tbuckley/cabot-search huggingface dataset:
Urinary α1-Microglobulin as a Marker of Nephropathy in Type 2 Diabetic Asian Subjects in Singapore
Authors: Ching-Ye Hong, Kenneth Hughes, Kee-Seng Chia, Vivian Ng, Sing-Lin Ling
Journal: Diabetes Care (2003)

OBJECTIVE—This study examines urinary α1-microglobulin as a marker of early nephropathy in type 2 diabetic Chinese, Malays, and Asian Indians in Singapore. RESEARCH DESIGN AND METHODS—A cross-sectional study was performed on 590 consecutive type 2 diabetic patients (296 males, 294 females) who were on routine follow-up at a primary care clinic. Information was obtained from interviews, case notes, and blood and urine samples. Because the distribution of urinary α1-microglobulin levels was highly skewed, these levels were log-transformed, and geometric means were calculated. There was correction for variability in urine flow by dividing by urine creatinine levels, given as mg/mmol urine creatinine, and adjustment for confounding variables. RESULTS—Urinary α1-microglobulin was higher in men than in women and was directly related to age, but no ethnic differences were apparent. It was directly related to duration of diabetes, with adjusted geometric means of 1.19 and 1.43 mg/mmol urine creatinine for a duration of &amp;lt;10 and ≥10 years, respectively (P = 0.07). Urinary α1-microglobulin was highest in patients on insulin, followed by those on oral medication and then those on diet alone (adjusted geometric means: 1.47, 1.36, and 0.86 mg/mmol urine creatinine, respectively; P = 0.01). Levels were also higher in patients with poor glucose control, as measured by HbA1c, fasting plasma glucose, and 2-h postprandial plasma glucose (P &amp;lt; 0.01 for each). Urinary α1-microglobulin was directly related to albuminuria, with adjusted geometric means for normoalbuminuria, microalbuminuria, and macroalbuminuria of 1.06, 1.47, and 4.72 mg/mmol urine creatinine, respectively (P &amp;lt; 0.01). However, of patients with normoalbuminuria, 33.6% had raised urinary α1-microglobulin. Likewise, of patients with normal urinary α1-microglobulin, 27.6% had albuminuria. CONCLUSIONS—Urinary α1-microglobulin was related to duration, severity, and control of diabetes. Urinary α1-microglobulin and albumin were directly related, but in some patients, one was present in the absence of the other. Hence, in addition to albuminuria (which measures glomerular dysfunction), urinary α1-microglobulin (which measures proximal tubular dysfunction) is useful for the early detection of nephropathy in diabetic subjects.
Care of the Potential Organ Donor
Authors: Kenneth E. Wood, Bryan N. Becker, John G. McCartney, Anthony M. D'Alessandro, Douglas B. Coursin
Journal: New England Journal of Medicine (2004)

Organ transplantation often depends on obtaining functioning organs from a donor who has recently died. This review presents a structured approach to management of the care of the brain-dead donor so as to achieve the greatest chance of a successful outcome in the recipient of the organs. Hypotension, hypothermia, diabetes insipidus, and cardiac dysfunction are common challenges to management. Brain death affects both hormone production and physiological responses in the donor.
Analysis and interpretation of cost data in randomised controlled trials: review of published studies
Authors: J. A Barber, S. G Thompson
Journal: BMJ (1998)

<b>Objective</b> To review critically the statistical methods used for health economic evaluations in randomised controlled trials where an estimate of cost is available for each patient in the study. <b>Design</b> Survey of published randomised trials including an economic evaluation with cost values suitable for statistical analysis; 45&nbsp;such trials published in 1995&nbsp;were identified from Medline. <b>Main outcome measures</b> The use of statistical methods for cost data was assessed interms of the descriptive statistics reported, use of statistical inference, and whether the reported conclusions were justified. <b>Results</b> Although all 45&nbsp;trials reviewed apparently had cost data for each patient, only 9&nbsp;(20%) reported adequate measures of variability for these data and only 25&nbsp;(56%) gave results of statistical tests or a measure of precision for the comparison of costs between the randomised groups. Only 16&nbsp;(36%) of the articles gave conclusions which were justified on the basis of results presented in the paper. No paper reported sample size calculations for costs <b>Conclusions</b> The analysis and interpretation of cost data from published trials reveal a lack of statistical awareness. Strong and potentially misleading conclusions about the relative costs of alternative therapies have often been reported in the absence of supporting statistical evidence. Improvements in the analysis and reporting of health economic assessments are urgently required. Health economic guidelines need to be revised to incorporate more detailed statistical advice.
Fluorouracil, Epirubicin, and Cyclophosphamide With Either Docetaxel or Vinorelbine, With or Without Trastuzumab, As Adjuvant Treatments of Breast Cancer: Final Results of the FinHer Trial
Authors: Heikki Joensuu, Petri Bono, Vesa Kataja, Tuomo Alanko, Riitta Kokko, Raija Asola, Tapio Utriainen, Taina Turpeenniemi-Hujanen, Sirkku Jyrkkiö, Kari Möykkynen, Leena Helle, Seija Ingalsuo, Marjo Pajunen, Mauri Huusko, Tapio Salminen, Päivi Auvinen, Hannu Leinonen, Mika Leinonen, Jorma Isola, Pirkko-Liisa Kellokumpu-Lehtinen
Journal: Journal of Clinical Oncology (2009)

