tbuckley/cabot-search huggingface dataset:
Oleic acid-induced cholelithiasis in the rabbit: Conversion of dietary oleic acid to cholestanol as a cause of calcium-bile salt gallstones
Authors: Sum P. Lee, Cliff Tasman-Jones, Valerie F. Carlisle
Journal: Hepatology (1987)

Rabbits fed a diet rich in oleic acid develop gallstones consisting of calcium salts of (5α)-glyco-allodeoxycholic acid. To study the metabolic pathway of oleic acid, we followed the changes in plasma, hepatic and biliary lip-ids in this animal model. In addition, to also determine the role played by intestinal microflora on biliary lipid metabolism, we added kanamycin to the oleic acid diet. Oleic acid-fed rabbits rapidly developed hypercholes-terolemia. This was associated with an increase in liver 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, accumulation of cholesterol as well as cholestanol in the liver and progressive saturation of cholesterol in bile. [ 14 C]oleic acid fed orally to rabbits was recovered in liver extracts as both cholesterol and cholestanol. With oleic acid feeding, there was a progressive increase in glyco-allodeoxycholic acid culminating in the formation of gallstones. Kanamycin supplement to the oleic acid diet resulted in the same changes in plasma and hepatic sterol metabolism compared with oleic acid-fed rabbits. There was, however, a striking difference in the biliary bile acid profile. Kanamycin supplementation dramatically reduced the proportion of 5α-dihydroxy bile acids, increased the proportion of 5β-trihydroxy bile acids and completely abolished gallstone formation. We postulate that, in the rabbit, oleic acid is used as a carbon source for cholesterol synthesis, and a high oleic acid diet increases hepatic cholesterogenesis. Hepatic cholesterol is then metabolized to form cholestanol, followed by (5α)-glyco-allocholic acid which is secreted into bile and transformed by gut bacteria to form (5α)-allodeoxycholic acid. Kanamycin abolished gallstone formation by inhibiting intestinal bacterial dehydroxylation.
Risk of pneumococcal septicaemia in patients with chronic lymphoproliferative malignancies
Authors: R Gowda, F M Razvi, G P Summerfield
Journal: BMJ (1995)

Guidelines for the prevention of infection in patients with an absent or dysfunctionalspleen have recently been prepared.1 However, another group of patients (with intact spleens) is also particularly susceptible to such infections. Lymphoproliferative malignancies such as chronic lymphocytic leukaemia, myeloma, and low grade non-Hodgkin's lymphoma are associated with immune paresis.2 Such patients are often treated with corticosteroids, and a combination of these two factors renders them vulnerable to infections with encapsulated organisms such as Streptococcus pneumoniae. These infections have a high morbidity and mortality. Over a period of 16 months we found that pneumococcal sepsis was a far greater problem in patients with lymphoproliferative disorders than in patients who had had a splenectomy; we decided to investigate further.

We studied all …
Role of MgSO4 in PICU management of children with status asthmaticus
Authors: Shahid Sheikh, Nadeem Khan, Melissa Frasure, Nancy Ryan-Wenger, Karen McCoy
Journal: European Respiratory Journal (2012)

Background: This retrospective study was done to understand the use of MgSO4 for treatment of children with status asthmaticus in a pediatric intensive care unit (PICU). Methods: Charts of all patients ≥ 5 years of age admitted to the PICU with status asthmaticus, at Nationwide Children9s Hospital, Columbus, OH, between 2000-2007 were reviewed. Results: Among 222 encounters, 203 received continuous albuterol, 216 received IV steroids, 113 receive Terbutaline, 17 received mechanical ventilation, and 57 (25.7%) received MgSO4. All patients survived. Children who received MgSO4 vs. those who did, median PICU and hospital stay were one day longer and differences were significant. There were no significant differences between groups in any other features. Significant improvements in median pH (p-0.027) and PaCO2 (p=0.017) were noted in both groups.  Conclusion: Among children admitted to PICU for status asthmaticus, MgSO4 recipients stayed longer in PICU and in the hospital though their acute illness was not significantly worse than those not receiving MgSO4 as observed by their initial CBG, need for mechanical ventilation or presence of air space disease on chest radiographs.
Lymphocyte abnormalities in ankylosing spondylitis.
Authors: P T Fan, P J Clements, D T Yu, G Opelz, R Bluestone
Journal: Annals of the Rheumatic Diseases (1977)

