tbuckley/cabot-search huggingface dataset:
Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis: findings from an open-label treatment extension
Authors: N. Ruperto, D. J. Lovell, R. Cuttica, P. Woo, S. Meiorin, C. Wouters, E. D. Silverman, Z. Balogh, M. Henrickson, J. Davidson, I. Foeldvari, L. Imundo, G. Simonini, J. Oppermann, S. Xu, Y.-K. Shen, S. Visvanathan, A. Fasanmade, A. Mendelsohn, A. Martini, E. H. Giannini
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objective</h3> To assess the long-term efficacy and safety of infliximab plus methotrexate in juvenile rheumatoid arthritis (JRA). <h3>Methods</h3> Patients eligible for the open-label extension (OLE, weeks 52–204) received infliximab 3–6 mg/kg every 8 weeks plus methotrexate. <h3>Results</h3> Of the 78/122 (64%) children entering the OLE, 42 discontinued infliximab, most commonly due to consent withdrawal (11 patients), lack of efficacy (eight patients) or patient/physician/sponsor requirement (eight patients). Infliximab (mean dose 4.4 mg/kg per infusion) was generally well tolerated. Infusion reactions occurred in 32% (25/78) of patients, with a higher incidence in patients positive for antibodies to infliximab (58%, 15/26). At week 204, the proportions of patients achieving ACR-Pedi-30/50/70/90 response criteria and inactive disease status were 44%, 40%, 33%, 24% and 13%, respectively. <h3>Conclusions</h3> In the limited population of JRA patients remaining in the study at 4 years, infliximab was safe and effective but associated with a high patient discontinuation rate. <b>Clinical trials registration number</b> NCT00036374.
Polymorphisms at the 5'-end of the apolipoprotein AI gene and severity of coronary artery disease.
Authors: X L Wang, S X Liu, R M McCredie, D E Wilcken
Journal: Journal of Clinical Investigation (1996)

Elevated HDL-cholesterol (C) and apo AI are associated with decreased coronary artery disease (CAD) risk. We determined distributions of two MspI polymorphisms of the apo AI gene, associated in other studies with increased HDL-C, among 644 patients aged < or = 65 years in relation to circulating lipids and CAD severity assessed angiographically. The rare allele distributions at both sites were in Hardy-Weinberg equilibrium in these patients but the base changes were not associated with HDL-C and apo AI levels. However, patients homozygous for the -75 bp substitution were more likely to have one or more significantly diseased vessels (> 50% luminal obstruction)(OR: 4.75, 95%CI: 1.10- 20.46) as also were patients with the rare +83 bp alleles (OR: 2.56, 95%CI: 1.13-5.81). While there was an additive effect of the two polymorphisms to have severe CAD (OR: 6.33, 95%CI: 1.33-30.02), the polymorphism at +83 bp remained significant in predicting CAD severity after adjusting for other variables in a logistic regression analysis (OR: 2.95, 95%CI: 1.26-6.90), which was also strongly associated with the positive family CAD history (P = 0.009). We conclude that patients with these base changes in this Australian coronary population do not have increased HDL-C and apo AI levels but do have more severe CAD.
Statistical tests for independent groups: time to event data
Authors: P. Sedgwick
Journal: BMJ (2012)

Researchers assessed the effectiveness of low dose, high frequency ultrasound when combined with standard care in healing venous leg ulcers that had previously been hard to heal. A multicentre randomised controlled trial with a study period of 12 months was performed. Ultrasonography was given for 12 weeks, after which participants returned to standard care alone. Control treatment was standard care alone.[1]

Trial participants were recruited if they had at least one venous leg ulcer of more than six months’ duration or greater than 5 cm2 in area and an ankle brachial pressure index >0.8. In total, 168 people were randomised to ultrasound and standard care and 169 to standard care alone. The primary outcome was time from randomisation until healing of the largest eligible leg ulcer, referred to as the reference ulcer. The researchers reported that no significant difference existed between treatment groups in the time until healing of the reference leg ulcer (P=0.61).

