tbuckley/cabot-search huggingface dataset:
Renal Hyperfiltration and the Development of Microalbuminuria in Type 1 Diabetes
Authors: Linda H. Ficociello, Bruce A. Perkins, Bijan Roshan, Janice M. Weinberg, Ann Aschengrau, James H. Warram, Andrzej S. Krolewski
Journal: Diabetes Care (2009)

OBJECTIVE The purpose of this study was to examine prospectively whether renal hyperfiltration is associated with the development of microalbuminuria in patients with type 1 diabetes, after taking into account known risk factors. RESEARCH DESIGN AND METHODS The study group comprised 426 participants with normoalbuminuria from the First Joslin Kidney Study, followed for 15 years. Glomerular filtration rate was estimated by serum cystatin C, and hyperfiltration was defined as exceeding the 97.5th percentile of the sex-specific distribution of a similarly aged, nondiabetic population (134 and 149 ml/min per 1.73 m2 for men and women, respectively). The outcome was time to microalbuminuria development (multiple albumin excretion rate &amp;gt;30 μg/min). Hazard ratios (HRs) for microalbuminuria were calculated at 5, 10, and 15 years. RESULTS Renal hyperfiltration was present in 24% of the study group and did not increase the risk of developing microalbuminuria. The unadjusted HR for microalbuminuria comparing those with and without hyperfiltration at baseline was 0.8 (95% CI 0.4–1.7) during the first 5 years, 1.0 (0.6–1.7) during the first 10 years, and 0.8 (0.5–1.4) during 15 years of follow-up. The model adjusted for baseline known risk factors including A1C, age at diagnosis of diabetes, diabetes duration, and cigarette smoking resulted in similar HRs. In addition, incorporating changes in hyperfiltration status during follow-up had minimal impact on the HRs for microalbuminuria. CONCLUSIONS Renal hyperfiltration does not have an impact on the development of microalbuminuria in type 1 diabetes during 5, 10, or 15 years of follow-up.
Whole-Genome Linkage and Association Scan in Primary, Nonsyndromic Vesicoureteric Reflux
Authors: Heather J. Cordell, Rebecca Darlay, Pimphen Charoen, Aisling Stewart, Ambrose M. Gullett, Heather J. Lambert, Sue Malcolm, Sally A. Feather, Timothy H.J. Goodship, Adrian S. Woolf, Rajko B. Kenda, Judith A. Goodship
Journal: Journal of the American Society of Nephrology (2009)

Primary vesicoureteric reflux accounts for approximately 10% of kidney failure requiring dialysis or transplantation, and sibling studies suggest a large genetic component. Here, we report a whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric reflux and reflux nephropathy. We used linkage and family-based association approaches to analyze 320 white families (661 affected individuals, generally from families with two affected siblings) from two populations (United Kingdom and Slovenian). We found modest evidence of linkage but no clear overlap with previous studies. We tested for but did not detect association with six candidate genes (AGTR2, HNF1B, PAX2, RET, ROBO2, and UPK3A). Family-based analysis detected associations with one single-nucleotide polymorphism (SNP) in the UK families, with three SNPs in the Slovenian families, and with three SNPs in the combined families. A case-control analysis detected associations with three additional SNPs. The results of this study, which is the largest to date investigating the genetics of reflux, suggest that major loci may not exist for this common renal tract malformation within European populations.
Economist says NICE should approve fewer costly drugs
Authors: Adrian O'Dowd
Journal: BMJ (2007)

A leading economist has recommended that the body that determines which drugs can be prescribed by the NHS in England and Wales should change its threshold, so that fewer expensive drugs are approved.

MPs on the health select committee heard from health economists last week as part of their inquiry into various aspects of the National Institute for Health and Clinical Excellence (NICE), including why its decisions and evaluation process are increasingly being challenged.

Peter Smith, director of the Centre for Health Economics, at the University of York, told MPs that NICE's current cost effectiveness threshold was between £20 000 …
Pitting oedema in early diffuse systemic scleroderma
Authors: H ENGLERT
Journal: Annals of the Rheumatic Diseases (2001)

The term “puffy skin” is not infrequently noted at initial presentation of patients with systemic scleroderma. However, this is generally described as “non-pitting” oedema. The following case history challenges the latter widely held assumption, showing that its measurement is simple and may offer a more sensitive method of assessing response to treatment than the modified Rodnan skin score.1 

