tbuckley/cabot-search huggingface dataset:
β-Cell–Mediated Signaling Predominates Over Direct α-Cell Signaling in the Regulation of Glucagon Secretion in Humans
Authors: Benjamin A. Cooperberg, Philip E. Cryer
Journal: Diabetes Care (2009)

OBJECTIVE Given evidence of both indirect and direct signaling, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans. RESEARCH DESIGN AND METHODS We measured plasma glucagon concentrations before and after ingestion of a formula mixed meal and, on a separate occasion, ingestion of the sulfonylurea glimepiride in 24 basal insulin-infused, demonstrably β-cell–deficient patients with type 1 diabetes and 20 nondiabetic, demonstrably β-cell–sufficient individuals; the latter were infused with glucose to prevent hypoglycemia after glimepiride. RESULTS After the mixed meal, plasma glucagon concentrations increased from 22 ± 1 pmol/l (78 ± 4 pg/ml) to 30 ± 2 pmol/l (103 ± 7 pg/ml) in the patients with type 1 diabetes but were unchanged from 27 ± 1 pmol/l (93 ± 3 pg/ml) to 26 ± 1 pmol/l (89 ± 3 pg/ml) in the nondiabetic individuals (P &amp;lt; 0.0001). After glimepiride, plasma glucagon concentrations increased from 24 ± 1 pmol/l (83 ± 4 pg/ml) to 26 ± 1 pmol/l (91 ± 4 pg/ml) in the patients with type 1 diabetes and decreased from 28 ± 1 pmol/l (97 ± 5 pg/ml) to 24 ± 1 pmol/l (82 ± 4 pg/ml) in the nondiabetic individuals (P &amp;lt; 0.0001). Thus, in the presence of both β-cell and α-cell secretory stimuli (increased amino acid and glucose levels, a sulfonylurea) glucagon secretion was prevented when β-cell secretion was sufficient but not when β-cell secretion was deficient. CONCLUSIONS These data indicate that, among the array of signals, indirect reciprocal β-cell–mediated signaling predominates over direct α-cell signaling in the regulation of glucagon secretion in humans.
Change in Peripheral Blood Leukocyte Telomere Length and Mortality in Breast Cancer Survivors
Authors: C. Duggan, R. Risques, C. Alfano, D. Prunkard, I. Imayama, S. Holte, K. Baumgartner, R. Baumgartner, L. Bernstein, R. Ballard-Barbash, P. Rabinovitch, A. McTiernan
Journal: JNCI Journal of the National Cancer Institute (2014)

Progressive telomere shortening with cell division is a hallmark of aging. Short telomeres are associated with increased cancer risk, but there are conflicting reports about telomere length and mortality in breast cancer survivors. We measured peripheral blood leukocyte telomere length at two time points in women enrolled in a multiethnic, prospective cohort of stage I to stage IIIA breast cancer survivors diagnosed between 1995 and 1999 with a median follow-up of 11.2 years. We evaluated associations between telomere length measured at mean 6 (baseline; LTL 0 ; n = 611) and 30 months (LTL 30 ; n = 478) after diagnosis and the change between those time points (n = 478), with breast cancer–specific and all-cause mortality using Cox proportional hazards models adjusted for possible confounders. Statistical tests were two-sided. There were 135 deaths, of which 74 were due to breast cancer. Neither baseline nor 30-month telomere length was associated with either all-cause or breast cancer–specific mortality (LTL 0 : hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.67 to 1.02; HR = 0.88; 95% CI = 0.67 to 1.15; LTL 30 : HR = 0.78, 95% CI = 0.59 to 1.05; HR = 0.86; 95% = CI = 0.58 to 1.26, respectively). However, participants whose telomeres shortened between baseline and 30 months were at a statistically significantly increased risk of breast cancer–specific (HR = 3.03; 95% CI = 1.11 to 8.18) and all-cause mortality (HR = 2.38; 95% CI = 1.28 to 4.39) compared with participants whose telomeres lengthened. When follow-up was censored at 5-years after diagnosis, LTL 0 (HR = 0.66; 95% CI = 0.45 to 0.96), LTL 30 (HR = 0.51; 95% CI = 0.29 to 0.92), and change in telomere length (HR = 3.45; 95% CI = 1.11 to 10.75) were statistically significantly associated with all-cause mortality. Telomere shortening was associated with increased risk of breast cancer–specific and all-cause mortality, suggesting that change in blood telomere length over time could be a biomarker of prognosis. Research on determinants of telomere length and change is needed.
Imaging: do erosions heal?
Authors: D van der Heijde
Journal: Annals of the Rheumatic Diseases (2003)

