halbesma, Frank T de Charro, Stephan J L Bakker, Dick de Zeeuw, Paul E de Jong, Ronald T Gansevoort
Journal: Journal of the American Society of Nephrology (2009)

It is unknown whether screening for albuminuria in the general population identifies individuals at increased risk for renal replacement therapy (RRT) or accelerated loss of renal function. Here, in a general population-based cohort of 40,854 individuals aged 28 to 75 yr, we collected a first morning void for measurement of urinary albumin. In a subset of 6879 individuals, we measured 24-h urinary albumin excretion and estimated GFR at baseline and during 6 yr of follow-up. Linkage with the national RRT registry identified 45 individuals who started RRT during 9 yr of follow-up. The quantity of albuminuria was associated with increased renal risk: the higher the level of albuminuria, the higher the risk of need for renal replacement therapy and the more rapid renal function decline. A urinary albumin concentration of > or =20 mg/L identified individuals who started RRT during follow-up with 58% sensitivity and 92% specificity. Of the identified individuals, 39% were previously unknown to have impaired renal function, and 50% were not being medically treated. Restricting screening to high-risk groups (e.g., known hypertension, diabetes, cardiovascular disease [CVD], older age) reduced the sensitivity of the test only marginally but failed to identify 45% of individuals with micro- and macroalbuminuria. In conclusion, individuals with elevated levels of urinary albumin are at increased risk for RRT and accelerated loss of renal function. Screening for albuminuria identifies patients at increased risk for progressive renal disease, 40 to 50% of whom were previously undiagnosed or untreated.
Chromosome microarrays in human reproduction
Authors: Evica Rajcan-Separovic
Journal: Human Reproduction Update (2012)

Chromosome microarray (CMA) testing allows automatic and easy identification of large chromosomal abnormalities detectable by conventional cytogenetics as well as the detection of submicroscopic chromosomal imbalances. A PubMed search was performed in order to review the current use of CMA testing in the field of human reproduction. Articles discussing the use of CMA in the preimplantation setting, ongoing pregnancies, miscarriages and patients with reproductive disorders were considered. A high rate of concordance between conventional methods of detecting chromosomal abnormalities [e.g. fluorescence in situ hybridization (FISH), karyotyping] and CMA was reported in the prenatal setting with CMA providing more comprehensive and detailed results as it investigates the whole genome at higher resolution. In preimplantation genetic screening, CMA is replacing FISH and the selection of embryos based on CMA has already resulted in live births. For ongoing pregnancies and miscarriages, CMA eliminates tissue culture failures and artifacts and allows a quick turnaround time. The detection of submicroscopic imbalances [or copy number variants (CNVs)] is beneficial when the imbalance has a clear clinical consequence but is challenging for previously undescribed imbalances, particularly for ongoing pregnancies. Recurrent CNVs have been documented in patients with reproductive disorders; however, the application of CMA in this field is still limited. CMA enhances reproductive medicine as it facilitates better understanding of the genetic aspects of human development and reproduction and more informed patient management. Further clinical validation of CMA in the prenatal setting, creation of practice guidelines and catalogs of newly discovered submicroscopic imbalances with clinical outcomes are areas that will require attention in the future.
Prediction of therapeutic failure after adrenaline injection plus heater probe treatment in patients with bleeding peptic ulcer
Authors: S K H Wong
Journal: Gut (2002)

Continued or recurrent bleeding after endoscopic treatment for bleeding ulcer is a major adverse prognostic factor. Identification of such ulcers may allow for alternate treatments.To determine factors predicting treatment failure with combined adrenaline injection and heater probe thermocoagulation.Consecutive patients with bleeding peptic ulcers who received endoscopic therapy between January 1995 and March 1998 were studied. Data on clinical presentation, endoscopic findings, and treatment outcomes were collected prospectively. Multiple logistic regression analysis was used to identify independent risk factors for treatment failure.During the study period, 3386 patients were admitted with bleeding peptic ulcers: 1144 (796 men, 348 women) with a mean age of 62.5 (SD 17.6) years required endoscopic treatment. There were 666 duodenal ulcers (58.2%), 425 gastric ulcers (37.2%), and 53 anastomotic ulcers (4.6%). Initial haemostasis was successful in 1128 patients (98.6%). Among them, 94 (8.2%) rebled in a median time of 48 hours (range 3-480). Overall failure rate was 9.6%. Mortality rate was 5% (57/1144). Multiple logistic regression analysis revealed that hypotension (odds ratio (OR) 2.21, 95% confidence interval (CI) 1.40-3.48), haemoglobin level less that 10 g/dl (OR 1.87, 95% CI 1.18-2.96), fresh blood in the stomach (OR 2.15, 95% CI 1.40-3.31), ulcer with active bleeding (OR 1.65, 95% CI 1.07-2.56), and large ulcers (OR 1.80, 95% CI 1.15-2.83) were independent factors predicting rebleeding.Larger ulcers with severe bleeding at presentation predict failure of endoscopic therapy.
Insulin resistance and obesity: how do they affect tau pathology?
Authors: Maud Gratuze, Noura El Khoury, Maya DicklerI, Marie-Amélie Papon, Carl Julien, François Marcouiller, Françoise Morin, Emmanuel Planel
Journal: Molecular Neurodegeneration (2013)