### CASE REPORT

A premenopausal computer analyst first presented in May 1998 with a two month history of finger stiffness. The next 10 months were spent investigating and treating the cause of her iron deficiency anaemia—gastric ectasia (watermelon stomach). The diagnosis of diffuse systemic scleroderma was made in March 1999. At this time she presented with persisting symptoms of skin stiffness, burning and pruritis, especially in the early morning, affecting the skin of her arms and legs, face, and upper chest. Clinical examination showed finger clawing, sclerodactyly, and scleroderma affecting her arms to the mid-upper arm, the face, neck, upper chest, thighs, and calves. Pitting oedema, noted in the forearms, upper arms, chest, and thighs, had the following characteristics: it occurred in areas of affected skin—typically it occurred in the advancing front of skin involvement, was slow to induce (of bees' wax …
Prioritizing CD4 Count Monitoring in Response to ART in Resource-Constrained Settings: A Retrospective Application of Prediction-Based Classification
Authors: Livio Azzoni, Andrea S. Foulkes, Yan Liu, Xiaohong Li, Margaret Johnson, Collette Smith, Adeeba bte Kamarulzaman, Julio Montaner, Karam Mounzer, Michael Saag, Pedro Cahn, Carina Cesar, Alejandro Krolewiecki, Ian Sanne, Luis J. Montaner
Journal: PLoS Medicine (2012)

Global programs of anti-HIV treatment depend on sustained laboratory capacity to assess treatment initiation thresholds and treatment response over time. Currently, there is no valid alternative to CD4 count testing for monitoring immunologic responses to treatment, but laboratory cost and capacity limit access to CD4 testing in resource-constrained settings. Thus, methods to prioritize patients for CD4 count testing could improve treatment monitoring by optimizing resource allocation.Using a prospective cohort of HIV-infected patients (n=1,956) monitored upon antiretroviral therapy initiation in seven clinical sites with distinct geographical and socio-economic settings, we retrospectively apply a novel prediction-based classification (PBC) modeling method. The model uses repeatedly measured biomarkers (white blood cell count and lymphocyte percent) to predict CD4(+) T cell outcome through first-stage modeling and subsequent classification based on clinically relevant thresholds (CD4(+) T cell count of 200 or 350 cells/µl). The algorithm correctly classified 90% (cross-validation estimate=91.5%, standard deviation [SD]=4.5%) of CD4 count measurements <200 cells/µl in the first year of follow-up; if laboratory testing is applied only to patients predicted to be below the 200-cells/µl threshold, we estimate a potential savings of 54.3% (SD=4.2%) in CD4 testing capacity. A capacity savings of 34% (SD=3.9%) is predicted using a CD4 threshold of 350 cells/µl. Similar results were obtained over the 3 y of follow-up available (n=619). Limitations include a need for future economic healthcare outcome analysis, a need for assessment of extensibility beyond the 3-y observation time, and the need to assign a false positive threshold.Our results support the use of PBC modeling as a triage point at the laboratory, lessening the need for laboratory-based CD4(+) T cell count testing; implementation of this tool could help optimize the use of laboratory resources, directing CD4 testing towards higher-risk patients. However, further prospective studies and economic analyses are needed to demonstrate that the PBC model can be effectively applied in clinical settings. Please see later in the article for the Editors' Summary.
Anaphylactic Shock due to Ingestion of Psyllium Laxative
Authors: RAIMO SUHONEN, ILKKA KANTOLA, FRED BJÖRKSTEN
Journal: Allergy (1983)

Psyllium, seed of Plantago ovata , is a major constituent of several bulk laxatives. There are several reports on its role as an occupational respiratory allergen. We describe a severe anaphylactic reaction caused by ingestion of psyllium laxative. The hypersensitivity to Plantago ovata was confirmed by skin testing and RAST. The possibility of hypersensitivity reaction to psyllium laxatives should be recognized and included in marketing information.
Autologous Pancreatic Islet Transplantation for Severe Trauma
Authors: Rahul M. Jindal, Camillo Ricordi, Craig D. Shriver
Journal: New England Journal of Medicine (2010)

