tbuckley/cabot-search huggingface dataset:
Pan-colonic decrease in interstitial cells of Cajal in patients with slow transit constipation
Authors: G L Lyford
Journal: Gut (2002)

<b>Background:</b> Interstitial cells of Cajal (ICC) are required for normal intestinal motility. ICC are found throughout the human colon and are decreased in the sigmoid colon of patients with slow transit constipation. <b>Aims:</b> The aims of this study were to determine the normal distribution of ICC within the human colon and to determine if ICC are decreased throughout the colon in slow transit constipation. <b>Patients:</b> The caecum, ascending, transverse, and sigmoid colons from six patients with slow transit constipation and colonic tissue from patients with resected colon cancer were used for this study. <b>Methods:</b> ICC cells were identified with a polyclonal antibody to c-Kit, serial 0.5 μm sections were obtained by confocal microscopy, and three dimensional software was employed to reconstruct the entire thickness of the colonic muscularis propria and submucosa. <b>Results:</b> ICC were located within both the longitudinal and circular muscle layers. Two networks of ICC were identified, one in the myenteric plexus region and another, less defined network, in the submucosal border. Caecum, ascending colon, transverse colon, and sigmoid colon displayed similar ICC volumes. ICC volume was significantly lower in the slow transit constipation patients across all colonic regions. <b>Conclusions:</b> The data suggest that ICC distribution is relatively uniform throughout the human colon and that decreased ICC volume is pan-colonic in idiopathic slow transit constipation.
Republished research: Treatment for acute anterior cruciate ligament tear: five year outcome of randomised trial
Authors: Richard B Frobell, Harald P Roos, Ewa M Roos, Frank W Roemer, Jonas Ranstam, L Stefan Lohmander
Journal: British Journal of Sports Medicine (2013)

Study question In young active adults with an acute anterior cruciate ligament (ACL) rupture, do patient reported or radiographic outcomes after five years differ between those treated with rehabilitation plus early ACL reconstruction and those treated with rehabilitation and optional delayed ACL reconstruction?

Summary answer At five years, patients assigned to rehabilitation plus early ACL reconstruction did not differ significantly in patient reported or radiographic outcomes from those assigned to initial rehabilitation with the option of having a later reconstruction if needed.

What is known and what this paper adds The relative efficacy of surgical reconstruction and …
Assessing the Quality and Value of Quality-of-Life Measurement in Breast Cancer Clinical Trials
Authors: Patricia A. Ganz
Journal: JNCI Journal of the National Cancer Institute (2011)

It was more than 30 years ago that the first efforts to incorporate quality-of-life (QOL) measurements into cancer treatment trials began in studies of women with advanced breast cancer (1). In that study, the investigators used an ad hoc instrument with linear analog scales to focus on the common side effects of chemotherapy that was being given to women with advanced metastatic breast cancer, and they proposed that self-report by the patient herself would provide valuable information about toxicity and tolerability. This proposed assessment strategy paralleled the first use of multimodal chemotherapy in the setting of metastatic breast cancer, in which endocrine therapies had dominated treatment for nearly a century. At that time, women routinely received radical mastectomy as primary surgery and no one would have dreamed of the dramatic changes that ensued in early detection, surgical management, and multimodal adjuvant therapies that are now standard for women with early-stage breast cancer (2). Nor would those early QOL investigators have anticipated the explosion in the development and psychometric evaluation of various tools to evaluate QOL and patient-reported outcomes (3), as well as the routine incorporation of these assessments in a wide range of randomized clinical trials of treatment and supportive care for women with breast cancer (4). In this issue of the Journal, Lemieux et al. (5) extend a previously published systematic review of randomized clinical trials in breast cancer that included studies published through 2000 (4). In this update of studies from 2001 to 2009, which used a systematic search and reporting strategy similar to that in the previous review, these authors further our understanding of how measurement of QOL outcomes adds value to randomized clinical trials in breast cancer. During the past decade, an impressive number of trials were published (n = 190) that added to those previously reported on (n = 66), reflecting the increasing interest in the inclusion of QOL and patient-reported outcomes in clinical trials, as well as the high volume of treatment and behavioral intervention research focused on patients with breast cancer. However, despite this expansion in the number of trials, the authors identified persistent limitations in the quality of statistical methods used in these studies—with new emphasis on description of statistical power and/or sample size calculation for the QOL outcomes, documentation of missing data, and reporting of the clinical significance of the QOL findings. Inclusion of these elements of trial design and analysis has become a standardized part of QOL study design in recent years, especially with respect to labeling claims for devices
Adenovirus-Mediated Overexpression of Tissue Inhibitor of Metalloproteinase-1 Reduces Atherosclerotic Lesions in Apolipoprotein E–Deficient Mice
Authors: M. Rouis, C. Adamy, N. Duverger, P. Lesnik, P. Horellou, M. Moreau, F. Emmanuel, J. M. Caillaud, P. M. Laplaud, C. Dachet, M. J. Chapman
Journal: Circulation (1999)