Tau is a microtubule-associated protein that is abundant in the central nervous system and expressed mainly in axons. Tau hyperphosphorylation can induce its aggregation, and is thought to induce neurofibrillary tangles formation in Alzheimer's disease (AD) and other tauopathies. Understanding the causes and consequences of tau pathology is important because it shows a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment.

The causes of sporadic AD are likely to be multifactorial, with external and biological factors interacting with genetic susceptibilities to accelerate the manifestation of the disease. Diabetes and obesity might be such accelerating factors since both are independently linked to cognitive decline, and since diabetes has been shown to increase the risk of AD. It has been suggested that the effects of diabetes and obesity on AD pathogenesis might be mediated by the concommitant insulin resistance that can be present in both medical conditions. However, recent data data suggest that obesity could accelerate tau pathology in the absence of insulin resistance.

To address this controversy, we used genetic models of diabetes and obesity (db/db mice and ob/ob mice) that present different degrees of insulin resistance. We found that both db/db and ob/ob mice had tau hyperphosphorylation, but also mild hypothermia, which is a powerful promoter of tau hyperphosphorylation. Maintaining the mice normothermic resulted in total rescue of tau phosphorylation in db/db mice, but not in ob/ob mice.

Our results suggest that insulin resistance induces tau hyperphosphorylation through hypothermia in both mouse models, but that ob/ob mice have additional upregulation of tau phosphorylation independant of temperature and insulin resistance.

This research will help understanding the link between diabetes, obesity and AD, and the development of future treatments or life style strategies destined to check the advance of the disease.
Bromocriptine and low dose cyclosporine in the treatment of experimental autoimmune uveitis in the rat.
Authors: A G Palestine, C G Muellenberg-Coulombre, M K Kim, M C Gelato, R B Nussenblatt
Journal: Journal of Clinical Investigation (1987)

The immunologic effects of bromocriptine and low dose cyclosporine on experimental autoimmune uveitis (EAU) induced in Lewis rats by S-antigen immunization were studied. Rats treated with a sub-optimal dose (low dose) of cyclosporine (2 mg/kg per d), bromocriptine (1.8 mg/kg per d), or both drugs were compared with untreated rats in regard to the development of EAU, lymphocyte proliferative responses, and anti-S-antigen serum antibodies. Bromocriptine alone decreased the incidence of EAU only in female rats (P less than 0.01), did not effect the lymphocyte proliferative response, but did significantly decrease antibody titers in both males (P less than 0.004) and females (P less than 0.0005). Low dose cyclosporine also partially decreased the incidence of EAU in female rats, but did not decrease antibody titers or lymphocyte proliferative responses. Bromocriptine plus low-dose cyclosporine led to more marked decreases in the incidence of EAU and anti-S-antigen antibody titers as well as in the lymphocyte proliferative assay (P less than 0.01 for males, P less than 0.0005 for females). This study suggests that bromocriptine can enhance the immunosuppression of low dose cyclosporine.
Development of a Peptide Inhibitor of Hyaluronan-Mediated Leukocyte Trafficking
Authors: Mark E. Mummert, Mansour Mohamadzadeh, Diana I. Mummert, Norikatsu Mizumoto, Akira Takashima
Journal: The Journal of Experimental Medicine (2000)

