tbuckley/cabot-search huggingface dataset:
Induction of Membranous Nephropathy in Rabbits by Administration of an Exogenous Cationic Antigen
Authors: Wayne A. Border, Harry, J. Ward, Elaine S. Kamil, Arthur H. Cohen
Journal: Journal of Clinical Investigation (1982)

We examined the role of antigenic electrical charge as a determinant of glomerular immune complex localization in the rabbit. Serum sickness nephritis was induced in groups of New Zealand white rabbits by daily 25-mg intravenous injections of bovine serum albumin (BSA) chemically modified to be cationic (pI > 9.5) or more anionic (pI, 3.5-4.6); an additional group received unmodified native BSA (pI, 4.5-5.1). Factors known to influence immune complex localization, e.g., molecular size of the administered antigen and resulting circulating immune complexes, immunogenicity, and disappearance time from the circulation were examined and found to be similar for both anionic and cationic BSA. Charge modification did increase the nonimmune clearance of cationic and anionic BSA compared with native BSA. Injected cationic BSA was shown in paired label experiments to bind directly to glomeruli compared with native BSA. The renal lesion produced by cationic BSA was markedly different from that found in rabbits given anionic or native BSA. Animals receiving cationic BSA uniformly developed generalized diffuse granular capillary wall deposits of IgG, C3, and BSA detected after 2 wk of injections and increasing until death at 6 wk. Qualitatively similar deposits were produced by the administration of low doses of cationic BSA of only 1 or 10 mg/d. In contrast, the injection of both anionic and native BSA resulted in mesangial deposits at 2 and 4 wk with capillary wall deposits appearing by 6 wk. Ultrastructural examination of animals receiving cationic BSA revealed pure, extensive formation of dense deposits along the lamina rara externa of the glomerular basement membrane whereas such deposits were absent or rare in animals injected with the anionic or native BSA. Albuminuria was significantly greater at 6 wk in the groups receiving cationic BSA with a mean of 280 mg/24 h compared with 53 mg/24 h in the combined groups injected with anionic or native BSA. Blood urea nitrogen values were similar in all groups at 2 and 4 wk but higher in the animals receiving cationic BSA at 6 wk.
Comparison of a Multiple Daily Insulin Injection Regimen (Basal Once-Daily Glargine Plus Mealtime Lispro) and Continuous Subcutaneous Insulin Infusion (Lispro) in Type 1 Diabetes
Authors: Geremia B. Bolli, David Kerr, Reena Thomas, Elisabetta Torlone, Agnès Sola-Gazagnes, Ester Vitacolonna, Jean Louis Selam, Philip D. Home
Journal: Diabetes Care (2009)

OBJECTIVE Insulin pump therapy (continuous subcutaneous insulin infusion [CSII]) and multiple daily injections (MDIs) with insulin glargine as basal insulin and mealtime insulin lispro have not been prospectively compared in people naïve to either regimen in a multicenter study. We aimed to help close that deficiency. RESEARCH DESIGN AND METHODS People with type 1 diabetes on NPH-based insulin therapy were randomized to CSII or glargine-based MDI (both otherwise using lispro) and followed for 24 weeks in an equivalence design. Fifty people were correctly randomized, and 43 completed the study. RESULTS Total insulin requirement (mean ± SD) at end point was 36.2 ± 11.5 units/day on CSII and 42.6 ± 15.5 units/day on MDI. Mean A1C fell similarly in the two groups (CSII −0.7 ± 0.7%; MDI −0.6 ± 0.8%) with a baseline-adjusted difference of −0.1% (95% CI −0.5 to 0.3). Similarly, fasting blood glucose and other preprandial, postprandial, and nighttime self-monitored plasma glucose levels did not differ between the regimens, nor did measures of plasma glucose variability. On CSII, 1,152 hypoglycemia events were recorded by 23 of 28 participants (82%) and 1,022 in the MDI group by 27 of 29 patients (93%) (all hypoglycemia differences were nonsignificant). Treatment satisfaction score increased more with CSII; however, the change in score was similar for the groups. Costs were ∼3.9 times higher for CSII. CONCLUSIONS In unselected people with type 1 diabetes naïve to CSII or insulin glargine, glycemic control is no better with the more expensive CSII therapy compared with glargine-based MDI therapy.
Pfizer steps up battle to defend control of pregabalin
Authors: A. Jack
Journal: BMJ (2015)

Pfizer’s actions over its biggest blockbuster drug sparks confusion

Pfizer has launched a charm offensive on UK doctors, after accusations of profiteering and concerns over increased paperwork for prescribers, and has taken to the courts to defend exclusive control over the main use of its valuable pain drug pregabalin.