Peripheral blood T (SRBC rosette) and B (AgG- and C-receptor) lymphocyte subpopulations and responsiveness to phytohaemagglutinin (PHA) were assayed in 40 patients with ankylosing spondylitis and in 55 normal subjects. There was no significant difference in the lymphocyte concentrations or responsiveness to PHA between the two groups. However, the percentages of T lymphocytes were significantly lower in the patients irrespective of their HLA typing. This was probably due to an increase in the 9null9 population since the percentages of both the AgG- and C-receptor cells were normal.
Inhibition of TRPC6 degradation suppresses ischemic brain damage in rats
Authors: Wanlu Du, Junbo Huang, Hailan Yao, Kechun Zhou, Bo Duan, Yizheng Wang
Journal: Journal of Clinical Investigation (2010)

Brain injury after focal cerebral ischemia, the most common cause of stroke, develops from a series of pathological processes, including excitotoxicity, inflammation, and apoptosis. While NMDA receptors have been implicated in excitotoxicity, attempts to prevent ischemic brain damage by blocking NMDA receptors have been disappointing. Disruption of neuroprotective pathways may be another avenue responsible for ischemic damage, and thus preservation of neuronal survival may be important for prevention of ischemic brain injury. Here, we report that suppression of proteolytic degradation of transient receptor potential canonical 6 (TRPC6) prevented ischemic neuronal cell death in a rat model of stroke. The TRPC6 protein level in neurons was greatly reduced in ischemia via NMDA receptor–dependent calpain proteolysis of the N-terminal domain of TRPC6 at Lys16. This downregulation was specific for TRPC6 and preceded neuronal death. In a rat model of ischemia, activating TRPC6 prevented neuronal death, while blocking TRPC6 increased sensitivity to ischemia. A fusion peptide derived from the calpain cleavage site in TRPC6 inhibited degradation of TRPC6, reduced infarct size, and improved behavioral performance measures via the cAMP response element–binding protein (CREB) signaling pathway. Thus, TRPC6 proteolysis contributed to ischemic neuronal cell death, and suppression of its degradation preserved neuronal survival and prevented ischemic brain damage.
REGULATION OF GENE EXPRESSION BY DIETARY FAT
Authors: Donald B. Jump, Steven D. Clarke
Journal: Annual Review of Nutrition (1999)

▪ Abstract Dietary fat is an important macronutrient for the growth and development of all organisms. In addition to its role as an energy source and its effects on membrane lipid composition, dietary fat has profound effects on gene expression, leading to changes in metabolism, growth, and cell differentiation. The effects of dietary fat on gene expression reflect an adaptive response to changes in the quantity and type of fat ingested. Specific fatty acid–regulated transcription factors have been identified in bacteria, amphibians, and mammals. In mammals, these factors include peroxisome proliferator–activated receptors (PPARα, -β, and -γ), HNF4α, NFκB, and SREBP1c. These factors are regulated by (a) direct binding of fatty acids, fatty acyl–coenzyme A, or oxidized fatty acids; (b) oxidized fatty acid (eicosanoid) regulation of G-protein–linked cell surface receptors and activation of signaling cascades targeting the nucleus; or (c) oxidized fatty acid regulation of intracellular calcium levels, which affect cell signaling cascades targeting the nucleus. At the cellular level, the physiological response to fatty acids will depend on (a) the quantity, chemistry, and duration of the fat ingested; (b) cell-specific fatty acid metabolism (oxidative pathways, kinetics, and competing reactions); (c) cellular abundance of specific nuclear and membrane receptors; and (d) involvement of specific transcription factors in gene expression. These mechanisms are involved in the control of carbohydrate and lipid metabolism, cell differentiation and growth, and cytokine, adhesion molecule, and eicosanoid production. The effects of fatty acids on the genome provide new insight into how dietary fat might play a role in health and disease.
Development and validation of a screening test for 12 common mutations of the cystic fibrosis CFTR gene
Authors: NH Robertson, SL Weston, SJ Kelly, NJ Duxbury, SR Pearce, P Elsmore, MB Webb, CR Newton, S Little
Journal: European Respiratory Journal (1998)

