tbuckley/cabot-search huggingface dataset:
Effects of polyamine imbalance on the induction of stress genes in hepatocarcinoma cells exposed to heat shock
Authors: M A Desiderio, L Tacchini, E Anzon, G Pogliaghi, L Radice, A Bernelli-Zazzera
Journal: Hepatology (1996)

The expression of hsp70-the inducible member of the corresponding heat shock gene family–of the oxidative stress marker gene heme oxygenase (HOx), and of the immediate early response genes c– fos and c– jun has been studied in FAO hepatocarcinoma cells depleted of polyamines and exposed to heat shock. Depletion of polyamines was obtained in short– term experiments (24–48 hours) by the use of alpha difluoromethylornithine (DFMO), a classical inhibitor of ornithine decarboxylase (ODC), or of the combination of the newly available inhibitors of ODC and S–adenosylmethionine decarboxylase, i.e., (2R,5R)–hept–6–yne–2,5–diamine (MAP) and 5′[(Z)–4–aminobut–2–enyl]methylanino–5– deoxyadeno–si ne (AbeAdo). Under our experimental conditions polyamine imbalance was realized without appreciable growth–related genes. Decreases of putrescine and spermidine 48 hours after DFMO prevented the induction of hsp70 messenger RNA (mRNA), whereas depletion spermidine and spermine obtained with MAP/AbeAdo decreased intensity and duration of post–heat shock accumulation of hsp70 mRNA. Inductions of HOx, c– jun and c– fos were also inhibited. Because MAP/AbeAdo caused also an intracelluar accumulation of putrescine, we tested the effect of exogenous putrescine, which was found to stabilize the mRNAs for hsp70 and c– jun . Hsp70 and HOx are thought to play a protective role, and the proteins of c– jun and c– fos constitute the transcription factor activator protein–1, which is involved in the transcription of many defensive products. Therefore, the integrity of polyamine pool seems to be a necessary permissive condition for an effective response of the cells to adverse environmental changes.
Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors.
Authors: M Trauner, M Arrese, H Lee, J L Boyer, S J Karpen
Journal: Journal of Clinical Investigation (1998)

Sodium-dependent uptake of bile acids across the hepatic basolateral membrane is rapidly and profoundly diminished during sepsis, thus contributing to the pathogenesis of sepsis-associated cholestasis. This effect is mediated by endotoxin or effector cytokines, which reduce expression of several hepatobiliary transporters, including the sodium-dependent bile acid transporter gene, ntcp. We test here the hypothesis that endotoxin treatment leads to impaired binding activity of ntcp promoter trans-acting factors, resulting in reduction of ntcp mRNA expression. After endotoxin administration, ntcp mRNA levels reached their nadir by 16 h, and nuclear run-on assays demonstrated a marked reduction in ntcp gene transcription. At 16 h after treatment, nuclear binding activities of two key factors that transactivate the ntcp promoter, hepatocyte nuclear factor (HNF) 1 and Footprint B binding protein (FpB BP), decreased to 44 and 47% of pretreatment levels, respectively, while levels of the other known ntcp promoter transactivator, signal transducer and activator of transcription 5, were unaffected. In contrast, the universal inflammatory response factors nuclear factor kappaB and activating protein 1 were both upregulated significantly. Examination of nuclear extracts obtained at sequential time points revealed that the maximal decrease in nuclear activities of both HNF1 and FpB BP preceded the nadir of ntcp mRNA expression by 6-10 h. Furthermore, these two nuclear factors returned towards normal levels before the recovery of ntcp mRNA levels observed by 48 h. Since HNF1alpha mRNA levels were unchanged at all time points, HNF1 is likely to be regulated posttranscriptionally by endotoxin. We conclude that the downregulation of ntcp gene expression by endotoxin is mediated at the level of transcription through tandem reductions in the nuclear binding activity of two critical transcription factors. These findings provide new insight into the coordinated downregulation of hepatobiliary transporters during sepsis.
Pancreatic-Pleural Fistula Demonstrated by Endoscopic Retrograde Cholangiopancreatography
Authors: P. Ondrejka, F. Siket, I. Sugár, J. Faller
Journal: Endoscopy (1996)

See also: Pancreaticopleural Fistula Treated by Transpapillary Implantation of a Plastic ProsthesisEndoscopy 1998; 30(08): 741-741DOI: 10.1055/s-2007-1001402
Chlorpropamide-alcohol flushing: a dominantly inherited trait associated with diabetes.
Authors: R D Leslie, D A Pyke
Journal: BMJ (1978)