Docetaxel has not been compared with vinorelbine as adjuvant treatment of early breast cancer. Efficacy and long-term safety of a short course of adjuvant trastuzumab administered concomitantly with chemotherapy for human epidermal growth factor receptor 2 (HER2) -positive cancer are unknown.One thousand ten women with axillary node-positive or high-risk node-negative breast cancer were randomly assigned to receive three cycles of docetaxel or vinorelbine, followed in both groups by three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Women with HER2-positive cancer (n = 232) were further assigned to either receive or not receive trastuzumab for 9 weeks with docetaxel or vinorelbine. The median follow-up time was 62 months after random assignment.Women assigned to docetaxel had better distant disease-free survival (DDFS) than those assigned to vinorelbine (hazard ratio [HR] = 0.66; 95% CI, 0.49 to 0.91; P = .010). In the subgroup of HER2-positive disease, patients treated with trastuzumab tended to have better DDFS than those treated with chemotherapy only (HR = 0.65; 95% CI, 0.38 to 1.12; P = .12; with adjustment for presence of axillary nodal metastases, HR = 0.57; P = .047). In exploratory analyses, docetaxel, trastuzumab, and FEC improved DDFS compared with docetaxel plus FEC (HR = 0.32; P = .029) and vinorelbine, trastuzumab, and FEC (HR = 0.31; P = .020). The median left ventricular ejection fraction of trastuzumab-treated patients remained unaltered during the 5-year follow-up; only one woman treated with trastuzumab was diagnosed with a heart failure.Adjuvant treatment with docetaxel improves DDFS compared with vinorelbine. A brief course of trastuzumab administered concomitantly with docetaxel is safe and effective and warrants further evaluation.
Genomic Variation of Human Papillomavirus Type 16 and Risk for High Grade Cervical Intraepithelial Neoplasia
Authors: L. F. Xi, L. A. Koutsky, D. A. Galloway, N. B. Kiviat, J. Kuypers, J. P. Hughes, C. M. Wheeler, K. K. Holmes
Journal: JNCI Journal of the National Cancer Institute (1997)

Epidemiologic studies have demonstrated strong and consistent associations between the detection of human papillomavirus (HPV) type 16 DNA and the risk of cervical intraepithelial neoplasia (CIN) and cervical cancer. However, HPV16 is also the most common type of HPV in the normal population, and only a minority of women with HPV16 infection develop cervical cancer. Studies of genomic heterogeneity in HPV16 have demonstrated the presence of multiple variant forms in all human populations examined to date. It is conceivable that the natural variants of HPV16 in a given population may not have the same biologic behavior.This study was designed to determine the association between natural variants of HPV16 and the risk of biopsy-confirmed CIN 2 or 3, the most important precancerous lesions of the uterine cervix.Prospective studies were conducted among 1) women attending a university and 2) women presenting to a sexually transmitted disease clinic. Subjects were eligible for inclusion in this investigation if the initial cytologic findings did not reveal CIN 2-3 and HPV16 DNA was detected by means of a polymerase chain reaction (PCR)-based method in one or more cervical or vulvovaginal samples. Eligible subjects were followed every 4 months with cervical Pap smears and colposcopic examinations. Women were referred for biopsy if cytology or colposcopy suggested CIN 2-3. Two groups of HPV16 variants, prototype-like and nonprototype-like, were determined by means of single-strand conformation polymorphism (SSCP) analysis of PCR products from the noncoding region of the viral genome. Representative SSCP patterns from HPV16 variants were further characterized by direct DNA sequencing of the PCR products. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated by Cox regression analysis.Prototype-like variants accounted for 79% of the HPV16 detected in university students and 86% of the virus detected in patients presenting to the sexually transmitted disease clinic. CIN 2-3 was confirmed by biopsy in nine of 57 HPV16-positive women attending the university and in 10 of 66 HPV16-positive women presenting to the sexually transmitted disease clinic. Among university students, those with HPV16 nonprototype-like variants were 6.5 (95% CI = 1.6-27.2) times more likely to develop CIN 2-3 than those with prototype-like variants. A similar association was observed among women presenting to the sexually transmitted disease clinic (RR = 4.5; 95% CI = 0.9-23.8).This study suggests that the risk of developing CIN 2-3 is not the same with all variants of HPV16 and that nonprototype-like variants confer a greater risk compared with prototype-like variants. The important genomic differences underlying this increased risk of CIN 2-3 remain to be determined.
The effects of intense pulsed light in a mouse model of skin carcinogenesis
Authors: A.I. Faustino‐Rocha, D. Rodrigues, R. Ferreira, B. Colaço, P.S. Gomes, M.J. Pires, A. Gama, P.A. Oliveira
Journal: British Journal of Dermatology (2015)