Which one of the following …
Loss of Nkx2.8 Deregulates Progenitor Cells in the Large Airways and Leads to Dysplasia
Authors: Jianmin Tian, Radma Mahmood, Robert Hnasko, Joseph Locker
Journal: Cancer Research (2006)

Abstract Nkx2.8, a homeodomain transcription factor, has been characterized in liver cancer and in the developing central nervous system. We now show that this factor is also expressed in the lung, where it localizes in adults to a discrete population of tracheobronchial basal cells. To target the mouse gene, the first exon was replaced by a LacZ marker gene joined to the intact 5′-untranslated region. Marker expression was observed throughout the lower respiratory tract, beginning on E11 in a few cells of the distal lung buds. The region of expression then spread upward. By neonatal day 1, expression was greatest in the large airways and the Nkx2.8−/− mice exhibited generalized tracheobronchial hyperplasia. Bromodeoxyuridine (BrdUrd) labeling studies showed that a higher rate of bronchial cell proliferation persisted at 6 to 8 months. In adults, Nkx2.8 marker expression decreased with progressive differentiation into ciliated and secretory cells. The cell localizations and patterns of coexpression with BrdUrd and differentiation markers suggest a progenitor relationship: the cells that most strongly express Nkx2.8 seem to function as tracheobronchial stem cells. Moreover, Nkx2.8 acts to limit the number of these progenitor cells because the marker-expressing population was greatly expanded in Nkx2.8−/− mice. Increased proliferation and an altered progenitor relationship caused progressive bronchial pathology, which manifested as widespread dysplasia in the large airways of 1-year-old Nkx2.8−/− mice. (Cancer Res 2006; 66(21): 10399-407)
The nitric oxide pathway in pre-eclampsia: pathophysiological implications
Authors: I. Buhimschi
Journal: Human Reproduction Update (1998)

Pre-eclampsia, one of the most significant health problems in human pregnancy, complicates approximately 6-8% of all gestations and is the leading cause of fetal growth retardation, infant morbidity and mortality, premature birth and maternal death. Recent research implicates free radicals in the pathophysiology of pre-eclampsia. This review covers the biochemistry of nitric oxide (NO) and possible interactions with other free radicals. Studies in the rat show that pregnancy is associated with enhanced production and responsiveness to NO in both reproductive tissues and blood vessels. Rats infused with NG-nitro-L-arginine methyl ester (L-NAME, a NO synthase inhibitor) have been used as an animal model of pre-eclampsia, and the effects of steroid hormones on blood pressure in this model have been tested. Results suggest that pre-eclampsia may be a state of NO deficiency. However, in humans there seem to be contradictions regarding the involvement of NO in maternal adaptation to pregnancy. It is suggested that NO may be one of several systems that act in concert to maintain a symbiotic relationship between mother and fetus. However, the input of each system may be genetically determined.
Long-Term Ambient Multipollutant Exposures and Mortality
Authors: Jaime E. Hart, Eric Garshick, Douglas W. Dockery, Thomas J. Smith, Louise Ryan, Francine Laden
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

population-based studies have demonstrated associations between ambient air pollution exposures and mortality, but few have been able to adjust for occupational exposures. Additionally, two studies have observed higher risks in individuals with occupational dust, gas, or fume exposure.
Carbon Monoxide Protects against Liver Failure through Nitric Oxide–induced Heme Oxygenase 1
Authors: Brian S. Zuckerbraun, Timothy R. Billiar, Sherrie L. Otterbein, Peter K.M. Kim, Fang Liu, Augustine M.K. Choi, Fritz H. Bach, Leo E. Otterbein
Journal: The Journal of Experimental Medicine (2003)

Carbon monoxide (CO) and nitric oxide (NO) each have mechanistically unique roles in various inflammatory disorders. Although it is known that CO can induce production of NO and that NO can induce expression of the cytoprotective enzyme heme oxygenase 1 (HO-1), there is no information whether the protective effect of CO ever requires NO production or whether either gas must induce expression of HO-1 to exert its functional effects. Using in vitro and in vivo models of tumor necrosis factor α–induced hepatocyte cell death in mice, we find that activation of nuclear factor κB and increased expression of inducible NO are required for the protective effects of CO, whereas the protective effects of NO require up-regulation of HO-1 expression. When protection from cell death is initiated by CO, NO production and HO-1 activity are each required for the protective effect showing for the first time an essential synergy between these two molecules in tandem providing potent cytoprotection.
Pesticides and Health Effects: Karpati et al. Respond
Authors: Adam Karpati, Mary C. Perrin, Jessica Leighton, Tom Matte, Joel Schwartz, R. Graham Barr
Journal: Environmental Health Perspectives (2005)