The US pharmaceutical giant has written to the medical press to emphasise to doctors its desire to continue investing in research and development in patients’ interests, while arguing that its top selling drug should remain partly protected from competition, despite the expiry of the original patent.

Berkeley Phillips, Pfizer’s UK medical director, and Seema Patel, its medical director for established UK pharma business, apologised to doctors for confusion and said, “Our intention was neither to cause confusion, nor add to your workload.” But they insisted on the need to defend the company’s intellectual property rights.

The letter follows concern among doctors in recent weeks after they received circulars from the NHS cautioning that they should seek to prescribe pregabalin by using its brand name (Lyrica) when they prescribe the drug to treat pain.1 Pfizer had cautioned commissioning groups that to do otherwise could be “unlawful.”

The actions highlight the …
Two different cis-acting regulatory regions direct cell-specific transcription of the collagen alpha 1(I) gene in hepatic stellate cells and in skin and tendon fibroblasts.
Authors: K Houglum, M Buck, J Alcorn, S Contreras, P Bornstein, M Chojkier
Journal: Journal of Clinical Investigation (1995)

The expression of the collagen alpha 1(I) gene in activated stellate cells plays an important role during liver fibrogenesis. To identify the critical cis-elements of the collagen alpha 1(I) gene in stellate cells, we used transgenic animals bearing various collagen alpha 1(I) regulatory regions directing the expression of either a human growth hormone minigene or the bacterial beta-galactosidase gene. We found that collagen alpha 1(I)-human growth hormone transgene expression was constitutively high in tendon and skin, provided the transgene contained the -2.3 to -0.44 kb collagen regulatory region. However in the liver, expression was stimulated several-fold, as was the endogeneous gene, by the fibrogenic hepatotoxin carbon tetrachloride. This stimulation occurred whether the collagen 5' regulatory region extended -2.3, -1.6 or -0.44 kb, and in the presence or absence of much of the first intron (+292 to +1607 bp). In addition, the -0.44 kb 5' region was sufficient for high-level transgene expression in stellate cells, following their activation by culture on plastic. In contrast, in skin and tendon, high-level transcription of the collagen alpha 1(I) gene required the -2.3 to -0.44 kb 5' flanking region. Thus, two different cis-regulatory regions direct cell-specific transcription of the collagen alpha 1(I) gene in stellate cells and in skin and tendon.
Medical Aspects of Liver Transplantation
Authors: David H. Van Thiel, Robert R. Schade, Judith S. Gavaler, Byers W. Shaw, Shunzaburo Iwatsuki, Thomas E. Starzl
Journal: Hepatology (1984)

The methods used to screen prospective candidates for orthotopic liver transplantation are described. Both the indication and the contraindications for the procedure are discussed. The timing of the procedure during the course of an individual candidate’s liver disease is also discussed. Additionally, the institutional requirements of a liver transplant center are identified. Finally, the problems experienced by a liver transplant patient and his physician during the postoperative period are identified and discussed.
Survival in renal vascular disease.
Authors: P J Conlon, K Athirakul, E Kovalik, S J Schwab, J Crowley, R Stack, C B McCants, D B Mark, T M Bashore, F Albers
Journal: Journal of the American Society of Nephrology (1998)