Funding sources: Ana I Faustino was supported by the Portuguese Foundation for Science and Technology (post‐graduation grant SFRH/BD/102099/2014). Conflicts of interest: none declared. Dear Editor, Intense pulsed light (IPL) has been used for the treatment of several skin conditions1 and in nonablative skin rejuvenation.2 IPL apparatus can be easily acquired and used by the general public at home.3 In this study, a mouse model of two‐stage skin carcinogenesis was used in order to evaluate the effects of IPL on skin carcinogenesis and to address the lack of existing studies in this field. Sixteen 21‐week‐old female DBA/2JRccHsd mice were used (Harlan Interfauna, Iberica, Spain). Procedures were carried out in accordance with European Union directive 2010/63/EU. Food and water were provided ad libitum. The 7,12‐dimethylbenz[a]anthracene (DMBA) and 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) (Sigma‐Aldrich, St Louis, MO, U.S.A.) were diluted in acetone at concentrations of 2·0 and 0·1 mmol L−1, respectively. Animals were divided into two groups: IPL exposed and non‐IPL exposed. The skin of the dorsal region of all animals was shaved using a machine clipper (Aesculap, Centre Valley, PA, U.S.A.), and this procedure was repeated every 2 weeks. Both groups received a single topical application of DMBA on that region. Four days later, TPA was applied topically to all animals, twice a week during 22 weeks. The IPL‐exposed animals received two applications of IPL on the dorsal region, at an intensity of 2 J cm−2, on the days of TPA application over 22 weeks (Lumea SC2001/00; Philips, Amsterdam, the Netherlands). Animals were observed daily, with body weight and food and water intake recorded weekly.
Primary ileal villous atrophy is often associated with microscopic colitis
Authors: P Marteau, A Lavergne-Slove, M Lemann, Y Bouhnik, P Bertheau, H Becheur, A Galian, J C Rambaud
Journal: Gut (1997)

Three cases of apparent primary villous atrophy of the terminal ileum in women with chronic diarrhoea are reported. Eight cases have previously been reported in the literature. Clinical characteristics are the presence of severe chronic secretory diarrhoea with episodes of hypokalaemia combined with signs of ileal malabsorption and/or efficacy of cholestyramine. Diagnosis is based on ileoscopy and histology. An association with microscopic colitis was present in the three patients and in four cases in the literature. The pathogenesis of primary ileal villous atrophy remains unknown and may involve dysimmunity. Its association with microscopic colitis may indicate a common pathogenesis or support the hypothesis that the faecal stream or bile salts play a role in the pathogenesis of microscopic colitis.
Using Gene-History and Expression Analyses to Assess the Involvement of LGI Genes in Human Disorders
Authors: Wenli Gu, Yann Gibert, Thierry Wirth, Andrea Elischer, Wilhelm Bloch, Axel Meyer, Ortrud K. Steinlein, Gerrit Begemann
Journal: Molecular Biology and Evolution (2005)