To the Editor: Autologous pancreatic islet transplantation has been successfully carried out after total pancreatectomy for chronic pancreatitis, and allogeneic islet-cell transplantation has had limited success.1,2 We report a case of successful islet transplantation from the pancreas after total pancreatectomy because of trauma. A 21-year-old airman serving in a remote part of Afghanistan was hit by three high-velocity bullets on November 21, 2009, and was rapidly transferred to Walter Reed Army Medical Center. As part of needed rescue surgery, a portion of the stomach, the gallbladder, the entire duodenum, and the head of the pancreas were removed. In addition, . . .
Nonerythrodermic, leukemic variant of cutaneous T-cell lymphoma with indolent clinical course: Th2-type tumor cells lacking T-cell receptor/CD3 expression and coinfiltrating tumoricidal CD8+ T cells
Authors: Yoshiki Tokura, Hiroaki Yagi, Naohiro Seo, Tomoko Takagi, Masahiro Takigawa
Journal: Journal of the American Academy of Dermatology (2000)
In Vivo Imaging of Radial Keratoneuritis in Patients with Acanthamoeba keratitis by Anterior-Segment Optical Coherence Tomography
Authors: Natsuko Yamazaki, Akira Kobayashi, Hideaki Yokogawa, Yasuhisa Ishibashi, Yosaburo Oikawa, Masaharu Tokoro, Kazuhisa Sugiyama
Journal: Ophthalmology (2014)
Neonatal Losartan Treatment Suppresses Renal Expression of Molecules Involved in Cell-Cell and Cell-Matrix Interactions
Authors: Yun Chen, Daina Lasaitiene, Britt G. Gabrielsson, Lena M.S. Carlsson, Ha[Combining Ring Above]kan Billig, Bjo[Combining Diaeresis] Carlsson, Niels Marcussen, Xiao-Feng Sun, Peter Friberg
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Lack of neonatal angiotensin II type 1 receptor (AT1) stimulation produces renal abnormalities characterized by papillary atrophy and impaired urinary concentrating ability, but the mechanisms involved are still unclear. DNA microarray was used to identify genes that are differentially expressed in renal medulla in response to neonatal treatment with AT1 receptor antagonist losartan (30 mg/kg per d), which commenced within 24 h after birth. The data showed that losartan treatment for 48 h downregulated 68 genes, ∼30% of which encode various components of cytoskeleton and cytoskeleton-associated proteins, extracellular matrix, and enzymes involved in extracellular matrix maturation or turnover. With the use of immunohistochemistry and Western immunoblot, the microarray data were confirmed and it was demonstrated that losartan suppressed renal expression of syndecan 2, α-smooth muscle actin, MHC class II, and leukocyte type 12-lipoxygenase by day 4. In addition, losartan inhibited medullary expression of integrin α6 and caused relocalization of integrins α6 and α3. Moreover, losartan inhibited cell proliferation in medullary tubules by day 9, as detected by Ki-67 immunostaining. This study provides new data supporting the contention that a lack of AT1 receptor stimulation results in abnormal matrix assembly, disturbed cell-cell and cell-matrix interactions, and subsequent abnormal tubular maturation. Moreover, regulation of the expression of leukocyte type 12-lipoxygenase and α-smooth muscle actin by the renin-angiotensin system in the immature kidney adds new knowledge toward the understanding of renal vascular development.
Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation
Authors: Yoshiaki Tsutsumi, Hiroaki Matsubara, Hiroya Masaki, Hiroki Kurihara, Satoshi Murasawa, Shinji Takai, Mizuo Miyazaki, Yoshihisa Nozawa, Ryoji Ozono, Keigo Nakagawa, Takeshi Miwa, Noritaka Kawada, Yasukiyo Mori, Yasunobu Shibasaki, Yohko Tanaka, Soichiro Fujiyama, Yohko Koyama, Atsuko Fujiyama, Hakuo Takahashi, Toshiji Iwasaka
Journal: Journal of Clinical Investigation (1999)

Angiotensin II (Ang II) is a potent vasopressor peptide that interacts with 2 major receptor isoforms — AT1 and AT2. Although blood pressure is increased in AT2 knockout mice, the underlying mechanisms remain undefined because of the low levels of expression of AT2 in the vasculature. Here we overexpressed AT2 in vascular smooth muscle (VSM) cells in transgenic (TG) mice. Aortic AT1 was not affected by overexpression of AT2. Chronic infusion of Ang II into AT2-TG mice completely abolished the AT1-mediated pressor effect, which was blocked by inhibitors of bradykinin type 2 receptor (icatibant) and nitric oxide (NO) synthase (L-NAME). Aortic explants from TG mice showed greatly increased cGMP production and diminished Ang II–induced vascular constriction. Removal of endothelium or treatment with icatibant and L-NAME abolished these AT2-mediated effects. AT2 blocked the amiloride-sensitive Na+/H+ exchanger, promoting intracellular acidosis in VSM cells and activating kininogenases. The resulting enhancement of aortic kinin formation in TG mice was not affected by removal of endothelium. Our results suggest that AT2 in aortic VSM cells stimulates the production of bradykinin, which stimulates the NO/cGMP system in a paracrine manner to promote vasodilation. Selective stimulation of AT2 in the presence of AT1 antagonists is predicted to have a beneficial clinical effect in controlling blood pressure.
Osteopontin Promotes Vascular Endothelial Growth Factor–Dependent Breast Tumor Growth and Angiogenesis via Autocrine and Paracrine Mechanisms
Authors: Goutam Chakraborty, Shalini Jain, Gopal C. Kundu
Journal: Cancer Research (2008)