A simple test was devised to identify people susceptible to chlorpropamide-alcohol flushing (CPAF). Subjects were given a placebo tablet, followed by sherry 12 and 36 hours later. They then received a chlorpropamide tablet and sherry again after 12 and 36 hours. This single-dose challenge test was given to non-insulin-dependent diabetics, insulin-dependent diabetics, and normal subjects. CPAF was common in the non-insulin-dependent diabetics but rare in the other groups. When the test was used in identical twins and families of affected subjects CPAF appeared to be a dominantly inherited trait. We conclude that facial flushing after alcohol in people taking chlorpropamide is related to non-insulin-dependent diabetes, especially when there is a strong family history of diabetes, but not to insulin-dependent diabetes. It is a dominantly inherited trait.
Overlapping pathways to transplant glomerulopathy: chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy
Authors: Seema Baid-Agrawal, Alton B. Farris, Manuel Pascual, Shamila Mauiyyedi, Mary Lin Farrell, Nina Tolkoff-Rubin, A. Bernard Collins, Ulrich Frei, Robert B. Colvin
Journal: Kidney International (2011)
Abstract 4477: Dual-targeting of AMPK and PI3K/mTOR in a panel of breast cancer cell lines
Authors: Violeta Serra Elizalde, Michelangelo Russillo, Maurizio Scaltriti, Olga Rodriguez, Marta Guzman, Serena Di Cosimo, José Baselga
Journal: Cancer Research (2010)

Abstract Several PI3K/AKT/mTOR pathway inhibitors are presently in early clinical trials for the treatment of cancer. Due to their mechanism of action, many of these compounds markedly increase the blood glucose levels. Metformin is an AMPK activator widely used in clinical practice to contrast hyperglycemia and is also known to reduce cancer risk as well as to improve cancer prognosis. The aim of this study is to explore the in vitro anti-tumor effect of metformin alone and in combination with the PI3K/mTOR inhibitor NVP-BEZ235 in a panel of breast cancer cell lines. Breast cancer cells (BT474, SKBR3, MCF7, MDA-468, MDA-231) were exposed to escalating doses of BEZ235 as single agent and in combination with metformin. Levels of phosphorylated and total AMPK, MAPK, EGFR, HER2 and S6 ribosomal protein were evaluated by western blot. Metformin induced dose-dependent growth inhibition. The combined treatment of NVP-BEZ235 plus metformin resulted in an inhibitory effect on cell proliferation greater than with either treatment alone in EGFR and HER2 positive breast cancer cell lines. At the IC50 of 20 mM we found that metformin activates AMPK reducing mTORC1 activity and, in turn, decreasing the levels of p-S6 ribosomal protein. Metformin treatment was also associated with reduced receptor tyrosine kinases (RTKs) expression (EGFR and HER2) and decreased p-MAPK. The dual PI3K/mTOR inhibitor NVP-BEZ235 potently decreases p-AKT and p-S6. As described for other mTOR inhibitors, NVP-BEZ235 increases MAPK phosphorylation by transactivation of several RTKs of the HER family. Treatment with metformin downregulates these RTKs preventing NVP-BEZ235-dependent MAPK pathway transactivation, providing a possible explanation for the potent anti-proliferative activity of the combination in HER2 positive breast cancer cell lines. The combination of metformin and NVP-BEZ235 significantly inhibits the growth of several breast cancer cell lines. We propose that inhibiting the PI3K/Akt/mTOR pathway in combination with metformin treatment would result in superior antitumor activity. Further studies are warranted to determine the applicability of this approach in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4477.
Effects of Practice Style in Managing Back Pain
Authors: Michael Von Korff
Journal: Annals of Internal Medicine (1994)