The results obtained using deoxyribonucleic acid (DNA) amplification-based tests must be accurate and reproducible. One such test that simultaneously detects any of 12 of the most common mutations of the cystic fibrosis transmembrane conductance regulator gene is presented in this report. An investigation was conducted into how changes of primer, DNA template and Taq DNA polymerase concentrations and of polymerase chain reaction annealing temperatures affect the test. A total of 383 DNA samples obtained from different laboratories was then examined. The preliminary studies defined the conditions under which accurate results are obtained even if the test is performed under suboptimal conditions. Subsequently, 377 (98.4%) of the DNA samples analysed were in full agreement with DNA typing results derived by other methods. The remaining 1.6% of samples were not mistyped, rather they were not scored owing to failure to detect control DNA sequences. These were also archival DNA preparations rather than freshly prepared samples from venous blood. Careful primer design and optimization of reaction conditions are important in the development of multiplex deoxyribonucleic acid amplification-based diagnostic tests. Providing the recommended protocols are followed, the test described here is simple to carry out, gives accurate results and works well if performed within defined operational windows for each reaction variable.
Down-regulation of Notch-1 Inhibits Invasion by Inactivation of Nuclear Factor-κB, Vascular Endothelial Growth Factor, and Matrix Metalloproteinase-9 in Pancreatic Cancer Cells
Authors: Zhiwei Wang, Sanjeev Banerjee, Yiwei Li, K.M. Wahidur Rahman, Yuxiang Zhang, Fazlul H. Sarkar
Journal: Cancer Research (2006)

Abstract Notch signaling plays a critical role in the pathogenesis and progression of human malignancies but the precise role and mechanism of Notch-1 for tumor invasion remains unclear. In our earlier report, we showed that down-regulation of Notch-1 reduced nuclear factor-κB (NF-κB) DNA-binding activity and matrix metalloproteinase-9 (MMP-9) expression. Because NF-κB, VEGF, and MMPs are critically involved in the processes of tumor cell invasion and metastasis, we investigated the role and mechanism(s) by which Notch-1 down-regulation (using molecular approaches) may lead to the down-regulation of NF-κB, vascular endothelial growth factor (VEGF), and MMP-9, thereby inhibiting invasion of pancreatic cancer cells through Matrigel. We found that the down-regulation of Notch-1 by small interfering RNA decreased cell invasion, whereas Notch-1 overexpression by cDNA transfection led to increased tumor cell invasion. Consistent with these results, we found that the down-regulation of Notch-1 reduced NF-κB DNA-binding activity and VEGF expression. Down-regulation of Notch-1 also decreased not only MMP-9 mRNA and its protein expression but also inactivated the pro-MMP-9 protein to its active form. Taken together, we conclude that the down-regulation of Notch-1 could be an effective approach for the down-regulation and inactivation of NF-κB and its target genes, such as MMP-9 and VEGF expression, resulting in the inhibition of invasion and metastasis. (Cancer Res 2006; 66(5): 2778-84)
The impact of obesity on the development and progression of rheumatoid arthritis
Authors: Axel Finckh, Carl Turesson
Journal: Annals of the Rheumatic Diseases (2014)