Background —To define the role of metalloproteinases (MMPs) in the development of lipid-rich atherosclerotic lesions in relation to the balance between proteolytic and antiproteolytic activities, we investigated the impact of adenovirus-mediated elevation in the circulating levels of human tissue inhibitor of MMP (TIMP-1) in atherosclerosis-susceptible apolipoprotein E–deficient (apoE −/− ) mice. Methods and Results —Infusion of apoE −/− mice fed a lipid-rich diet with rAd.RSV.TIMP-1 (1×10 11 viral particles) resulted in high hepatic expression of TIMP-1. At 2 weeks after injection, plasma TIMP-1 levels ranged from 7 to 24 μg/mL (mean 14.8±6.8). Marked overexpression of TIMP-1 was transient, with levels of TIMP-1 decreasing to 2.5 to 8 μg/mL (mean 4.3±2.1) at 4 weeks. Plasma lipid and lipoprotein levels in mice treated with rAd.RSV.TIMP-1 were similar to those treated with rAd.RSV.βGal. However, rAd.RSV.TIMP-1–infused mice displayed a marked reduction (≈32%; P &lt;0.05) in mean lesion area per section (512±121 μm 2 ×10 3 ; n=12 sections from 4 animals) as compared with rAd.RSV.βGal-infused mice (750±182 μm 2 ×10 3 ; n=12 sections from 4 animals). Similarly, marked reduction in macrophage deposition as well as MMP-2, MMP-3, and MMP-13 antigens was observed. Conclusions —Histological and immunohistologic analyses of atherosclerotic lesions revealed increases in collagen, elastin, and smooth muscle α-actin content in mice treated with rAd.RSV.TIMP-1. These qualitative and quantitative features were the consequence of TIMP-1 infiltration from plasma to arterial intima, as immunohistochemical analyses revealed an abundance of TIMP-1 specifically in lesions of rAd.RSV.TIMP-1–treated mice.
Interactions between Plexin-A2, Plexin-A4, and Semaphorin 6A Control Lamina-Restricted Projection of Hippocampal Mossy Fibers
Authors: Fumikazu Suto, Miu Tsuboi, Haruyuki Kamiya, Hidenobu Mizuno, Yuji Kiyama, Shoji Komai, Masayuki Shimizu, Makoto Sanbo, Takeshi Yagi, Yasushi Hiromi, Alain Chédotal, Kevin J. Mitchell, Toshiya Manabe, Hajime Fujisawa
Journal: Neuron (2007)
Deficiency in the Formation of 20-Hydroxyeicosatetraenoic Acid Enhances Renal Ischemia-Reperfusion Injury
Authors: Yoshikazu Muroya, Fan Fan, Kevin R. Regner, John R. Falck, Michael R. Garrett, Luis A. Juncos, Richard J. Roman
Journal: Journal of the American Society of Nephrology (2015)

Ischemia-reperfusion (IR) injury is the most common cause of AKI. The susceptibility to develop AKI varies widely among patients. However, little is known about the genes involved. 20-Hydroxyeicosatetraenoic acid (20-HETE) has an important role in the regulation of renal tubular and vascular function and has been implicated in IR injury. In this study, we examined whether a deficiency in the renal formation of 20-HETE enhances the susceptibility of Dahl salt-sensitive (SS) rats to ischemic AKI. Transfer of chromosome 5 containing the CYP4A genes responsible for the formation of 20-HETE from the Brown Norway (BN) rat onto the SS genetic background increased renal 20-HETE levels after ischemia and reduced plasma creatinine levels (±SEM) 24 hours after IR from 3.7±0.1 to 2.0±0.2 mg/dl in an SS.5(BN)-consomic strain. Transfer of this chromosome also prevented the secondary decline in medullary blood flow and ischemia that develops 2 hours after IR in the susceptible SS strain. Blockade of the synthesis of 20-HETE with HET0016 reversed the renoprotective effects in SS.5(BN) rats. Similar results were observed in an SS.5(Lew)-congenic strain, in which a smaller region of chromosome 5 containing the CYP4A genes from a Lewis rat was introgressed onto the SS genetic background. These results indicate that 20-HETE has a protective role in renal IR injury by maintaining medullary blood flow and that a genetic deficiency in the formation of 20-HETE increases the susceptibility of SS rats to ischemic AKI.
Hepatocyte cytotoxicity is facilitated by asialoglycoprotein receptor
Authors: Clifford S. Guy, Sherri L. Rankin, Tomasz I. Michalak
Journal: Hepatology (2011)