Abstract Angiogenesis is the hallmark of cancer, and development of aggressiveness of primary tumor depends on de novo angiogenesis. Here, using multiple in vitro and in vivo models, we report that osteopontin (OPN) triggers vascular endothelial growth factor (VEGF)–dependent tumor progression and angiogenesis by activating breast tumor kinase (Brk)/nuclear factor–inducing kinase/nuclear factor-κB (NF-κB)/activating transcription factor-4 (ATF-4) signaling cascades through autocrine and paracrine mechanisms in breast cancer system. Our results revealed that both exogenous and tumor-derived OPN play significant roles in VEGF-dependent tumor angiogenesis. Clinical specimen analysis showed that OPN and VEGF expressions correlate with levels of neuropilin-1, Brk, NF-κB, and ATF-4 in different grades of breast cancer. Consequently, OPN plays essential role in two key aspects of tumor progression: VEGF expression by tumor cells and VEGF-stimulated neovascularization. Thus, targeting OPN and its regulated signaling network could be a novel strategy to block tumor angiogenesis and may develop an effective therapeutic approach for the management of breast cancer. [Cancer Res 2008;68(1):152–61]
Endothelin and sex hormones modulate the fibronectin synthesis by cultured human skin scleroderma fibroblasts
Authors: S Soldano, P Montagna, B Villaggio, A Parodi, G Gianotti, A Sulli, B Seriolo, M E Secchi, M Cutolo
Journal: Annals of the Rheumatic Diseases (2008)

To evaluate the influence of endothelin-1 (ET-1) and sex hormones on cell proliferation and extracellular matrix (ECM) synthesis (ie, fibronectin, laminin) by cultured normal and scleroderma (SSc) human skin fibroblasts (FBs).Primary cultures of FBs were treated with ET-1 and sex hormones (17beta-oestradiol or testosterone) for 24 h. Cell growth was analysed by methiltetrazolium salt test, ECM synthesis was evaluated by immunocytochemistry and western blot, both at 24 h.In normal FBs, ET-1 and 17beta-oestradiol, as well as their combination, increased cell growth (p<0.001, p<0.001, p<0.01 vs untreated cells (control), respectively) and fibronectin synthesis (p<0.05, p<0.05, p<0.01 vs control, respectively). By contrast, testosterone either alone or in combination with ET-1 did not influence cell proliferation, but decreased fibronectin synthesis (p<0.05, testosterone vs control). In SSc FBs, ET-1 and 17beta-oestradiol alone or their combination induced an increased fibronectin synthesis (p<0.05, p<0.05, p<0.01 vs control, respectively). Unexpectedly, testosterone induced an increase of fibronectin synthesis (p<0.05 vs control).ET-1 and 17beta-oestradiol seem to exert a profibrotic effect in normal and SSc culture FBs and might suggest their synergistic effect in the pathogenesis of the fibrotic process in SSc.
A Phase I Study of 17-Allylaminogeldanamycin in Relapsed/Refractory Pediatric Patients with Solid Tumors: A Children's Oncology Group Study
Authors: Brenda J. Weigel, Susan M. Blaney, Joel M. Reid, Stephanie L. Safgren, Rochelle Bagatell, John Kersey, Joseph P. Neglia, S. Percy Ivy, Ashish M. Ingle, Luke Whitesell, Richard J. Gilbertson, Mark Krailo, Matthew Ames, Peter C. Adamson
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To determine the recommended phase 2 dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG). Experimental Design: 17-AAG was administered as a 60-min infusion, on days 1, 4, 8, and 11 of a 21-day cycle at dose levels of 150, 200, 270, and 360 mg/m2/dose. Pharmacokinetic studies and evaluations for Hsp72 and Akt levels in peripheral blood mononuclear cells were done during the first course of therapy. Results: Seventeen patients (7 males), median 7 years of age (range, 1-19 years), were enrolled using a standard dose escalation scheme. No DLTs were observed. Although there were no objective responses, three patients remain on therapy at 6+, 7+, and 9+ months with stable disease. One patient with hepatoblastoma had a reduction in α-fetoprotein and stable disease over three cycles. At 270 mg/m2/dose, the Cmax and areas under the plasma concentration-time curves of 17-AAG were 5,303 ± 1,591 ng/mL and 13,656 ± 4,757 ng/mL h, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.24 ± 0.80 h. Induction of Hsp72, a surrogate marker for inhibition of Hsp90, was detected at the 270 mg/m2 dose level. Conclusions: Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT. Evidence for drug-induced modulation of Hsp90 systemically was also detected. The recommended phase II dose of 17-AAG is 360 mg/m2/d. Non-DMSO–containing formulations may improve acceptance of this drug by children and their families.
Airway Hyperresponsiveness, Inflammation, and Subepithelial Collagen Deposition in Recently Diagnosed versus Long-standing Mild Asthma
Authors: LOUIS-PHILIPPE BOULET, HÉLÈNE TURCOTTE, MICHEL LAVIOLETTE, FRANÇOISE NAUD, MARIE-CLAUDE BERNIER, SIMON MARTEL, JAMILA CHAKIR
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