Objective: To assess the effects of a practice style of back pain management consistent with self-care (infrequent prescribing of pain medications and bed rest) on long-term functional outcomes, costs of care, and patient satisfaction. Design: A quasi-experimental observational study in which primary care physicians (n = 44) were categorized according to one of three practice style groups defined by a low, moderate, or high frequency of prescribing pain medications and bed rest for many patients (average, 24 patients per physician). Setting: Primary care practices of a large, staff model health maintenance organization, Group Health Cooperative of Puget Sound. Patients: Consecutive patients with back or neck pain of participating primary care physicians. Patients were interviewed 1 month (n = 1071) and 1 year and 2 years (n = 911) after their index visits. Results: Patients in the three practice style groups rated similarly the quality of medical care received for back pain. Patients treated by physicians who infrequently prescribed pain medications and bed rest were more satisfied with education about back pain. On a scale of 0 to 10, the mean rating of agreement with the statement, "After your visit with the doctor, you fully understood how to take care of your back problem," was 5.6 ±3.6 among patients of physicians who frequently prescribed medication and rest and was 6.6 ±3.5) among those who infrequently prescribed medication and bed rest. At 1 month, 30% of patients of physicians who infrequently prescribed medications and bed rest were graded as having moderate to severe activity limitation because of back pain, whereas 37% of patients in the moderate group had this grading, and 46% of patients of physicians who frequently prescribed were graded as having moderate to severe activity limitation. Differences in activity limitation by practice style group were no longer evident at 1 or 2 years of follow-up. The total 1-year costs of back care were higher among patients seen by physicians who frequently prescribed bed rest and pain medications (cost, $768 ±$1592) than among those seen by physicians who infrequently prescribed (cost, $428 ±$665), due largely to differences in inpatient and specialty care costs. The adjusted difference in costs, after controlling for case-mix variables, was $277 (95% CI, $85.50 to $471.32). Conclusions: A practice style consistent with back pain self-care yielded similar long-term pain and functional outcomes at lower cost and was associated with higher satisfaction with patient education compared with a practice style characterized by more frequent prescribing of pain medications and bed rest.
Administration of Anti-CD3 Antibodies Modulates the Immune Response to an Infusion of α-glucosidase in Mice
Authors: Toya Ohashi, Sayoko Iizuka, Yohta Shimada, Takashi Higuchi, Yoshikatsu Eto, Hiroyuki Ida, Hiroshi Kobayashi
Journal: Molecular Therapy (2012)

Animal and human studies of enzyme replacement therapy (ERT) for Pompe disease (PD) have indicated that antibodies (Abs) generated against infused recombinant human α-glucosidase (rhGAA) can have a negative impact on the therapeutic outcome and cause hypersensitivity reactions. We showed that parenteral administration of anti-CD3 Abs into mice can reduce the titer of anti-human GAA Abs in wild-type mice administered the enzyme. Mice that had been treated with anti-CD3 Abs and then subjected to a secondary challenge with rhGAA showed a lower increase in Ab titers than control mice. Moreover, the administration of anti-CD3 Abs also reduced the levels of pre-existing Abs. Treatment with anti-CD3 Abs also prevented a lethal hypersensitivity reaction and reduced the Ab titers in a mouse model of PD. Mice treated with anti-CD3 Abs showed reduced numbers of CD4+ and CD8+ cells, and an increased ratio of CD4+CD25+/CD4+ and CD4+CD25+FoxP3+/CD4+ cells. When the CD4+CD25+ cells were depleted using anti-CD25 Abs, the observed reduction in Abs against the enzyme by anti-CD3 Abs was abrogated. This suggests that CD4+CD25+ cells are important for the immune suppressive activity of anti-CD3 Abs. In summary, anti- CD3 Abs are useful for inducing immune tolerance to ERT for PD. Animal and human studies of enzyme replacement therapy (ERT) for Pompe disease (PD) have indicated that antibodies (Abs) generated against infused recombinant human α-glucosidase (rhGAA) can have a negative impact on the therapeutic outcome and cause hypersensitivity reactions. We showed that parenteral administration of anti-CD3 Abs into mice can reduce the titer of anti-human GAA Abs in wild-type mice administered the enzyme. Mice that had been treated with anti-CD3 Abs and then subjected to a secondary challenge with rhGAA showed a lower increase in Ab titers than control mice. Moreover, the administration of anti-CD3 Abs also reduced the levels of pre-existing Abs. Treatment with anti-CD3 Abs also prevented a lethal hypersensitivity reaction and reduced the Ab titers in a mouse model of PD. Mice treated with anti-CD3 Abs showed reduced numbers of CD4+ and CD8+ cells, and an increased ratio of CD4+CD25+/CD4+ and CD4+CD25+FoxP3+/CD4+ cells. When the CD4+CD25+ cells were depleted using anti-CD25 Abs, the observed reduction in Abs against the enzyme by anti-CD3 Abs was abrogated. This suggests that CD4+CD25+ cells are important for the immune suppressive activity of anti-CD3 Abs. In summary, anti- CD3 Abs are useful for inducing immune tolerance to ERT for PD.
Testicular differentiation factor SF-1 is required for human spleen development
Authors: David Zangen, Yotam Kaufman, Ehud Banne, Ariella Weinberg-Shukron, Abdulsalam Abulibdeh, Benjamin P. Garfinkel, Dima Dweik, Moein Kanaan, Núria Camats, Christa Flück, Paul Renbaum, Ephrat Levy-Lahad
Journal: Journal of Clinical Investigation (2014)