Mutations in the leucine-rich, glioma-inactivated 1 gene, LGI1, cause autosomal-dominant lateral temporal lobe epilepsy via unknown mechanisms. LGI1 belongs to a subfamily of leucine-rich repeat genes comprising four members (LGI1–LGI4) in mammals. In this study, both comparative developmental as well as molecular evolutionary methods were applied to investigate the evolution of the LGI gene family and, subsequently, of the functional importance of its different gene members. Our phylogenetic studies suggest that LGI genes evolved early in the vertebrate lineage. Genetic and expression analyses of all five zebrafish lgi genes revealed duplications of lgi1 and lgi2, each resulting in two paralogous gene copies with mostly nonoverlapping expression patterns. Furthermore, all vertebrate LGI1 orthologs experience high levels of purifying selection that argue for an essential role of this gene in neural development or function. The approach of combining expression and selection data used here exemplarily demonstrates that in poorly characterized gene families a framework of evolutionary and expression analyses can identify those genes that are functionally most important and are therefore prime candidates for human disorders.
Antiangiogenesis Targeting Tumor Microenvironment Synergizes Glucuronide Prodrug Antitumor Activity
Authors: Ting-Yi Juan, Steve R. Roffler, Hsien-San Hou, Shih-Ming Huang, Kai-Chuan Chen, Yu-Lin Leu, Zeljko M. Prijovich, Cheng-Ping Yu, Chang-Chieh Wu, Guang-Huan Sun, Tai-Lung Cha
Journal: Clinical Cancer Research (2009)

Abstract Purpose: This study is aimed at investigating the in vivo antitumor activity of a novel cell-impermeable glucuronide prodrug, 9-aminocamptothecin glucuronide (9ACG), and elucidating the synergistically antitumor effects of antiangiogenesis therapy by targeting the tumor microenvironment. Experimental Design: We analyzed the antitumor effects of 9ACG alone or combined with antiangiogenic monoclonal antibody DC101 on human tumor xenografts by measuring tumor growth and mouse survival in BALB/c nu/nu nude and NOD/SCID mice. The drug delivery, immune response, and angiogenesis status in treated tumors were assessed by high performance liquid chromatography, immunohistochemistry, and immunofluorescence assays. Results: We developed a nontoxic and cell-impermeable glucuronide prodrug, 9ACG, which can only be activated by extracellular β-glucuronidase to become severely toxic. 9ACG possesses potent antitumor activity against human tumor xenografts in BALB/c nu/nu nude mice but not for tumors implanted in NOD/SCID mice deficient in macrophages and neutrophils, suggesting that these cells play an important role in activating 9ACG in the tumor microenvironment. Most importantly, antiangiogenic monoclonal antibody DC101 potentiated single-dose 9ACG antitumor activity and prolonged survival of mice bearing resistant human colon tumor xenografts by providing strong β-glucuronidase activity and prodrug delivery through enhancing inflammatory cell infiltration and normalizing tumor vessels in the tumor microenvironment. We also show that inflammatory cells (neutrophils) were highly infiltrated in advanced human colon cancer tissues compared with normal counterparts. Conclusions: Our study provides in vivo evidence that 9ACG has potential for prodrug monotherapy or in combination with antiangiognesis treatment for tumors with infiltration of macrophage or neutrophil inflammatory cells.
Point-of-Care Ultrasonography
Authors: Christopher L. Moore, Joshua A. Copel
Journal: New England Journal of Medicine (2011)

Compact ultrasound technology has facilitated growth in point-of-care uses in many specialties. This review includes videos demonstrating the use of ultrasonography to guide central venous access, detect pneumothorax, detect evidence of hemorrhage after trauma, and screen for abdominal aortic aneurysm.
Impaired Notch Signaling Promotes <i>De novo</i> Squamous Cell Carcinoma Formation
Authors: Aaron Proweller, Lili Tu, John J. Lepore, Lan Cheng, Min Min Lu, John Seykora, Sarah E. Millar, Warren S. Pear, Michael S. Parmacek
Journal: Cancer Research (2006)