Renal artery stenosis (RAS) is a relatively uncommon but important potentially reversible cause of renal failure. Little is known about the natural history of ischemic renal disease secondary to RAS. In previous reports, these researchers examined the incidence and risk factors associated with RAS. The study presented here investigates the long-term follow-up of these patients, specifically the effect of RAS on 4-yr, all-cause mortality in a group of 1235 patients undergoing diagnostic cardiac catheterization and abdominal aortography. A total of 1235 consecutive patients undergoing cardiac catheterization also underwent an abdominal flush aortogram. Significant RAS was considered present if one or more renal artery had 50% or greater narrowing in luminal diameter. Four-year unadjusted survival for patients with RAS was 65% compared with 86% for patients undergoing catheterization without significant RAS. Factors associated with decreased 4-yr survival included increased age, increased serum creatinine, presence of RAS, peripheral vascular disease, congestive heart failure, diabetes, hypertension, and reduced ejection fraction. Using the Cox proportional hazards model, the factors associated with decreased 4-yr survival were the presence of significant RAS, reduced ejection fraction, elevated serum creatinine, and symptoms of congestive heart failure. These observations indicate that the presence of significant RAS is a strong independent predictor of 4-yr survival in this patient population.
Rheumatoid Factor and Immune Networks
Authors: D A Carson, P P Chen, R I Fox, T J Kipps, F Jirik, R D Goldfien, G Silverman, V Radoux, S Fong
Journal: Annual Review of Immunology (1987)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
Interaction of <i>FKBP5</i> Gene Variants and Adverse Life Events in Predicting Depression Onset: Results From a 10-Year Prospective Community Study
Authors: Petra Zimmermann, Tanja Brückl, Agnes Nocon, Hildegard Pfister, Elisabeth B. Binder, Manfred Uhr, Roselind Lieb, Terrie E. Moffitt, Avshalom Caspi, Florian Holsboer, Marcus Ising
Journal: American Journal of Psychiatry (2011)

The FKBP5 gene modulates function of glucocorticoid receptors and has been frequently studied as a risk factor for depression and suicidality. This long-term study found a gene-by-environment effect for minor variants in the gene in the presence of trauma but not deprivation.
Patients with Idiopathic Pulmonary Fibrosis with Antibodies to Heat Shock Protein 70 Have Poor Prognoses
Authors: Rehan A. Kahloon, Jianmin Xue, Arpit Bhargava, Eva Csizmadia, Leo Otterbein, Daniel J. Kass, Jessica Bon, Makoto Soejima, Marc C. Levesque, Kathleen O. Lindell, Kevin F. Gibson, Naftali Kaminski, Gunjan Banga, Chester V. Oddis, Joseph M. Pilewski, Frank C. Sciurba, Michael Donahoe, Yingze Zhang, Steven R. Duncan
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Rationale: Diverse autoantibodies are present in most patients with idiopathic pulmonary fibrosis (IPF). We hypothesized that specific autoantibodies may associate with IPF manifestations.Objectives: To identify clinically relevant, antigen-specific immune responses in patients with IPF.Methods: Autoantibodies were detected by immunoblots and ELISA. Intrapulmonary immune processes were evaluated by immunohistochemistry. Anti–heat shock protein 70 (HSP70) IgG was isolated from plasma by immunoaffinity. Flow cytometry was used for leukocyte functional studies.Measurements and Main Results: HSP70 was identified as a potential IPF autoantigen in discovery assays. Anti-HSP70 IgG autoantibodies were detected by immunoblots in 3% of 60 control subjects versus 25% of a cross-sectional IPF cohort (n = 122) (P = 0.0004), one-half the patients with IPF who died (P = 0.008), and 70% of those with acute exacerbations (P = 0.0005). Anti-HSP70 autoantibodies in patients with IPF were significantly associated with HLA allele biases, greater subsequent FVC reductions (P = 0.0004), and lesser 1-year survival (40 ± 10% vs. 80 ± 5%; hazard ratio = 4.2; 95% confidence interval, 2.0–8.6; P < 0.0001). HSP70 protein, antigen–antibody complexes, and complement were prevalent in IPF lungs. HSP70 protein was an autoantigen for IPF CD4 T cells, inducing lymphocyte proliferation (P = 0.004) and IL-4 production (P = 0.01). IPF anti-HSP70 autoantibodies activated monocytes (P = 0.009) and increased monocyte IL-8 production (P = 0.049). ELISA confirmed the association between anti-HSP70 autoreactivity and IPF outcome. Anti-HSP70 autoantibodies were also found in patients with other interstitial lung diseases but were not associated with their clinical progression.Conclusions: Patients with IPF with anti-HSP70 autoantibodies have more near-term lung function deterioration and mortality. These findings suggest antigen-specific immunoassays could provide useful clinical information in individual patients with IPF and may have implications for understanding IPF progression.
Long-term Effects of Nurse Home Visitation on Children's Criminal and Antisocial Behavior
Authors: David Olds, Charles R. Henderson, Jr, Robert Cole, John Eckenrode, Harriet Kitzman, Dennis Luckey, Lisa Pettitt, Kimberly Sidora, Pamela Morris, Jane Powers
Journal: JAMA (1998)