This study aimed at documenting airway inflammation and subepithelial collagen deposition in patients using only inhaled β2-agonists with either recently diagnosed asthma (RDA: ⩽ 2 yr, n = 16) or long-standing asthma (LSA: ⩾ 13 yr, n = 16) and at the influence of an intense inhaled corticosteroid (ICS) treatment on these parameters, in relation to changes in airway responsiveness. Patients had a methacholine inhalation test and a bronchoscopy with bronchial biopsies before and after an 8-wk treatment with inhaled fluticasone propionate (FP), 1,000 μ g/day. Baseline FEV1 (mean ± SEM) was normal and similar in both groups (RDA: 98.1 ± 2.7, LSA: 94.5 ± 4.6%). Geometric mean methacholine PC20 was lower in LSA than in RDA (0.44 versus 3.37 mg/ml) at baseline and improved similarly by 1.85 and 1.86 double concentrations with FP treatment. PC20 normalized ( ⩾ 16 mg/ml) in five patients with RDA and two patients with LSA. Baseline mean bronchial cell counts (per mm2 connective tissue surface) for CD3+, CD4+, CD8+, CD25+, EG1+, CD45ro+, and AA1+ cells were similar in both groups. With FP, EG1+ (p < 0.001), EG2+ (p = 0.018), and AA1+ counts (p = 0.009) decreased significantly in both groups while CD45ro+ (p = 0.02) counts decreased only in LSA. Baseline type 1 and type 3 collagen deposition underneath the basement membrane was similar in RDA and LSA and did not change significantly after FP. This study shows that recent compared to long-standing mild asthma is associated with a similar degree of airway inflammation and subepithelial fibrosis, and a similar improvement in airway hyperresponsiveness after 8 wk on high-dose ICS. It also indicates that once asthma becomes symptomatic, airway responsiveness cannot normalize in most subjects over such a time period, even with a high dose of ICS.
Modulation of Pancreatic Cancer Chemoresistance by Inhibition of TAK1
Authors: Davide Melisi, Qianghua Xia, Genni Paradiso, Jianhua Ling, Tania Moccia, Carmine Carbone, Alfredo Budillon, James L. Abbruzzese, Paul J. Chiao
Journal: JNCI Journal of the National Cancer Institute (2011)

BackgroundTGF-β-activated kinase-1 (TAK1), a mitogen-activated protein kinase kinase kinase, functions in the activation of nuclear factor κB (NF-κB) and activator protein-1, which can suppress proapoptotic signaling pathways and thus promote resistance to chemotherapeutic drugs. However, it is not known if inhibition of TAK1 is effective in reducing chemoresistance to therapeutic drugs against pancreatic cancer.
Audit of a melanoma screening day in the U.K.: clinical results, participant satisfaction and perceived value
Authors: S.A. Holme, S. Varma, M.M.U. Chowdhury, D.L. Roberts
Journal: British Journal of Dermatology (2001)

Background The incidence of cutaneous malignant melanoma (MM) has risen significantly over the last 50 years in caucasian populations. Mortality is related to the Breslow thickness of the lesion, and early detection followed by complete surgical excision is crucial to reducing this. Skin screening events have been advocated as a means of detecting greater numbers of MMs in the earlier and thinner stages. Objectives To assess the feasibility and effectiveness of this approach in the U.K. Methods The Department of Dermatology, Singleton Hospital, Swansea, U.K. offered a 1-day melanoma screening event in summer 1998 at which 832 consecutive individuals were seen. A postal questionnaire 1 year after the event audited participant perceived value and satisfaction. Results Three MMs were identified (yield 1 : 277), all < 0·75 mm in thickness. Despite high participant satisfaction and perceived value, the pick-up rate of malignancy was significantly lower than at rapid access pigmented lesion clinics. Conclusions In a country such as the U.K., with comprehensive health coverage and a low incidence of MM, triage for melanoma and referral to specialists by general practitioners may be more cost and time effective.