The inducible co-stimulatory molecule (ICOS)/ICOS ligand (ICOSL) co-stimulatory pathway is critical in T cell activation, differentiation, and effector function. Its role was investigated in a model of Th1-driven crescentic glomerulonephritis (GN). GN was induced by sensitizing mice to sheep globulin (day 0) and challenging them with sheep anti-mouse glomerular basement membrane antibody (Ab; day 10). Disease and immune responses were assessed on day 20. For testing the role of ICOSL in the induction of GN, control or anti-ICOSL mAb were administered from days 0 to 8. For examining the role of ICOSL in the effector phase of GN, treatment lasted from days 10 to 18. Blockade of ICOSL during the induction of GN increased glomerular accumulation of CD4+ T cells and macrophages and augmented renal injury. These results correlated with attenuated splenocyte production of protective Th2 cytokines IL-4 and IL-10 and decreased apoptosis of splenic CD4+ T cells. ICOSL was upregulated within glomeruli of mice with GN. Inhibition of ICOSL during the effector phase of GN enhanced glomerular T cell and macrophage accumulation and augmented disease, without affecting the systemic immune response (cytokine production, T cell apoptosis/proliferation, Ab levels). Increased presence of leukocytes in glomeruli of mice that received anti-ICOSL mAb was associated with enhanced cellular proliferation and upregulation of P-selectin and intercellular adhesion molecule-1 within glomeruli. These studies demonstrate that ICOSL is protective during the induction of GN by augmenting Th2 responses and CD4+ T cell apoptosis. They also show that ICOSL is upregulated in nephritic glomeruli, where it locally reduces accumulation of T cells and macrophages and attenuates renal injury.
Acupuncture for Patients With Migraine
Authors: Klaus Linde, Andrea Streng, Susanne Jürgens, Andrea Hoppe, Benno Brinkhaus, Claudia Witt, Stephan Wagenpfeil, Volker Pfaffenrath, Michael G Hammes, Wolfgang Weidenhammer, Stefan N Willich, Dieter Melchart
Journal: JAMA (2005)

Acupuncture is widely used to prevent migraine attacks, but the available evidence of its benefit is scarce.To investigate the effectiveness of acupuncture compared with sham acupuncture and with no acupuncture in patients with migraine.Three-group, randomized, controlled trial (April 2002-January 2003) involving 302 patients (88% women), mean (SD) age of 43 (11) years, with migraine headaches, based on International Headache Society criteria. Patients were treated at 18 outpatient centers in Germany.Acupuncture, sham acupuncture, or waiting list control. Acupuncture and sham acupuncture were administered by specialized physicians and consisted of 12 sessions per patient over 8 weeks. Patients completed headache diaries from 4 weeks before to 12 weeks after randomization and from week 21 to 24 after randomization.Difference in headache days of moderate or severe intensity between the 4 weeks before and weeks 9 to 12 after randomization.Between baseline and weeks 9 to 12, the mean (SD) number of days with headache of moderate or severe intensity decreased by 2.2 (2.7) days from a baseline of 5.2 (2.5) days in the acupuncture group compared with a decrease to 2.2 (2.7) days from a baseline of 5.0 (2.4) days in the sham acupuncture group, and by 0.8 (2.0) days from a baseline if 5.4 (3.0) days in the waiting list group. No difference was detected between the acupuncture and the sham acupuncture groups (0.0 days, 95% confidence interval, -0.7 to 0.7 days; P = .96) while there was a difference between the acupuncture group compared with the waiting list group (1.4 days; 95% confidence interval; 0.8-2.1 days; P<.001). The proportion of responders (reduction in headache days by at least 50%) was 51% in the acupuncture group, 53% in the sham acupuncture group, and 15% in the waiting list group.Acupuncture was no more effective than sham acupuncture in reducing migraine headaches although both interventions were more effective than a waiting list control.
Come home to a real fire
Authors: D Cameron
Journal: BMJ (1994)

Conversation overheard:

“Anyway the referral letter to the casualty SHO was in Welsh. So the casualty officer, who was Indian, wrote back in Urdu. Ho, ho. Serve the GP right.“