It has been recently identified that hepatocytes can act as cytotoxic effectors and can kill contacted cells by way of CD95 ligand-CD95 and perforin-dependent pathways. However, it remained unknown whether hepatocyte-mediated cell killing is indiscriminant or is directed toward targets with particular cell surface characteristics, as well as whether hepatocytes have the capacity to directly eliminate contacted lymphocytes. In this study, we found that desialylation of surface glycoproteins significantly augments cell susceptibility to hepatocyte-mediated killing. Using asialofetuin as a competitive ligand, and by silencing gene transcription with specific small interfering RNA, we found that the asialoglycoprotein receptor (ASGPR) is involved in hepatocyte recognition of cells predestined for killing, including activated autologous T lymphocytes.Hepatocytes are constitutively equipped in the molecular machinery capable of eliminating cells brought into contact with their surface in a manner that is reliant, at least in part, upon the recognition of terminally desialylated glycoproteins by hepatocyte ASGPR. The study adds a new dimension to the physiological role of hepatic ASGPR and provides further evidence that hepatocytes can actively contribute to intrahepatic immune regulation and moderation of the local inflammatory response.
ADHD: A Diabetic Hyperglycemic Dilemma
Authors: David Ernest Henley, Christopher Glatthaar
Journal: Diabetes Care (2004)

This report describes transient self-limiting hyperglycemia following recreational ingestion of dexamphetamine. Amphetamines are noncatecholamine sympathomimetic amines with central nervous system stimulant activity. Dexamphetamine is used to treat narcolepsy and ADHD (attention deficit/hyperactivity disorder). It may also be abused for recreational purposes. Dexamphetamine, the dextro isomer of d,l-amphetamine sulfate, can induce hyperglycemia in rats (1).

A slender 20-year-old woman presented to her family doctor with a 10-day history of dizziness, nausea, diarrhea, lethargy, and loss of 6 kg in weight over recent months. Her temperature was 37.3°C, blood pressure 120/70 mmHg, and pulse rate 120 bpm. Finger prick blood glucose …
New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment
Authors: Francisco Cervantes, Brigitte Dupriez, Arturo Pereira, Francesco Passamonti, John T. Reilly, Enrica Morra, Alessandro M. Vannucchi, Ruben A. Mesa, Jean-Loup Demory, Giovanni Barosi, Elisa Rumi, Ayalew Tefferi
Journal: Blood (2008)
Acute liver graft failure due to emergence of lamivudine resistant hepatitis B virus: rapid resolution during treatment with adefovir
Authors: D Mutimer, B H Feraz-Neto, R Harrison, K O'Donnell, J Shaw, P Cane, D Pillay
Journal: Gut (2001)

<h3>BACKGROUND</h3> Strategies for prevention of liver graft reinfection by hepatitis B virus (HBV) have been developed during recent years. Initially, passive immunoprophylaxis with high titre HBV immunoglobulin (HBIg), followed by lamivudine prophylaxis, and then the combination of lamivudine and HBIg have been employed. However, suboptimal use of the combination may be associated with failure of prophylaxis reflected by the emergence of HBV species with genetic changes that confer resistance to lamivudine and HBIg. Reinfection of the graft by HBV can be associated with rapid development of liver failure. <h3>CASE REPORT</h3> A 43 year old HBV infected man received lamivudine before transplantation, and lamivudine and HBIg after transplantation. Despite prophylaxis, graft reinfection and severe hepatitis were observed. The observed serological evolution and genetic sequencing of the emergent HBV species suggested selection of lamivudine resistant and surface antigen escape mutants consecutively. Adefovir treatment began after the devlopment of graft failure. <h3>OUTCOME</h3> A rapid exponential decline in serum HBV titre was observed. Liver function tests normalised and signs of liver failure resolved. <h3>CONCLUSION</h3> The use of HBIg and lamivudine permits prevention of graft reinfection by HBV for the majority of patients. Adefovir, a potent inhibitor of lamivudine resistant HBV, should be used when failure of prophylaxis is associated with graft hepatitis.
Celecoxib Inhibits Prostate Cancer Growth: Evidence of a Cyclooxygenase-2-Independent Mechanism
Authors: Manish I. Patel, Kotha Subbaramaiah, Baoheng Du, Mindy Chang, Peiying Yang, Robert A. Newman, Carlos Cordon-Cardo, Howard T. Thaler, Andrew J. Dannenberg
Journal: Clinical Cancer Research (2005)