A program of home visitation by nurses has been shown to affect the rates of maternal welfare dependence, criminality, problems due to use of substances, and child abuse and neglect. However, the long-term effects of this program on children's antisocial behavior have not been examined.To examine the long-term effects of a program of prenatal and early childhood home visitation by nurses on children's antisocial behavior.Fifteen-year follow-up of a randomized trial. Interviews were conducted with the adolescents and their biological mothers or custodial parents.Semirural community in New York.Between April 1978 and September 1980, 500 consecutive pregnant women with no previous live births were recruited, and 400 were enrolled. A total of 315 adolescent offspring participated in a follow-up study when they were 15 years old; 280 (89%) were born to white mothers, 195 (62%) to unmarried mothers, 151 (48%) to mothers younger than 19 years, and 186 (59%) to mothers from households of low socioeconomic status at the time of registration during pregnancy.Families in the groups that received home visits had an average of 9 (range, 0-16) home visits during pregnancy and 23 (range, 0-59) home visits from birth through the child's second birthday. The control groups received standard prenatal and well-child care in a clinic.Children's self-reports of running away, arrests, convictions, being sentenced to youth corrections, initiation of sexual intercourse, number of sex partners, and use of illegal substances; school records of suspensions; teachers' reports of children's disruptive behavior in school; and parents' reports of the children's arrests and behavioral problems related to the children's use of alcohol and other drugs.Adolescents born to women who received nurse visits during pregnancy and postnatally and who were unmarried and from households of low socioeconomic status (risk factors for antisocial behavior), in contrast with those in the comparison groups, reported fewer instances (incidence) of running away (0.24 vs 0.60; P = .003), fewer arrests (0.20 vs 0.45; P = .03), fewer convictions and violations of probation (0.09 vs 0.47; P<.001), fewer lifetime sex partners (0.92 vs 2.48; P= .003), fewer cigarettes smoked per day (1.50 vs 2.50; P= .10), and fewer days having consumed alcohol in the last 6 months (1.09 vs 2.49; P = .03). Parents of nurse-visited children reported that their children had fewer behavioral problems related to use of alcohol and other drugs (0.15 vs 0.34; P = .08). There were no program effects on other behavioral problems.This program of prenatal and early childhood home visitation by nurses can reduce reported serious antisocial behavior and emergent use of substances on the part of adolescents born into high-risk families.
Phase II Trial of Bevacizumab and Erlotinib in Carcinomas of Unknown Primary Site: The Minnie Pearl Cancer Research Network
Authors: John D. Hainsworth, David R. Spigel, Cindy Farley, Dana S. Thompson, Dianna L. Shipley, F. Anthony Greco
Journal: Journal of Clinical Oncology (2007)

Treatment remains poor for many patients with carcinoma of unknown primary site (CUP), and no effective second-line treatment has been identified. Combination inhibition of vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) with bevacizumab and erlotinib has proved efficacious and well tolerated in other solid tumors. We therefore have evaluated the efficacy and toxicity of this combination in patients with CUP.Patients with CUP who either had received previous chemotherapy or were previously untreated with poor-prognosis clinical features were eligible for this study. All patients received bevacizumab 10 mg/kg IV every 2 weeks, along with erlotinib 150 mg orally daily. Patients were re-evaluated after 8 weeks of treatment; those with objective response or stable disease continued treatment until disease progression.Forty-seven (92%) of 51 patients received at least 8 weeks of treatment. Five patients (10%) had partial responses, and 29 patients (61%) had stable disease as the best response. The median survival for the entire group was 7.4 months, with 33% of patients alive at 1 year. This regimen was well tolerated by most patients.The combination of bevacizumab and erlotinib has substantial activity in the treatment of patients with CUP. The median survival is superior to survival previously reported with second-line chemotherapy, and is similar to the results of many first-line chemotherapy trials in this setting. This regimen merits further evaluation in patients with CUP.
Measles Virus Nucleoprotein Induces a Regulatory Immune Response and Reduces Atherosclerosis in Mice
Authors: Hafid Ait-Oufella, Branka Horvat, Yann Kerdiles, Olivier Herbin, Pierre Gourdy, Jamila Khallou-Laschet, Régine Merval;, Bruno Esposito;, Alain Tedgui, Ziad Mallat
Journal: Circulation (2007)