“Clever dick. Probably a cottage burner on his nights off. Come home to a real fire, eh? Bet he dresses up as a druid and prances about with a trumpet at the Eisteddfod.“

“And all that money they spend putting up the signs around the hospital in Welsh as well - people get even …
P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 Determine the Pharmacokinetics of Etoposide
Authors: Jurjen S. Lagas, Lin Fan, Els Wagenaar, Maria L.H. Vlaming, Olaf van Tellingen, Jos H. Beijnen, Alfred H. Schinkel
Journal: Clinical Cancer Research (2009)

Despite the extensive use of etoposide for the treatment of different malignant neoplasms, its main pharmacokinetic determinants are not completely defined. We aimed to study the impact of P-glycoprotein (P-gp/ABCB1) and the multidrug resistance proteins ABCC2 (MRP2) and ABCC3 (MRP3) on the pharmacokinetics of etoposide.Abcb1a/1b(-/-), Abcc2(-/-), Abcc3(-/-), Abcb1a/1b;Abcc2(-/-), and Abcc2;Abcc3(-/-) mice were used to investigate the separate and combined impact of P-gp, Abcc2, and Abcc3 on the in vivo behavior of etoposide.P-gp restricted the oral (re)uptake of unchanged etoposide, and mediated its excretion across the gut wall. In contrast, hepatobiliary excretion was almost entirely dependent on Abcc2. Yet, complete loss of Abcc2 did not result in elevated liver or plasma concentrations of etoposide. Instead, Abcc2(-/-) mice displayed an increased hepatic formation of etoposide glucuronide, which was secreted via Abcc3 from the liver to the blood circulation and eliminated with the urine. Combination Abcc2;Abcc3(-/-) mice had highly increased accumulation of etoposide glucuronide in their livers, whereas both single knockouts did not, indicating that Abcc2 and Abcc3 provide alternative pathways for the hepatic elimination of etoposide glucuronide.P-gp, ABCC2, and ABCC3 significantly affect the pharmacokinetics of etoposide and/or etoposide glucuronide. Variation in transporter expression or activity may explain the high variation in oral availability of etoposide (25-80%) among cancer patients. However, despite the fact that substantial variations in transporter activity can occur, we believe that cancer patients are often relatively protected from etoposide toxicity due to overlapping functions of these transporters in the elimination of etoposide.
Prostaglandins and nitric oxide mediate insulin-induced vasodilation in the human forearm
Authors: Saskia van Veen, Peter C Chang
Journal: Cardiovascular Research (1997)

To determine the involvement of prostaglandins, nitric oxide, and beta-adrenoceptor activation in insulin-induced vasodilation in the human forearm.Fifteen normal subjects were studied. Insulin was administered into the brachial artery in the presence of saline, the cyclo-oxygenase inhibitor indomethacin (0.65 microgram/kg/min), the inhibitor of nitric oxide synthase NG-mono-methyl-L-arginine (L-NMMA, 30 micrograms/kg/min), or the non-selective beta-adrenoceptor blocker propranolol (0.2 microgram/kg/min). Forearm vascular resistance (FVR) was derived from forearm blood flow and concomitantly measured intra-arterial blood pressure.Insulin decreased FVR by 32 +/- 5% (P < 0.01). Both indomethacin and L-NMMA inhibited insulin-induced vasodilation, while propranolol had no effect. Single infusion of indomethacin was without effect on vascular tone, while single infusion of L-NMMA increased FVR by 81 +/- 19% (P < 0.01).Insulin has vasodilating properties in skeletal muscle vasculature that is mediated by increases in nitric oxide, that subsequently stimulates prostaglandin release. The latter appears to be a novel vascular action of insulin.
Randomized Phase II Window Trial of Two Schedules of Irinotecan With Vincristine in Patients With First Relapse or Progression of Rhabdomyosarcoma: A Report From the Children's Oncology Group
Authors: Leo Mascarenhas, Elizabeth R. Lyden, Philip P. Breitfeld, David O. Walterhouse, Sarah S. Donaldson, Charles N. Paidas, David M. Parham, James R. Anderson, William H. Meyer, Douglas S. Hawkins
Journal: Journal of Clinical Oncology (2010)