In her letter, Ziem raises the issue of exacerbations of respiratory illness and other health effects of pesticide exposure that we did not measure in our study (Karpati et al. 2004). Our analysis was designed to evaluate only whether a population-level effect on emergency department visits, specifically on asthma and other respiratory illnesses, was evident following pyrethroid pesticide spraying. Similar study designs, despite their limitations, have proven to be sensitive methods of identifying population-level health impacts from exposure to criteria air pollutants from exposure to unusual events, such as smoke from forest fires. Moreover, our analysis did identify adverse population-level health effects of elevated ozone and particulates. As we noted in our discussion, the results of the analysis for pesticide exposure do not rule out the possibility that certain individuals might have been affected by exposure to the agent. Also, our focus was on emergency department visits, which generally signify more serious illness, although in urban neighborhoods even milder illnesses are often treated in such settings. However, if, in fact, certain individuals experienced asthma exacerbations following exposure, we believe our study demonstrates that their number was small enough that it did not result in a population-level increase in emergency department visits for asthma and chronic obstructive pulmonary disease.

In our analysis we evaluated only respiratory complications of pesticide spraying to control West Nile virus, and we did not purport to measure possible neurotoxic or other nonrespiratory effects. Also, we did not evaluate the efficacy of pesticide spraying for mosquito control or its cost–benefit ratio with regard to pesticide-related health effects.
Host Responses in Human Skin After Conventional Intradermal Injection or Microneedle Administration of Virus‐Like‐Particle Influenza Vaccine
Authors: Marc Pearton, Daniela Pirri, Sang‐Moo Kang, Richard W. Compans, James C. Birchall
Journal: Advanced Healthcare Materials (2013)

Abstract Miniaturized microneedle devices are being developed for painlessly targeting vaccines to the immune cell populations in skin. As skin immunization studies are generally restricted to animal models however, where skin architecture and immunity is greatly different to human, surprisingly little is known about the local human response to intradermal (ID) vaccines. Here surgically excised human skin is used to explore for the first time the complex molecular and cellular host responses to a candidate influenza vaccine comprising nanoparticulate virus‐like‐particles (VLPs), administered via conventional hypodermic injection or reduced scale microneedles. Responses at the molecular level are determined by microarray analysis (47,296 discrete transcripts) and validated by quantitative PCR (96 genes). Cellular response is probed through monitoring migration of dendritic cells in viable skin tissue. Gene expression mapping, ontological analysis, and qPCR reveal up‐regulation of a host of genes responsible for key immunomodulatory processes and host viral response, including cell recruitment, activation, migration, and T cell interaction following both ID and microneedle injection of VLPs; the response from the microneedles being more subtle. Significant morphological and migratory changes to skin dendritic cells are also apparent following microneedle VLP delivery. This is the first study displaying the global, multifaceted immunological events that occur at the site of vaccine deposition in human skin and will subsequently influence the degree and nature of innate and adaptive immune responses. An increased understanding of the detailed similarities and differences in response against antigen administered via different delivery modalities will inform the development of improved vaccines and vaccine delivery systems.
Observed and expected frequency of comorbid chronic diseases in rheumatic patients
Authors: E Loza, J A Jover, L Rodriguez-Rodriguez, L Carmona
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> To estimate and compare the observed and expected prevalence of the co-existence of rheumatic diseases (RD) with other chronic conditions. <h3>Methods:</h3> The self-reported diagnosis of chronic conditions was obtained from the 2192 participants in a national health survey (Spain, 1999–2000) We compared the estimated prevalence of the co-existence of a RD with other chronic conditions, to the expected prevalence using two-sample test of proportion. <h3>Results:</h3> The observed (O) prevalence was significantly higher than expected (E) in the following combination of self-reported diseases: RD+arterial hypertension (O/E ratio = 1.88), RD+diabetes mellitus (O/E ratio = 2.07), RD+hypercholesterolemia (O/E ratio = 1.87), RD+cardiological (O/E ratio = 1.83), and RD+digestive diseases (O/E ratio = 2.07). The prevalence of selected co-existent pairs of diseases is more frequent with increasing age and differs between women and men. <h3>Conclusions:</h3> The excess in prevalence of some combinations of diseases may serve as a reminder to the rheumatologists that many of their patients will have co-existent disease of which they need to be aware to properly plan their management. It may also be a sign of common risk factors between diseases or of adverse events.
Hamstrings are most susceptible to injury during the late swing phase of sprinting
Authors: Elizabeth S Chumanov, Anthony G Schache, Bryan C Heiderscheit, Darryl G Thelen
Journal: British Journal of Sports Medicine (2011)