Recent studies clearly suggest that regulatory T cells play a critical role in the control of the immunoinflammatory response in atherosclerosis and substantially limit lesion development. Measles virus infection or vaccination is associated with immune depression, in part through the induction of an antiinflammatory response by measles virus nucleoprotein. We hypothesized that the antiinflammatory properties of measles virus nucleoprotein may limit the development atherosclerosis.Here, we show for the first time that repetitive administration of measles virus nucleoprotein to apolipoprotein E-deficient mice promotes an antiinflammatory T-regulatory-cell type 1-like response and inhibits macrophage and T-cell accumulation within the lesions. Treatment with measles virus nucleoprotein significantly reduces the development of new atherosclerotic plaques and markedly inhibits the progression of established lesions. The antiatherosclerotic potential of nucleoprotein is retained in its short N-terminal segment. The protective effects on lesion size are lost in mice with lymphocyte deficiency.Our findings identify a novel mechanism of immune modulation by measles virus nucleoprotein through the promotion of a regulatory T-cell response and suggest that this property may be harnessed for treating atherosclerosis, the first cause of heart disease and stroke.
Combined Inhibitory Effects of Green Tea Polyphenols and Selective Cyclooxygenase-2 Inhibitors on the Growth of Human Prostate Cancer Cells Both <i>In vitro</i> and <i>In vivo</i>
Authors: Vaqar Mustafa Adhami, Arshi Malik, Najia Zaman, Sami Sarfaraz, Imtiaz Ahmad Siddiqui, Deeba Nadeem Syed, Farrukh Afaq, Farrukh Sierre Pasha, Mohammad Saleem, Hasan Mukhtar
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Cyclooxygenase-2 (COX-2) inhibitors hold promise for cancer chemoprevention; however, recent toxicity concerns suggest that new strategies are needed. One approach to overcome this limitation is to use lower doses of COX-2 inhibitors in combination with other established agents with complementary mechanisms. In this study, the effect of (−)epigallocatechin-3-gallate (EGCG), a promising chemopreventive agent from green tea, was tested alone and in combination with specific COX-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo. Experimental Design: Human prostate cancer cells LNCaP, PC-3, and CWR22Rν1 were treated with EGCG and NS398 alone and in combination, and their effect on growth and apoptosis was evaluated. In vivo, athymic nude mice implanted with androgen-sensitive CWR22Rν1 cells were given green tea polyphenols (0.1% in drinking water) and celecoxib (5 mg/kg, i.p., daily, 5 days per week), alone and in combination, and their effect on tumor growth was evaluated. Results: Combination of EGCG (10-40 μmol/L) and NS-398 (10 μmol/L) resulted in enhanced (a) cell growth inhibition; (b) apoptosis induction; (c) expression of Bax, pro-caspase-6, and pro-caspase-9, and poly(ADP)ribose polymerase cleavage; (d) inhibition of peroxisome proliferator activated receptor γ; and (e) inhibition of nuclear factor-κB compared with the additive effects of the two agents alone, suggesting a possible synergism. In vivo, combination treatment with green tea polyphenols and celecoxib resulted in enhanced (a) tumor growth inhibition, (b) lowering of prostate-specific antigen levels, (c) lowering of insulin-like growth factor-I levels, and (d) circulating levels of serum insulin-like growth factor binding protein-3 compared with results of single-agent treatment. Conclusions: These data suggest synergistic and/or additive effects of combinatorial chemopreventive agents and underscore the need for rational design of human clinical trials.