It was shown previously that reparative changes in erosions can be seen in individual joints and individual patients. Whether repair may occur at a group level, and can be induced by treatment, is not known. This manuscript describes a means of visualising data obtained in a clinical trial by the use of probability plots to better understand the results. These probability plots give a good insight into the coherence of the data. They can also be used to make the interpretation of repair at a group level easier. Probability plots also explain the hazard of using binomial cut off points to compare treatment effects. The interference of true repair with measurement error is demonstrated. Repair at a group level is suggested if the mean progression score is statistically significantly different from zero, which can be visualised by a 95% confidence interval of this mean change score below zero. Application of this technique may give us better information on the effects of new drugs on the induction of repair.
Physician Supply: Primary Catalyst of Change
Authors: J. Alexander McMahon
Journal: JAMA (1986)

The Medicare prospective pricing system's dramatic entry into the health care scene 31/2 years ago has led many people to view it as the watershed event in health care delivery of this decade. Granted, the new system has wrought major changes and the attention it is getting is not altogether undeserved. However, the diagnosis related groups (DRG) system is only number 3 on my list of change agents. As prospective pricing went into effect, there were other more important changes already occurring in the health care environment. The increase in the number of physicians in the United States, in my opinion, has had the most far-reaching impact on the health care world. Over the course of the past 15 years, the number of practicing physicians increased by 60%. For the first time, physicians began competing for patients, working as salaried employees, and going into some of the new alternative delivery
Changes in Britain's Health Care
Authors: J. Gary Maxwell
Journal: JAMA (1996)

NEARLY 50 years after its enactment, the National Health Service (NHS) in Great Britain is in abrupt and profound change. Four recent, major initiatives are inextricably interrelated. First, the general practitioner (GP) has become a fundholder, adding to his or her roles as caregiver and gatekeeper the additional and intrinsically contradictory roles of purchaser, actuary, accountant, and entrepreneur. Second, there is to be mandatory reduction of work hours of physicians in training to 56 hours or less per week. Third, shortening of specialist training is planned to bring British training into equivalency with that of the European community. Fourth, the former financial-administrative units and educational units (regions) are to be eliminated and replaced by fewer, presumably more efficient, units (trusts). Many British professionals consider these changes profoundly antithetical to the ethos of the NHS. Full implementation will have serious and unpredictable consequences for the delivery of health care and for
Striatal Dopaminergic Abnormalities in Human Cocaine Users
Authors: Karley Y. Little, Lian Zhang, Timothy Desmond, Kirk A. Frey, Gregory W. Dalack, Bader J. Cassin
Journal: American Journal of Psychiatry (1999)

Previous human postmortem experiments have shown an abnormally high number of dopamine uptake sites in the striatum of chronic cocaine users, which might contribute to cocaine withdrawal symptoms such as depression and suicidality. Previous inconsistencies in results were perhaps related to selective radioligand affinity changes or a coexisting loss of dopamine neurons.In the present study, binding of the cocaine analog [3H]WIN 35428 to the dopamine transporter was assayed in postmortem striatal samples from 15 cocaine-using subjects and 15 matched comparison subjects to determine whether there were differences in number of binding sites or in affinity. Binding to the vesicular monoamine transporter, a measure of total dopaminergic terminals, was also assessed by using the radioligand (+)-[3H]dihydrotetrabenazine (DTBZ).Striatal [3H]WIN 35428 binding sites were significantly more numerous in the cocaine users: the mean Bmax value was 9.0 fmol bound/microg protein (SD = 2.8) for the cocaine users but only 6.0 (SD = 1.7) for the comparison subjects. Severity of chronic cocaine use was significantly related to [3H]WIN 35428 binding level. [3H]DTBZ binding was significantly lower in the cocaine users (mean = 330 nCi/mg, SD = 42) than in the comparison subjects (mean = 374, SD = 68).The present results confirm that cocaine users have a high number of dopamine transporter binding sites on dopaminergic neurons, despite an apparent low number of total dopamine terminals. These abnormalities may contribute to the abnormalities in subjective experience and behavior characteristic of chronic cocaine abusers.
Molecular analysis of allergenic proteins in bovine dander
Authors: J. Rautiainen, J. Pentikäinen, M. Rytkönen, A. Linnala‐Kankkunen, J. Pelkonen, T. Virtanen, R. Mäntyjärvi
Journal: Allergy (1996)