It is well recognised that the hamstrings are susceptible to acute strain injury during high-speed running. However, the particular phase of the sprinting gait cycle at which hamstring injury occurs remains a debated topic. Video footage and athlete anecdotes have contributed to the discussion, but do not provide sufficient temporal resolution to fully answer the question. In this paper, we briefly review: (A) biomechanical data obtained from healthy athletes; (B) case studies of injuries during biomechanical experiments; and (C) clinical outcomes from intervention studies. We believe all of these support the premise that late swing phase is the likely time when the biarticular hamstrings are most vulnerable to injury.

Early …
Expression and Signaling Activity of Wnt-5a/Discoidin Domain Receptor-1 and Syk Plays Distinct but Decisive Roles in Breast Cancer Patient Survival
Authors: Janna Dejmek, Karin Leandersson, Jonas Manjer, Anders Bjartell, Stefan O. Emdin, Wolfgang F. Vogel, Göran Landberg, Tommy Andersson
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The loss of Wnt-5a, a G-protein-coupled receptor ligand, or Syk, an intracellular kinase, has in separate studies been associated with poor prognosis of breast cancer patients. Both proteins are involved in cell adhesion, a key event in epithelial cancer metastasis. Here, we have investigated whether Syk is part of the Wnt-5a/discoidin domain receptor-1 (DDR1) signaling pathway and if a signaling interaction of these proteins is important for breast cancer–specific survival. Experimental Design: The signaling interactions between Wnt-5a/DDR1 and Syk were addressed in mammary cell lines. Their mRNA and protein levels and the respective clinical correlates were investigated in 94 cases of primary breast cancer. Results: The expression of Wnt-5a and Syk correlated in four of five tumor cell lines. However, despite a constitutive association between Syk and the Wnt-5a-dependent adhesion receptor DDR1, we found no evidence of a Wnt-5a/DDR1-mediated activation of Syk. Instead, β1 integrins initiate the adhesion-induced activation of Syk. In tumors from breast cancer patients, the protein expression of Wnt-5a and Syk were differently regulated at the translational and transcriptional level, respectively. Analysis of breast cancer–specific survival revealed that the presence of Wnt-5a and Syk in primary tumors has good predictive value for a favorable outcome. Intriguingly, a simultaneous loss of both proteins did not reduce survival more than loss of either. Conclusions: Despite the difference in regulation of Wnt-5a and Syk protein expression and their lack of signaling interaction, our clinical data indicate that a favorable prognosis in breast cancer requires the expression and signaling activity of both.
Genetic differences define severity of renal damage after L-NAME-induced hypertension in rats.
Authors: R P Van Dokkum, H J Jacob, A P Provoost
Journal: Journal of the American Society of Nephrology (1998)

Genetic factors are important in determining the susceptibility to renal damage. In a backcross of the hypertensive and proteinuric fawn-hooded Erasmus University Rotterdam (FHH/EUR) rat with the normotensive, nonproteinuric August Copenhagen Irish (ACI/EUR) rat, two genes (denoted Rf-1 and Rf-2) were genetically mapped for parameters of functional and structural renal damage. The aim of the present study was to investigate the susceptibility to functional and structural renal damage in heterozygous (FHH X ACI) F1 rats compared with the parental FHH and ACI strains at similar levels of systolic BP (SBP). BP elevation was induced by chronic treatment with NG-nitro-L-arginine methyl ester (L-NAME) in either a low dose (LD, 75 to 100 mg/L) or a high dose (HD, 175 to 250 mg/L) in the drinking fluid. Survival of FHH rats and, to a lesser extent, F1 rats, was adversely affected by L-NAME treatment. All ACI rats except for one ACI-HD animal survived. In all strains, L-NAME caused a dose-dependent increase in SBP. At similar levels of SBP, the increase in functional renal damage, as indicated by the level of albuminuria, was higher in F1 compared with ACI, but lower compared with FHH. The same differences were found for the level of structural renal damage, as indicated by the incidence of glomerulosclerosis. Both the SBP and the average BP burden (SBP-Av), defined as SBP averaged over the period of follow-up, directly correlated with the level of albuminuria and incidence of glomerulosclerosis in all strains. However, the increase in the degree of renal damage per mmHg increase in SBP or SBP-Av was significantly higher in the F1 rats compared with ACI, but lower compared with FHH rats. Values for these F1 rats were closer to the ACI rats than to values for the FHH rats and increased above an SBP level of 180 mmHg. The F1 rats, being heterozygous for Rf-1 and Rf-2, as well as for other potential genes responsible for renal disease, were largely, but not completely, protected from hypertension-induced renal damage. It is concluded that complete susceptibility to hypertension-associated renal damage in rats primarily depends on the presence of predisposing genes for renal failure even after a significant increase in BP.
Depletion of the enteric nervous system by gene targeting results in haemorrhagic necrosis of the ileum
Authors: T T MacDONALD
Journal: Gut (1998)