The transcription factor steroidogenic factor 1 (SF-1; also known as NR5A1) is a crucial mediator of both steroidogenic and nonsteroidogenic tissue differentiation. Mutations within SF1 underlie different disorders of sexual development (DSD), including sex reversal, spermatogenic failure, ovarian insufficiency, and adrenocortical deficiency. Here, we identified a recessive mutation within SF1 that resulted in a substitution of arginine to glutamine at codon 103 (R103Q) in a child with both severe 46,XY-DSD and asplenia. The R103Q mutation decreased SF-1 transactivation of TLX1, a transcription factor that has been shown to be essential for murine spleen development. Additionally, the SF1 R103Q mutation impaired activation of steroidogenic genes, without affecting synergistic SF-1 and sex-determining region Y (SRY) coactivation of the testis development gene SOX9. Together, our data provide evidence that SF-1 is required for spleen development in humans via transactivation of TLX1 and that mutations that only impair steroidogenesis, without altering the SF1/SRY transactivation of SOX9, can lead to 46,XY-DSD.
Diabetic Peripheral Neuropathies
Authors: YADOLLAH HARATI
Journal: Annals of Internal Medicine (1987)

Diabetic peripheral neuropathies are a group of heterogeneous syndromes with considerable morbidity. At least 50% of diabetic patients develop one or several of these neuropathies within 25 years after the diagnosis. In recent years several pathogenetic mechanisms have been proposed, with the newest findings suggesting a link between several of these hypotheses. The hypoxic hypothesis has revived the role of vascular factors in the pathogenesis of diabetic peripheral neuropathies. Although the exact role of hyperglycemia in the development of peripheral neuropathy is not known, the balance of evidence indicates that attainment and maintenance of normal blood glucose remains the cornerstone of treatment of diabetes and diabetic neuropathies. There is no convincing evidence that any of the treatments devised to correct the metabolic derangements in nerve are of sufficient value or safety to be recommended for routine use.
Modulation of nicotinamide adenine dinucleotide and poly(adenosine diphosphoribose) metabolism by the synthetic "C" nucleoside analogs, tiazofurin and selenazofurin. A new strategy for cancer chemotherapy.
Authors: N A Berger, S J Berger, D M Catino, S J Petzold, R K Robins
Journal: Journal of Clinical Investigation (1985)

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) and selenazofurin (2-beta-D-ribofuranosylselenazole-4-carboxamide) are synthetic "C" nucleosides whose antineoplastic activity depends on their conversion to tiazofurin-adenine dinucleotide and selenazofurin-adenine dinucleotide which are analogs of NAD. The present study was conducted to determine whether these nucleoside analogs and their dinucleotide derivatives interfere with NAD metabolism and in particular with the NAD-dependent enzyme, poly(ADP-ribose) polymerase. Incubation of L1210 cells with 10 microM tiazofurin or selenazofurin resulted in inhibition of cell growth, reduction of cellular NAD content, and interference with NAD synthesis. Using [14C]nicotinamide to study the uptake of nicotinamide and its conversion to NAD, we showed that the analogs interfere with NAD synthesis, apparently by blocking formation of nicotinamide mononucleotide. The analogs also serve as weak inhibitors of poly(ADP-ribose) polymerase, which is an NAD-utilizing, chromatin-bound enzyme, whose function is required for normal DNA repair processes. Continuous incubation of L1210 cells in tiazofurin or selenazofurin resulted in progressive and synergistic potentiation of the cytotoxic effects of DNA-damaging agents, such as 1,3-bis(2-chloroethyl)-1-nitrosourea or N-methyl-N'-nitro-N-nitrosoguanidine. These studies provide a basis for designing chemotherapy combinations in which tiazofurin or selenazofurin are used to modulate NAD and poly(ADP-ribose) metabolism to synergistically potentiate the effects of DNA strand-disrupting agents.
Sociodemographic variables for general practices: use of census data
Authors: F A. Majeed, D. G Cook, J. Poloniecki, J. Griffiths, C. Stones
Journal: BMJ (1995)

Measures of the social, ethnic, and demographic characteristics of general practice populations are essential both for planning health services and for research. Such measures can be derived by combining census data for electoral wards with postcoded data from a family health services authority's age-sex register.1 Because electoral wards have large populations (typically 5000-15000 people), the patients registered with individual general practices will rarely be representative of a ward, and this will reduce the accuracy of census derived variables. Enumeration districts, however, have smaller populations (typically 200-600 people). We (a) derived estimates of age structure of practice populations based on enumeration districts and electoral wards and compared them with those obtained from the authority's age-sex registry and (b) compared the predictive power of variables derived from enumeration districts and electoral wards in explaining the variation in breast cancer screening rates among these practices.