An analytic procedure was established to characterize bovine dander proteins with allergenic properties. The proteins from dander extract were separated by size‐exclusion gel filtration, and the fractions were studied with SDS‐PAGE followed by immunoblotting. An 11‐kDa allergen was found in the same gel filtration fractions as 20‐ and 22‐kDa allergens, and this suggests that the 11‐kDa allergen is a dimer in its native form. Our method also detected two separate 22‐kDa allergens. The primary structure of the major bovine dander allergen (BDA20) was also studied. A protein sequencer was used to determine the amino acid sequences of enzymatically cleaved peptides. The homology searches revealed that BDA20 is not a previously known bovine protein.
Role of Breast Cancer Resistance Protein in the Bioavailability and Fetal Penetration of Topotecan
Authors: J. W. Jonker
Journal: JNCI Journal of the National Cancer Institute (2000)

Background and Methods: Breast cancer resistance protein (BCRP/MXR/ABCP) is a multidrug-resistance protein that is a member of the adenosine triphosphate-binding cassette family of drug transporters. BCRP can render tumor cells resistant to the anticancer drugs topotecan, mitoxantrone, doxorubicin, and daunorubicin. To investigate the physiologic role of BCRP, we used polarized mammalian cell lines to determine the direction of BCRP drug transport. We also used the BCRP inhibitor GF120918 to assess the role of BCRP in protecting mice against xenobiotic drugs. Bcrp1, the murine homologue of BCRP, was expressed in the polarized mammalian cell lines LLC-PK1 and MDCK-II, and the direction of Bcrp1-mediated transport of topotecan and mitoxantrone was determined. To avoid the confounding drug transport provided by P-glycoprotein (P-gp), the roles of Bcrp1 in the bioavailability of topotecan and the effect of GF120918 were studied in both wild-type and P-gp-deficient mice and their fetuses. Results: Bcrp1 mediated apically directed transport of drugs in polarized cell lines. When both topotecan and GF120918 were administered orally, the bioavailability (i.e., the extent to which a drug becomes available to a target tissue after administration) of topotecan in plasma was dramatically increased in P-gp-deficient mice (greater than sixfold) and wild-type mice (greater than ninefold), compared with the control (i.e., vehicle-treated) mice. Furthermore, treatment with GF120918 decreased plasma clearance and hepatobiliary excretion of topotecan and increased (re-)uptake by the small intestine. In pregnant GF120918-treated, P-gp-deficient mice, relative fetal penetration of topotecan was twofold higher than that in pregnant vehicle-treated mice, suggesting a function for BCRP in the maternal–fetal barrier of the placenta. Conclusions: Bcrp1 mediates apically directed drug transport, appears to reduce drug bioavailability, and protects fetuses against drugs. We propose that strategic application of BCRP inhibitors may thus lead to more effective oral chemotherapy with topotecan or other BCRP substrate drugs.
High-Dose Statins in Acute Coronary Syndromes
Authors: Steven E. Nissen
Journal: JAMA (2004)

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Mortality by Stage for Right- Versus Left-Sided Colon Cancer: Analysis of Surveillance, Epidemiology, and End Results–Medicare Data
Authors: Jennifer M. Weiss, Patrick R. Pfau, Erin S. O'Connor, Jonathan King, Noelle LoConte, Gregory Kennedy, Maureen A. Smith
Journal: Journal of Clinical Oncology (2011)