Selective cyclooxygenase-2 (COX-2) inhibitors may suppress carcinogenesis by both COX-2-dependent and COX-2-independent mechanisms. The primary purpose of this study was to evaluate whether celecoxib or rofecoxib, two widely used selective COX-2 inhibitors, possess COX-2-independent antitumor activity.PC3 and LNCaP human prostate cancer cell lines were used to investigate the growth inhibitory effects of selective COX-2 inhibitors in vitro. To complement these studies, we evaluated the effect of celecoxib on the growth of PC3 xenografts.COX-1 but not COX-2 was detected in PC3 and LNCaP cells. Clinically achievable concentrations (2.5-5.0 micromol/L) of celecoxib inhibited the growth of both cell lines in vitro, whereas rofecoxib had no effect over the same concentration range. Celecoxib inhibited cell growth by inducing a G(1) cell cycle block and reducing DNA synthesis. Treatment with celecoxib also led to dose-dependent inhibition of PC3 xenograft growth without causing a reduction in intratumor prostaglandin E(2). Inhibition of tumor growth occurred at concentrations (2.37-5.70 micromol/L) of celecoxib in plasma that were comparable with the concentrations required to inhibit cell growth in vitro. The highest dose of celecoxib led to a 52% reduction in tumor volume and an approximately 50% decrease in both cell proliferation and microvessel density. Treatment with celecoxib caused a marked decrease in amounts of cyclin D1 both in vitro and in vivo.Two clinically available selective COX-2 inhibitors possess different COX-2-independent anticancer properties. The anticancer activity of celecoxib may reflect COX-2-independent in addition to COX-2-dependent effects.
Association of Elevated Serum PO4, Ca × PO4 Product, and Parathyroid Hormone with Cardiac Mortality Risk in Chronic Hemodialysis Patients
Authors: SANTHI K. GANESH, AUSTIN G. STACK, NATHAN W. LEVIN, TEMPIE HULBERT-SHEARON, FRIEDRICH K. PORT
Journal: Journal of the American Society of Nephrology (2001)

Hyperphosphatemia is highly prevalent among patients with end-stage renal disease (ESRD) and is associated with increased mortality risk in hemodialysis (HD) patients. The mechanism through which this mortality risk is mediated is unclear. Data from two national random samples of HD patients (n = 12,833) was used to test the hypothesis that elevated serum PO4 contributes mainly to cardiac causes of death. During a 2-yr follow-up, the cause-specific relative risk (RR) of death for patients was analyzed separately for several categories of cause of death, including coronary artery disease (CAD), sudden death, and other cardiac causes, cerebrovascular and infection. Cox regression models were fit for each of the eight cause of death categories, adjusting for patient demographics and non-cardiovascular comorbid conditions. Time at risk for each cause-specific model was censored at death that resulted from any of the other causes. Higher mortality risk was seen for patients in the high PO4 group (>6.5mg/dl) compared with the lower PO4 group (≤6.5mg/dl) for death resulting from CAD (RR 1.41; P < 0.0005), sudden death (RR 1.20; P < 0.01), infection (RR 1.20; P < 0.05), and unknown causes (RR 1.25; P < 0.05). Patients in the high PO4 group also had non-significantly increased RR of death from other cardiac and cerebrovascular causes of death. The RR of sudden death was also strongly associated with elevated Ca × PO4 product (RR 1.07 per 10 mg2/dl2; P < 0.005) and serum parathyroid hormone levels greater than 495 pg/ml (RR 1.25; P < 0.05). This study identifies strong relationships between elevated serum PO4, Ca × PO4 product, and parathyroid hormone and cardiac causes of death in HD patients, especially deaths resulting from CAD and sudden death. More vigorous measures to reduce the prevalence of these factors in HD patients may result in improved survival.
Assessment of Safety and Long-Term Outcomes of Initial Treatment With Placebo in TADS
Authors: Betsy D. Kennard, Susan G. Silva, Taryn L. Mayes, Paul Rohde, Jennifer L. Hughes, Benedetto Vitiello, Christopher J. Kratochvil, John F. Curry, Graham J. Emslie, Mark A. Reinecke, John S. March
Journal: American Journal of Psychiatry (2009)