The family health services authority provided a database …
Sodium-Independent Active Potassium Reabsorption in Proximal Tubule of the Dog
Authors: Laurence H. Beck, Dorothy Senesky, Martin Goldberg
Journal: Journal of Clinical Investigation (1973)

Prior studies of proximal tubule reabsorption have failed to distinguish conclusively between a separate active K+ transport system and K+ movement linked to Na+ reabsorption. To attempt to dissociate movement of K+ from Na+ and Ca++, recollection micropuncture experiments were performed in proximal tubules of intact and thyroparathyroidectomized (TPTX) dogs under two different conditions known to inhibit Na+ reabsorption: saline expansion to 5% body wt, and 5 mg/kg acetazolamide. A control hydropenic group was also studied. Tubular concentrations of K+, Na+, and Ca++ were measured by electron probe analysis. During initial collections, mean+/-SEM tubular fluid/plasma (TF/P)(K+) was 1.07 +/-0.05, 1.05+/-0.05, and 1.00+/-0.03 in intact hydropenic (n = 7), saline (n = 6), and acetazolamide (n = 8) groups; fractional reabsorption (FR) of K+ in proximal tubules was 0.35, 0.39, and 0.31 respectively. After saline, (TF/P)(Inul in) fell from 1.81 to 1.34 (P < 0.01); (TF/P)(K+), (TF/P)(Na+), and tubular fluid/ultrafiltrate, (TF/UF)(Ca++) did not change, so that FR of all three ions fell proportionately. After acetazolamide, however, despite a 24% inhibition of FR of Na+ and Ca++, (TF/P)(K+) fell to 0.85+/-0.04 (P < 0.005) so that FR of K+ was unchanged at 0.34. In three corresponding groups of TPTX dogs, similar results were obtained. Acetazolamide (n = 7) inhibited FR of Na+ and Ca++ by 41%, but (TF/P)(K+) fell from 1.03+/-0.03 to 0.89+/-0.04 (P < 0.005) so that FR of K+ was unchanged (0.36-0.34).A separate uphill transport system for K+ in proximal tubules is therefore unmasked by acetazolamide, a drug which selectively inhibits Na+ (and Ca++) reabsorption. Saline, on the other hand, inhibits net reabsorption of all three ions, probably by increasing passive backflux via intercellular channels.
GPs refer too many women for genetic tests
Authors: L. Eaton
Journal: BMJ (2002)

Many GPs are unnecessarily referring women for genetic tests for breast and ovarian cancer, a report from the Cancer Research Campaign and Imperial Cancer Research Fund has said.

The two charities—which will merge in February—have said that many GPs lack confidence in counselling patients about inherited cancer risks. As a result, they tend to refer women who have a family history of breast …
Stature and personality.
Authors: F. Richardson
Journal: BMJ (1968)

subheadings, so that all the drugs of similar action were to be found together.The antidepressives are a case in point.Instead of all antidepressives being listed alphabetically, as in MIMS, Medindex classified them into monoamine oxidase inhibitors, thymoleptics, and others.Other useful sections were the paragraphs of indications and safety factors at the beginning of each section, and the index of official and other approved names.I am sure there must be many general practitioners who regret the passing of Medindex as much as I do.
Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: Implications for gene therapy
Authors: André Larochelle, Josef Vormoor, Helmut Hanenberg, Jean C.Y. Wang, Mickie Bhatia, Tsvee Lapidot, Thomas Moritz, Barbara Murdoch, Xiang Li Xiao, Ikunoshin Kato, David A. WIlliams, John E. Dick
Journal: Nature Medicine (1996)
PLGAs bearing carboxylated side chains: Novel matrix formers with improved properties for controlled drug delivery
Authors: C. Regnier-Delplace, O. Thillaye du Boullay, F. Siepmann, B. Martin-Vaca, P. Demonchaux, O. Jentzer, F. Danède, M. Descamps, J. Siepmann, D. Bourissou
Journal: Journal of Controlled Release (2013)
FACIAL DIPLEGIA IN LYMPHATIC LEUKEMIA
Authors: PAUL H. GARVEY
Journal: JAMA (1933)

Bilateral paralysis of the facial nerves is rather uncommon. It is usually associated with infections of the nervous system, such as polyneuritis and gummatous basal meningitis. A leukemic origin of the disorder is extraordinary. In view of the infrequency of leukemia as a cause of facial diplegia, we have thought it worth while to report the clinical and pathologic observations in a patient who presented this picture. We have included in this report the clinical data in two other cases of acute leukemia in which a unilateral facial paralysis occurred. <h3>REPORT OF CASES</h3><h3>Case 1.—Clinical History.</h3>