Recent studies have reported increased mortality for right-sided colon cancers but had limited adjustment for patient characteristics and conflicting results by stage. We examined the relationship between colon cancer location (right- v left-side) and 5-year mortality by stage.We identified Medicare beneficiaries from 1992 to 2005 with American Joint Commission on Cancer stages I to III primary adenocarcinoma of the colon who underwent surgery for curative intent through Surveillance, Epidemiology, and End Results (SEER) -Medicare data. Adjusted hazard ratios (HRs) and 95% CIs for predictors of all-cause 5-year mortality were obtained by using Cox proportional hazards regression.Of 53,801 patients, 67% had right-sided colon cancer. Patients with right-sided cancer were more likely to be older, to be women, to be diagnosed with a more advanced stage, and to have more poorly differentiated tumors. Adjusted Cox regression showed no significant difference in mortality between right- and left-sided cancers for all stages combined (HR, 1.01; 95% CI, 0.98 to 1.04; P = .598) or for stage I cancers (HR, 0.95; 95% CI, 0.88 to 1.03; P = .211). Stage II right-sided cancers had lower mortality than left-sided cancers (HR, 0.92; 95% CI, 0.87 to 0.97; P = .001), and stage III right-sided cancers had higher mortality (HR, 1.12; 95% CI, 1.06 to 1.18; P < .001).When analysis was adjusted for multiple patient, disease, comorbidity, and treatment variables, no overall difference in 5-year mortality was seen between right- and left-sided colon cancers. However, within stage II disease, right-sided cancers had lower mortality; within stage III, right-sided cancers had higher mortality.
Correlation of Hemodynamic Impact and Morphologic Degree of Renal Artery Stenosis in a Canine Model
Authors: STEFAN O. SCHOENBERG, MICHAEL BOCK, FRIEDRICH KALLINOWSKI, ARMIN JUST
Journal: Journal of the American Society of Nephrology (2000)

In a noninvasive comprehensive magnetic resonance (MR) examination, the morphologic degree of renal artery stenosis was correlated to corresponding changes in renal artery flow dynamics. Different degrees of stenosis were created with the use of a chronically implanted inflatable arterial cuff in seven dogs. For each degree of stenosis, an ultrafast three-dimensional gadolinium MR angiography with high spatial resolution was performed, followed by cardiac-gated MR flow measurements with high temporal resolution for determination of pulsatile flow profiles and mean flow. Flow was also measured by a chronically implanted flow probe. In three of the dogs, trans-stenotic pressure gradients (DeltaP) also were measured via implanted catheters. Five different degrees of stenosis could be differentiated in the MR angiograms (0%, 30%, 50%, 80%, >90%). The MR flow data agreed with the flow probe within +/-20%. Stenoses between 30 and 80% gradually reduced the early systolic peak (Max(1)) of the flow profile but only minimally affected the midsystolic peak (Max(2)) or mean flow. Stenoses of more than 90% significantly depressed mean flow by more than 50%. The ratio between Max(1) and Max(2) (Rmax(1/2)) gradually fell with the degree of stenosis. The onset of significant mean flow reduction and DeltaP was indicated by a drop of Rmax(1/2) below 1 to 1.2. Thus, the analysis of high-resolution flow profiles allows detection of early hemodynamic changes even at degrees of stenoses not associated with a reduction of mean flow. Rmax(1/2) allows differentiation of the grade of hemodynamic compromise for a given morphologic stenosis independent of mean flow in a single comprehensive MR examination.
NAD(P)H Oxidase Inhibition Attenuates Neuronal Chronotropic Actions of Angiotensin II
Authors: Chengwen Sun, Kathleen W. Sellers, Colin Sumners, Mohan K. Raizada
Journal: Circulation Research (2005)

It is well established that the central cardiovascular effects of angiotensin II (Ang II) involve superoxide production. However, the intracellular mechanism by which reactive oxygen species (ROS) signaling regulates neuronal Ang II actions remains to be elucidated. In the present study, we have used neuronal cells in primary cultures from the hypothalamus and brain stem areas to study the role of ROS on the cellular actions of Ang II. Ang II increases neuronal firing rate, an effect mediated by the AT 1 receptor subtype and involving inhibition of the delayed rectifier potassium current ( I Kv ). This increase in neuronal activity was associated with increases in NADPH oxidase activity and ROS levels within neurons, the latter evidenced by an increase in ethidium fluorescence. The increases in NADPH oxidase activity and ethidium fluorescence were blocked by either the AT 1 receptor antagonist losartan or by the selective NAD(P)H oxidase inhibitor gp91ds-tat. Extracellular application of the ROS scavenger, Tempol, attenuated the Ang II–induced increase in neuronal firing rate by 70%. In addition, gp91ds-tat treatment resulted in a 50% inhibition of Ang II–induced increase in firing rate. In contrast, the ROS generator Xanthine-Xanthine oxidase significantly increased neuronal firing rate. Finally, Ang II inhibited neuronal I Kv, and this inhibition was abolished by gp91ds-tat treatment. These observations demonstrate, for the first time, that Ang II regulates neuronal activity via a series of events that includes ROS generation and inhibition of I Kv . This signaling seems to be a critical cellular event in central Ang II regulation of cardiovascular function.
Induction of murine autoimmune disease by chronic polyclonal B cell activation.
Authors: L Hang, J H Slack, C Amundson, S Izui, A N Theofilopoulos, F J Dixon
Journal: The Journal of Experimental Medicine (1983)