Objective: The authors examined whether initial assignment to receive placebo for 12 weeks followed by open active treatment as clinically indicated was associated with different levels of benefit and risk of harm across 36 weeks as compared with initial assignment to receive active treatments. Method: Adolescents with major depressive disorder (N=439) were randomly assigned to receive an initial 12 weeks of treatment with fluoxetine, cognitive-behavioral therapy (CBT), combination treatment with fluoxetine and CBT, or clinical management with placebo; those assigned to placebo received open active treatment as clinically indicated after 12 weeks of placebo. Assessments were conducted every 6 weeks for 36 weeks. The primary outcome measures were response and remission based on scores on the Children’s Depression Rating Scale–Revised and the Clinical Global Impression improvement subscale. Results: At week 36, the response rate was 82% in the placebo/open group and 83% in the active treatment groups. The remission rate was 48% in the placebo/open group and 59% in the active treatment groups, a difference that approached statistical significance. Patients who responded to placebo generally retained their response. Those who did not respond to placebo subsequently responded to active treatment at the same rate as those initially assigned to active treatments. There were no differences between groups in rates of suicidal events, study retention, or symptom worsening. Conclusions: Remission rates at 9 months were lower in patients treated initially with placebo, but 3 months of placebo treatment was not associated with any harm or diminished response to subsequent treatment.
BRCA2-Deficient Sarcomatoid Mammary Tumors Exhibit Multidrug Resistance
Authors: Janneke E. Jaspers, Wendy Sol, Ariena Kersbergen, Andreas Schlicker, Charlotte Guyader, Guotai Xu, Lodewyk Wessels, Piet Borst, Jos Jonkers, Sven Rottenberg
Journal: Cancer Research (2014)

Abstract Pan- or multidrug resistance is a central problem in clinical oncology. Here, we use a genetically engineered mouse model of BRCA2-associated hereditary breast cancer to study drug resistance to several types of chemotherapy and PARP inhibition. We found that multidrug resistance was strongly associated with an EMT-like sarcomatoid phenotype and high expression of the Abcb1b gene, which encodes the drug efflux transporter P-glycoprotein. Inhibition of P-glycoprotein could partly resensitize sarcomatoid tumors to the PARP inhibitor olaparib, docetaxel, and doxorubicin. We propose that multidrug resistance is a multifactorial process and that mouse models are useful to unravel this. Cancer Res; 75(4); 732–41. ©2014 AACR.
Metabolic Bone Disease in Chronic Kidney Disease
Authors: Kevin J. Martin, Esther A. González
Journal: Journal of the American Society of Nephrology (2007)

Metabolic bone disease is a common complication of chronic kidney disease (CKD) and is part of a broad spectrum of disorders of mineral metabolism that occur in this clinical setting and result in both skeletal and extraskeletal consequences. Detailed research in that past 4 decades has uncovered many of the mechanisms that are involved in the initiation and maintenance of the disturbances of bone and mineral metabolism and has been translated successfully from "bench to bedside" so that efficient therapeutic strategies now are available to control the complications of disturbed mineral metabolism. Recent emphasis is on the need to begin therapy early in the course of CKD. Central to the assessment of disturbances in bone and mineral metabolism is the ability to make an accurate assessment of the bone disease by noninvasive means. This remains somewhat problematic, and although measurements of parathyroid hormone are essential, recently recognized difficulties with these assays make it difficult to provide precise clinical practice guidelines for the various stages of CKD at the present time. Further research and progress in this area continue to evaluate the appropriate interventions to integrate therapies for both the skeletal and extraskeletal consequences with a view toward improving patient outcomes.
Inherited destiny? Genetics and gestational diabetes mellitus
Authors: Richard M Watanabe
Journal: Genome Medicine (2011)

Despite years of investigation, very little is known about the genetic predisposition for gestational diabetes mellitus (GDM). However, the advent of genome-wide association and identification of loci contributing to susceptibility to type 2 diabetes mellitus has opened a small window into the genetics of GDM. More importantly, the study of the genetics of GDM has not only illuminated potential new biology underlying diabetes in pregnancy, but has also provided insights into fetal outcomes. Here, I review some of the insights into GDM and fetal outcomes gained through the study of both rare and common genetic variation. I also discuss whether recent testing of type 2 diabetes mellitus susceptibility loci in GDM case-control samples changes views of whether GDM is a distinct form of diabetes. Finally, I examine how the study of susceptibility loci can be used to influence clinical care, one of the great promises of the new era of human genome analysis.