Hyaluronan (HA), a high molecular weight glycosaminoglycan, is expressed abundantly in the extracellular matrix and on cell surfaces. Although HA is known to bind many adhesion molecules, little information has been available with respect to its direct physiological role. In this study, we developed a novel 12-mer (GAHWQFNALTVR) peptide inhibitor of HA, termed “Pep-1,” by using phage display technology. Pep-1 showed specific binding to soluble, immobilized, and cell-associated forms of HA, and it inhibited leukocyte adhesion to HA substrates almost completely. Systemic, local, or topical administration of Pep-1 inhibited the expression of contact hypersensitivity responses in mice by blocking skin-directed homing of inflammatory leukocytes. Pep-1 also inhibited the sensitization phase by blocking hapten-triggered migration of Langerhans cells from the epidermis. These observations document that HA plays an essential role in “two-way” trafficking of leukocytes to and from an inflamed tissue, and thus provide technical and conceptual bases for testing the potential efficacy of HA inhibitors (e.g., Pep-1) for inflammatory disorders.
Sensory stimulation in dementia
Authors: A. Burns
Journal: BMJ (2002)

Unlike many other vertebrates, a healthy mammalian retina does not grow throughout life and lacks a ciliary margin zone capable of actively generating new neurons. The isolation of stem-like cells from the ciliary epithelium has led to speculation that the mammalian retina and/or surrounding tissues may retain neurogenic potential capable of responding to retinal damage. Using genetically altered mouse lines with varying degrees of retinal ganglion cell loss, we show that the retinal margin responds to ganglion cell loss by prolonging specific neurogenic activity, as characterized by increased numbers of <i>Atoh7<sup>LacZ</sup></i>-expressing cells. The extent of neurogenic activity correlated with the degree of ganglion cell deficiency. In the pars plana, but not the retinal margin, cells remain proliferative into adulthood, marking the junction of pars plana and retinal margin as a niche capable of producing proliferative cells in the mammalian retina and a potential cellular source for retinal regeneration.
Fibrosis regression induced by intravenous gammaglobulin treatment
Authors: H Amital
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objectives:</b> To review case histories of patients in whom fibrosis played a significant role in the pathogenesis of their disease, and to determine whether intravenous gammaglobulin (IVIg) contributed to the regression of their fibrotic condition. <b>Methods:</b> Eight patients with excess fibrotic reaction in the course of diverse diseases were analysed; a tendency that reverted with different IVIg treatment options. Myelofibrosis was predominant in three patients (a patient with a myeloproliferative syndrome, one with systemic lupus erythematosus, and one with Sjögren's syndrome). Three patients had scleroderma as their main feature, one patient had hepatitis C cirrhosis, and one had idiopathic thrombocytopenic purpura. <b>Results:</b> Fibrotic excess was reduced in all the patients by IVIg treatment. In five patients the disease as a whole benefited from the infusion of immunoglobulins. <b>Conclusion:</b> IVIg may enhance resorption of fibrosis and promote healing in patients with fibrotic associated disorders.
Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling
Authors: M Beeram, Q.-T.N. Tan, R.R. Tekmal, D Russell, A Middleton, L.A. deGraffenried
Journal: Annals of Oncology (2007)

BackgroundResistance to endocrine therapy is a major impediment in breast cancer therapeutics. The Phosphatidylinositol-3-OH kinase (PI3K)/Protein kinase B (Akt/PKB) kinase signaling pathway has been implicated in altering breast cancer response to multiple therapies. How Akt modulates response is an area of significant clinical relevance.MethodsWe have used an in vitro model to discern the effects of robust Akt activity on breast cancer cellular response to endocrine therapies.ResultsHigh levels of Akt activity confer resistance to the aromatase inhibitor Letrozole (Let) and the selective estrogen receptor (ER) down-regulator Fulvestrant (ICI). Akt-induced resistance is not due to failure of these endocrine agents to inhibit estrogen receptor α activity. Instead, resistance is characterized by altered cell cycle and apoptotic response. Cotreatment with low concentrations of the mTOR inhibitor RAD-001 and either Let or ICI restores response of the resistant cells to levels observed in the responsive cells treated with either Let or ICI as a single agent.ConclusionsOur preliminary findings in experiments with RAD-001 indicate that cotreatment with mTOR inhibitors and either Let or ICI reverses the Akt-mediated resistance and restores responsiveness to antiestrogens. Concurrent ER and mTOR inhibition is therefore an effective strategy to overcome growth factor-induced resistance and bears significant implications for optimal clinical development of these agents in breast cancer treatment.
A Phase I Study of Quisinostat (JNJ-26481585), an Oral Hydroxamate Histone Deacetylase Inhibitor with Evidence of Target Modulation and Antitumor Activity, in Patients with Advanced Solid Tumors
Authors: Balaji Venugopal, Richard Baird, Rebecca S. Kristeleit, Ruth Plummer, Richard Cowan, Adam Stewart, Nele Fourneau, Peter Hellemans, Yusri Elsayed, Steve Mcclue, Johan W. Smit, Ann Forslund, Charles Phelps, John Camm, T.R. Jeffry Evans, Johann S. de Bono, Udai Banerji
Journal: Clinical Cancer Research (2013)