To compare response rates for two schedules of irinotecan with vincristine in patients with rhabdomyosarcoma at first relapse or disease progression.Patients with first relapse or progression of rhabdomyosarcoma and an unfavorable prognosis were randomly assigned to one of two treatment schedules of irinotecan with vincristine: regimen 1A included irinotecan 20 mg/m(2)/d intravenously for 5 days at weeks 1, 2, 4, and 5 with vincristine 1.5 mg/m(2) administered intravenously on day 1 of weeks 1, 2, 4, and 5; regimen 1B included irinotecan 50 mg/m(2)/d intravenously for 5 days at weeks 1 and 4 with vincristine as in regimen 1A. Disease response was assessed at week 6. Those with responsive disease continued to receive 44 weeks of multiagent chemotherapy that incorporated the assigned irinotecan-vincristine regimen.Ninety-two eligible patients were randomly assigned (1A, 45; 1B, 47). Response could be assessed in 89 patients (1A, 42; 1B, 47). There were five complete responses and six partial responses on regimen 1A (response rate, 26%; 95% CI, 16% to 42%) and 17 partial responses on regimen 1B (response rate, 37%; 95% CI, 25% to 51%; P = .36). Neutropenia was less common on regimen 1A (P = .04). One-year failure-free and overall survival rates for regimen 1A were 37% (95% CI, 23% to 51%) and 55% (95% CI, 39% to 69%), respectively, and for 1B, they were 38% (95% CI, 25% to 53%) and 60% (95% CI, 44% to 72%).There was no difference in the response rates between the two irinotecan-vincristine schedules. We recommend the shorter, more convenient regimen (1B) for further investigation.
Cleavage of β-Catenin by Calpain in Prostate and Mammary Tumor Cells
Authors: Jonathan Rios-Doria, Rainer Kuefer, Stephen P. Ethier, Mark L. Day
Journal: Cancer Research (2004)

Abstract Mutations in the NH2-terminal regulatory domain of the β-catenin gene lead to aberrant stabilization and accumulation of the protein and increased TCF/LEF-dependent transcription. Although these mutations are common in some cancers, they are infrequent in prostate and breast cancer. We have found that metastatic prostate cancer specimens, obtained through a rapid autopsy tissue procurement program, expressed a novel Mr 75,000 proteolytic fragment of β-catenin (β-cat75). β-Cat75 was also expressed in multiple prostate and breast cancer cell lines and was closely associated with the activity of the calcium-dependent protease, calpain. In a prostate cancer cDNA microarray, m-calpain RNA levels were found to be significantly increased in metastatic disease compared with normal prostate. We showed calpain-dependent generation of β-cat75 in cell culture and in vitro. Molecular mapping revealed that calpain cleavage removed the NH2-terminal regulatory domain of the β-catenin protein. Treatment of MCF-7 cells with ionomycin led to increased accumulation of β-cat75 in the nucleus and TCF-dependent transcriptional activity. Overexpression of a similar β-catenin fragment that lacks the NH2-terminal 132 amino acids and has transforming potential activated TCF-dependent transcription. Given the low frequency of mutation-induced activation of β-catenin in prostate and breast cancers, proteolytic cleavage of β-catenin by calpain may represent a novel mechanism by which the protein is activated during tumorigenesis.
Effect of the function of polymorphonuclear leukocytes and interleukin-1 beta on wound healing in patients with diabetic foot infections
Authors: O. Oncul, S. Yildiz, U. Soyogul Gurer, E. Yeniiz, T. Qyrdedi, C. Top, P. Gocer, B. Akarsu, A. Cevikbas, S. Cavuslu
Journal: Journal of Infection (2006)