Abstract Signaling through Notch receptors in the skin has been implicated in the differentiation, proliferation, and survival of keratinocytes, as well as in the pathogenesis of basal cell carcinoma (BCC). To determine the composite function of Notch receptor–mediated signaling in the skin and overcome potential redundancies between receptors, conditional transgenic mice were generated that express the pan-Notch inhibitor, dominant-negative Mastermind Like 1 (DNMAML1), to repress all canonical [CBF-1/Suppressor of hairless/LAG-1 (CSL)–dependent] Notch signaling exclusively in the epidermis. Here, we report that DNMAML1 mice display hyperplastic epidermis and spontaneously develop cutaneous squamous cell carcinoma (SCC) as well as dysplastic precursor lesions, actinic keratoses. Mice expressing epidermal DNMAML1 display enhanced accumulation of nuclear β-catenin and cyclin D1 in suprabasilar keratinocytes and in lesional cells from SCCs, which was also observed in human cutaneous SCC. These results suggest a model wherein CSL-dependent Notch signaling confers protection against cutaneous SCC. The demonstration that inhibition of canonical Notch signaling in mice leads to spontaneous formation of SCC and recapitulates the disease in humans yields fundamental insights into the pathogenesis of SCC and provides a unique in vivo animal model to examine the pathobiology of cutaneous SCC and for evaluating novel therapies. (Cancer Res 2006; 66(15): 7438-44)
Cytomegalovirus exploits IL-10–mediated immune regulation in the salivary glands
Authors: Ian R. Humphreys, Carl de Trez, April Kinkade, Chris A. Benedict, Michael Croft, Carl F. Ware
Journal: The Journal of Experimental Medicine (2007)

The salivary glands represent a major site of cytomegalovirus replication and transmission to other hosts. Despite control of viral infection by strong T cell responses in visceral organs cytomegalovirus replication continues in the salivary glands of mice, suggesting that the virus exploits the mucosal microenvironment. Here, we show that T cell immunity in the salivary glands is limited by the induction of CD4 T cells expressing the regulatory cytokine interleukin (IL)-10. Blockade of IL-10 receptor (IL-10R) with an antagonist antibody dramatically reduced viral load in the salivary glands, but not in the spleen. The mucosa-specific protection afforded by IL-10R blockade was associated with an increased accumulation of CD4 T cells expressing interferon γ, suggesting that IL-10R signaling limits effector T cell differentiation. Consistent with this, an agonist antibody targeting the tumor necrosis factor receptor superfamily member OX40 (TNFRSF4) enhanced effector T cell differentiation and increased the number of interferon γ–producing T cells, thus limiting virus replication in the salivary glands. Collectively, the results indicate that modulating effector T cell differentiation can counteract pathogen exploitation of the mucosa, thus limiting persistent virus replication and transmission.
Early Treatment With Lisinopril and Spironolactone Preserves Cardiac and Skeletal Muscle in Duchenne Muscular Dystrophy Mice
Authors: Jill A. Rafael-Fortney, Neeraj S. Chimanji, Kevin E. Schill, Christopher D. Martin, Jason D. Murray, Ranjit Ganguly, Jenna E. Stangland, Tam Tran, Ying Xu, Benjamin D. Canan, Tessily A. Mays, Dawn A. Delfín, Paul M.L. Janssen, Subha V. Raman
Journal: Circulation (2011)

Background— Nearly universal cardiomyopathy in Duchenne muscular dystrophy (DMD) contributes to heart failure and death. Because DMD patients show myocardial fibrosis well before functional impairment, we postulated that earlier treatment using drugs with antifibrotic effect may be beneficial. Methods and Results— Three groups of 10 utrn +/− ; mdx , or “het” mice, deficient for dystrophin and haploinsufficient for utrophin with skeletal myopathy and cardiomyopathy that closely mimics clinical DMD were studied. One het group received spironolactone and lisinopril starting at 8 weeks of life (het-treated-8); a second received the same starting at 4 weeks of life (het-treated-4), and the third het group was untreated. At 20 weeks, all mice had normal ejection fractions though circumferential strain rate was abnormal (−0.21±0.08) in untreated hets. This improved to −0.40±0.07 in het-treated-8 mice ( P =0.003) and further improved to −0.56±0.10 in het-treated-4 mice ( P =0.014 for het-treated-4 versus het-treated-8). Treated mice showed less cardiomyocyte damage, with a 44% reduction in intracardiomyocyte serum immunoglobulin G localization in het-treated-8 mice ( P &lt;0.0001) and a further 53% reduction in het-treated-4 mice ( P =0.0003 versus het-treated-8); matrix metalloproteinases were similarly reduced. Cardiac, limb, and diaphragm function by ex vivo muscle testing remained at 80% of normal with early treatment compared to a decline to 40% of normal skeletal muscle function without treatment. Conclusions— These findings offer clinically available medications with proven antifibrotic effect as a new therapeutic strategy in DMD. Early initiation greatly attenuated myocardial disease and, for the first time with these drugs, improved skeletal myopathy. Thus, early initiation of such agents warrants further clinical evaluation to maintain ambulatory, respiratory, and cardiac function for patients with DMD and related myopathies.