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic and pharmacodynamic profile of quisinostat, a novel hydroxamate, pan-histone deacetylase inhibitor (HDACi).In this first-in-human phase I study, quisinostat was administered orally, once daily in three weekly cycles to patients with advanced malignancies, using a two-stage accelerated titration design. Three intermittent schedules were subsequently explored: four days on/three days off; every Monday, Wednesday, Friday (MWF); and every Monday and Thursday (M-Th). Toxicity, pharmacokinetics, pharmacodynamics, and clinical efficacy were evaluated at each schedule.Ninety-two patients were treated in continuous daily (2-12 mg) and three intermittent dosing schedules (6-19 mg). Treatment-emergent adverse events included: fatigue, nausea, decreased appetite, lethargy, and vomiting. DLTs observed were predominantly cardiovascular, including nonsustained ventricular tachycardia, ST/T-wave abnormalities, and other tachyarhythmias. Noncardiac DLTs were fatigue and abnormal liver function tests. The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of quisinostat increased proportionally with dose. Pharmacodynamic evaluation showed increased acetylated histone 3 in hair follicles, skin and tumor biopsies, and in peripheral blood mononuclear cells as well as decreased Ki67 in skin and tumor biopsies. A partial response lasting five months was seen in one patient with melanoma. Stable disease was seen in eight patients (duration 4-10.5 months).The adverse event profile of quisinostat was comparable with that of other HDACi. Intermittent schedules were better tolerated than continuous schedules. On the basis of tolerability, pharmacokinetic predictions, and pharmacodynamic effects, the recommended dose for phase II studies is 12 mg on the MWF schedule.
Structure of the T cell antigen receptor (TCR): two CD3 epsilon subunits in a functional TCR/CD3 complex.
Authors: A de la Hera, U Müller, C Olsson, S Isaaz, A Tunnacliffe
Journal: The Journal of Experimental Medicine (1991)

Transgenic mice carrying and expressing the human CD3 epsilon gene incorporate the corresponding protein product into T cell receptor (TCR)/CD3 complexes on thymocyte and T cell surfaces. The chimeric antigen receptors allow normal T cell development and selection of repertoires in vivo and are able to transduce activation signals in vitro. We have exploited the ability to distinguish mouse (m) and human (h)CD3 epsilon chains to analyze the stoichiometry of CD3 epsilon in transgenic mouse TCRs. Immunoprecipitation and fluorescence resonance energy transfer experiments demonstrate that such TCRs can contain both h- and mCD3 epsilon chains, implying that more than one CD3 epsilon subunit occurs per TCR. Antigen comodulation studies are consistent with a stochastic use of h- or mCD3 epsilon during receptor assembly, and further suggest a structure for the TCR/CD3 complex with two CD3 epsilon chains. The determination of CD3 epsilon subunit stoichiometry, together with existing biochemical data, allows the generation of a minimal model for the structure of the TCR and illustrates the potential value of the transgenic approach to the analysis of complex receptors.
Non-invasive markers associated with liver fibrosis in non-alcoholic fatty liver disease
Authors: I N Guha, J Parkes, P R Roderick, S Harris, W M Rosenberg
Journal: Gut (2006)

The diagnosis of fibrosis within liver disease is important for prognosis, stratification for treatment, and monitoring of treatment efficacy. The rising incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) has driven the search for accurate non-invasive tools of liver fibrosis within this condition. With the aid of a systematic review, we explore how the field has evolved from the discovery of simple blood parameters to panel markers of liver fibrosis. We will discuss the biological plausibility, limitations, potential uses, and emerging diagnostic techniques of non-invasive markers in this rapidly expanding field.
Properties of mutant contractile proteins that cause hypertrophic cardiomyopathy
Authors: C S Redwood, J C Moolman-Smook, H Watkins
Journal: Cardiovascular Research (1999)