In vivo, prolonged polyclonal activation of B cells by the nonantigenic but potent mitogenic lipid A portion of lipopolysaccharide (LPS-R595) resulted in acceleration of the late life systemic lupus erythematosus disease of female MRL/n, BXSB, and NZW mice, mimicking the time, form, and histopathological features characteristic of their early life disease counterparts, i.e., MRL/l females, BXSB males, and (NZB X NZW)F1 females. Similar polyclonal B cell activation of "immunologically normal" mice has less effect and led to a limited expression of autoimmune disease. This R595-induced autoimmunity and immune complex-mediated disease seemed to be the direct result of activation of the immune system and not from other effects of endotoxin since C3H/HeJ, a strain lacking lymphocyte receptors for LPS-R595, had neither serological nor histological evidence of autoimmune disease despite identical treatment.
Chemokinome characterization in human lung macrophages following stimulation with Th2-type cytokines IL-4 or IL-13
Authors: Stanislas Grassin Delyle, Amparo Buenestado, Charlotte Abrial, Marion Brollo, Emmanuel Naline, Philippe Devillier
Journal: European Respiratory Journal (2012)

Background:  Macrophages may acquire polarized phenotypes, the two extremes being the proinflammatory (M1) and immunoregulatory (M2) phenotypes characterized by surface markers and chemokinome profiles. Reprogramming of AM toward a partially M2-polarized phenotype has been suggested to contribute to COPD pathogenesis. We thus sought to characterize the phenotype of human lung macrophages (LM) following stimulation with the Th2-type cytokines IL-4 and IL-13.   Methods:  LM were isolated from human resected lungs challenged for 24 or 48hrs with IL-4 or IL-13 (1-150 ng/mL). Cytokines transcript expression was assessed with RT-qPCR, whereas proteins of M1 (TNF-α, CCL3, CCL4 and CXCL8) and M2 cytokines (CCL13, CCL17 and CCL22) were quantified in supernatants.   Results:  Unstimulated LM exhibited a rather undifferenciated phenotype, with weak M1/M2 cytokines expression. On the other hand, transcriptome analysis of 80 cytokines gene revealed that only four M2-type transcripts levels were increased (4- to 8-fold) following stimulation with IL-13 (CCL13, CCL17, CCL22 and CCL26). M2-type cytokine production at the protein level was also concentration-dependently increased (3- to 20-fold), whereas M1 cytokines were unaffected. CCL13 and CCL22 increase was maximal at 48hrs, while the maximum was reached at 24hrs for CCL17. The results obtained with IL-4 were similar, except that IL-4 potency was greater than IL-13 since the low 10 ng/mL concentration provided submaximal cytokines increases.   Conclusions:  Our data demonstrate that IL-4 and IL-13 favours LM polarization toward the immunoregulatory M2 phenotype characterized by the expression of CCL13, CCL17, CCL22 and CCL26.
Re: Risk of Perforation After Colonoscopy and Sigmoidoscopy: A Population-Based Study
Authors: R. E. Schoen, T. R. Levin
Journal: JNCI Journal of the National Cancer Institute (2003)

Gatto et al. (1) report on perforation rates after sigmoidoscopy and colonoscopy to better inform clinicians making screening decisions. However, the perforation rates for sigmoidoscopy far exceed those reported in the screening setting, including 1/50 000 in the Kaiser Permanente Colorectal Cancer Prevention (CoCaP) sigmoidoscopy screening program (2); 1/40 332 in the U.K. screening trial (3); and 1/25 000 in a series from the Mayo Clinic, Scottsdale, AZ (4). The elevated sigmoidoscopy perforation rate reported by Gatto et al. is due to inclusion of failed colonoscopy and special, high-risk sigmoidoscopy. Their broad inclusion criteria are demonstrated by the codes used for sigmoidoscopy, which include sigmoidoscopy with polypectomy, control of bleeding, decompression of volvulus, and removal of a foreign body. The inclusion of high-risk procedures and failed colonoscopy explains their observed 30to 50-fold increase in sigmoidoscopy perforations compared with the perforation rate in screening populations. As such, their results do not inform clinicians about sigmoidoscopy screening decisions. Their anomalous results demonstrate the pitfall of using procedure codes in an ad-