Over the past few years it has become increasingly clear that new insights into the physiology of the gut are being made by non-gastroenterologists, often working on “blue-sky” projects with no clinical relevance. One such project, published in Cell earlier this year, illustrates this point well.

Astrocytes are cells with branching cytoplasmic processes which surround nerves. Some of the processes are directed towards capillaries and others towards neurones. They provide structural support for the neurone, play a role in maintaining the blood–brain barrier, and are also important in repair after injury. They contain a characteristic protein–glial fibrillary acidic protein (GFAP). Bush and colleagues used the GFAP promoter to target the thymidine kinase of herpes simplex virus (HSV-TK) into astrocytes in transgenic mice. In proliferating cells exposed to the antiviral agent ganciclovir (GCV), HSV-TK metabolises GCV to produce toxic nucleotides which kill the cells expressing the transgene. Untreated transgenic mice are normal. However, when GCV was given to the transgenic mice in subcutaneous miniosmotic pumps, starting at about two weeks after implantation, the mice began to die. By 20 days treatment mortality was 100%.

When the mice were analysed, the cause of death was …
Molecular Pathology of Head and Neck Cancer: Implications for Diagnosis, Prognosis, and Treatment
Authors: Sara I. Pai, William H. Westra
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

The prototypic head and neck squamous cell carcinoma (HNSCC) arises from the mucosal lining of the upper aerodigestive tract, demonstrates squamous differentiation microscopically, involves older men with a long history of cigarette smoking and alcohol consumption, and is treated by multimodality therapy. HNSCC has long been regarded as a uniform disease process requiring a methodical and unwavering therapeutic approach. Divergence in epidemiologic trends among HNSCCs arising from different anatomic sites has introduced a view that, morphologic repetition aside, head and neck cancers form a heterogeneous group. This view has been supported at the molecular genetic level. A more complete understanding of the molecular genetics of head and neck cancer is providing new insights into long-held but poorly comprehended concepts such as field cancerization and is introducing various biomarkers with potential application for diagnosing, staging, monitoring, and prognosticating HNSCC.
Real World Effectiveness of Rosiglitazone Added to Maximal (Tolerated) Doses of Metformin and a Sulfonylurea Agent
Authors: Rajiv Roy, Maria Navar, Gladys Palomeno, Mayer B. Davidson
Journal: Diabetes Care (2004)

Patients with newly diagnosed type 2 diabetes who have no or only mild symptoms should be started on a regimen of diet and exercise. Unfortunately, as many as 95% of patients do not achieve adequate control after 3 months of nonpharmacologic therapy (1). When medical therapy is initiated, patients are often started on either a low dose of a sulfonylurea agent or metformin. If control is not attained with the maximal dose of one, the second is usually added until adequate control is achieved or a maximal dose is reached. Since glitazones are so expensive, we use them only after maximal (tolerated) doses of metformin and sulfonylurea agents are reached and control remains unsatisfactory. Only a few studies (2–6) have examined the effectiveness of adding a glitazone as the third oral agent. These have used mean A1C levels as the outcome, which does not provide information on the proportion of patients who can be expected to respond.

Our algorithm-based approach mandates starting small doses of either a sulfonylurea agent (lean patients) or metformin (obese patients) and titrating the dose upward in a stepwise fashion every 2 weeks until either a fasting plasma glucose (FPG) concentration of ≤130 mg/dl is attained or a maximal (tolerated in the case of metformin) dose is reached. If the …