Hypertrophic cardiomyopathy (HCM) is one of the most frequently occurring inherited cardiac disorders, affecting up to 1 in 500 of the population. Molecular genetic analysis has shown that HCM is a disease of the sarcomere, caused by mutations in certain contractile protein genes. To date seven disease-associated genes have been identified, those encoding beta-myosin heavy chain, both regulatory and essential myosin light chains, myosin binding protein-C, cardiac troponin T, cardiac troponin I and alpha-tropomyosin. Here we review the analyses of how these mutations affect the in vitro contractile protein function and the hypotheses derived to explain the development of the disease state.
Assessment of Platelet to Lymphocyte Ratio to Predict Stent Thrombosis in Patients with ST Elevation Myocardial Infarction
Authors: Abdulkadir Yildiz, Murat Yuksel, Mustafa Oylumlu, Mehmet Zihni Bilik, Halit Acet, Mehmet Ata Akil, Nihat Polat, Mesut Aydin, Faruk Ertas, Hasan Kaya, Yahya Islamoglu, Mehmet Ali Elbey, Habip Cil
Journal: Journal of the American College of Cardiology (2013)
Relation of antivimentin antibodies to anticardiolipin antibodies in systemic lupus erythematosus.
Authors: M A Blaschek, M Boehme, J Jouquan, A M Simitzis, S Fifas, P Le Goff, P Youinou
Journal: Annals of the Rheumatic Diseases (1988)

Tests for antivimentin antibodies (AVA) were performed on 50 systemic lupus erythematosus (SLE) and 63 control sera by indirect immunofluorescence and enzyme linked immunosorbent assay (ELISA). The prevalence was significantly raised in SLE (38% and 50% of sera positive for IgM-AVA and IgG-AVA, respectively, by immunofluorescence; 36% and 64% of sera positive for IgM-AVA and IgG-AVA, respectively, by ELISA) in comparison with the control sera. A significant correlation existed between IgM-AVA, on the one hand, and anticardiolipin antibodies (ACA) and anti-single-stranded DNA (ssDNA), on the other. A stepwise principal component analysis demonstrated that IgM-AVA and IgG-AVA accounted for 71% of the total variance in SLE (50 patients x 5 parameters = total variance). Twenty ACA positive serum samples from patients with syphilis were therefore tested for the presence of AVA, but hardly any were found to be positive. IgM-AVA from patients with SLE were inhibited by cardiolipin and absorbed with ssDNA. An association between AVA positivity and arthralgia was also shown in SLE.
Hair loss in women: medical and cosmetic approaches to increase scalp hair fullness
Authors: R. Sinclair, M. Patel, T.L. Dawson, A. Yazdabadi, L. Yip, A. Perez, N.W. Rufaut
Journal: British Journal of Dermatology (2011)

Androgenetic alopecia affects both men and women. In men it produces male pattern hair loss with bitemporal recession and vertex baldness. In women it produces female pattern hair loss (FPHL) with diffuse alopecia over the mid‐frontal scalp. FPHL occurs as a result of nonuniform hair follicle miniaturization within follicular units. Diffuse alopecia is produced by a reduction in the number of terminal fibres per follicular unit. Baldness occurs only when all hairs within the follicular units are miniaturized and is a relatively late event in women. The concepts of follicular units and primary and secondary hair follicles within follicular units are well established in comparative mammalian studies, particularly in sheep. However, discovery of these structures in the human scalp hair and investigation of the changes in follicular unit anatomy during the development of androgenetic alopecia have provided a clearer understanding of the early stages of androgenetic alopecia and how the male and female patterns of hair loss are related. FPHL is the most common cause of alopecia in women and approximately one‐third of adult caucasian women experience hair loss. The impact of FPHL is predominantly psychological. While men anticipate age‐related hair loss, hair loss in women is usually unexpected and unwelcome at any age. Treatment options to arrest hair loss progression and stimulate partial hair regrowth for FPHL include the androgen receptor antagonists spironolactone and cyproterone acetate, the 5α‐reductase inhibitor finasteride and the androgen‐independent hair growth stimulator minoxidil. These treatments appear to work best when initiated early. Hair transplantation should be considered in advanced FPHL that is resistant to medical treatments. Hair transplantation requires well‐preserved hair growth over the occipital donor area. The psychological impact of FPHL may also be reduced by cosmetic products that improve the appearance of the hair. These agents work to minimize hair fibre breakage, improve hair volume or conceal visible bald scalp.