tbuckley/cabot-search huggingface dataset:
Reducing Inappropriate Polypharmacy
Authors: Ian A. Scott, Sarah N. Hilmer, Emily Reeve, Kathleen Potter, David Le Couteur, Deborah Rigby, Danijela Gnjidic, Christopher B. Del Mar, Elizabeth E. Roughead, Amy Page, Jesse Jansen, Jennifer H. Martin
Journal: JAMA Internal Medicine (2015)

Inappropriate polypharmacy, especially in older people, imposes a substantial burden of adverse drug events, ill health, disability, hospitalization, and even death. The single most important predictor of inappropriate prescribing and risk of adverse drug events in older patients is the number of prescribed drugs. Deprescribing is the process of tapering or stopping drugs, aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies. A deprescribing protocol is proposed comprising 5 steps: (1) ascertain all drugs the patient is currently taking and the reasons for each one; (2) consider overall risk of drug-induced harm in individual patients in determining the required intensity of deprescribing intervention; (3) assess each drug in regard to its current or future benefit potential compared with current or future harm or burden potential; (4) prioritize drugs for discontinuation that have the lowest benefit-harm ratio and lowest likelihood of adverse withdrawal reactions or disease rebound syndromes; and (5) implement a discontinuation regimen and monitor patients closely for improvement in outcomes or onset of adverse effects. Whereas patient and prescriber barriers to deprescribing exist, resources and strategies are available that facilitate deliberate yet judicious deprescribing and deserve wider application.
Development and evaluation of taste-masked dry suspension of cefuroxime axetil for enhancement of oral bioavailability
Authors: Yuqian Du, Yinglei Zhai, Juhong Zhang, Chunnuan Wu, Cong Luo, Jin Sun, Zhonggui He
Journal: Asian Journal of Pharmaceutical Sciences (2013)

Cefuroxime axetil (CA) is an ester prodrug of cefuroxime with an unpleasant taste when administrated orally. This work was to mask the bitter taste of CA and enhance its oral bioavailability. Dry suspensions were prepared by means of wet granulation method and solid dispersion method. Binders, suspending agents and other compositions involved in the formulation were optimized. The differential scanning calorimetry (DSC) analysis indicated that CA was amorphous in the solid dispersion with stearic acid as the carrier, which contributed to an improvement of the dissolution rate. Taste evaluation was performed by three volunteers and taste masking was successfully achieved by the methods mentioned above. A pH 7.0 phosphate buffer was adopted to study the in vitro dissolution performance of the three formulations, i.e., two self-made dry suspensions and the commercial one. With a better release characteristic and a satisfying taste masking ability, the solid dispersion suspension was selected as the optimal formulation for the further pharmacokinetic study in beagle dogs. The values of Cmax and AUC0–12 for the solid dispersion suspension were about 1.78-fold and 2.17-fold higher than these of reference suspension, respectively. The obtained results demonstrated that the solid dispersion can efficiently mask the bitter taste of CA and significantly enhance its oral bioavailability.
Matrix collagen type and pore size influence behaviour of seeded canine chondrocytes
Authors: Stefan Nehrer, Howard A. Breinan, Arun Ramappa, Gretchen Young, Sonya Shortkroff, Libby K. Louie, Clement B. Sledge, Ioannis V. Yannas, Myron Spector
Journal: Biomaterials (1997)
Cerebral Microvascular Responses to Hypercholesterolemia
Authors: Mami Ishikawa, Karen Y. Stokes, John H. Zhang, Anil Nanda, D. Neil Granger
Journal: Circulation Research (2003)

Although hypercholesterolemia is widely accepted as a major risk factor for coronary artery and peripheral vascular diseases, its role in the pathogenesis of stroke is controversial. The objectives of this study were to determine how hypercholesterolemia affects the cerebral microcirculation under resting conditions and after ischemia-reperfusion (I/R). Platelet- and leukocyte-endothelial cell interactions and oxidant production (using the oxidant-sensitive fluorochrome dihydrorhodamine-123) were monitored by intravital videomicroscopy in the cerebral microvasculature of mice placed on either a normal (ND) or cholesterol-enriched diet (HCD). Platelets labeled with carboxyfluorescein diacetate succinimidyl ester (CFDASE) and leukocytes labeled with rhodamine 6G were seen to roll and firmly adhere, with a corresponding increase in oxidant production, in venules of mice on HCD, but not ND. Immunoneutralization of P-selectin attenuated the platelet- and leukocyte-endothelial cell interactions and the enhanced oxidant production associated with HCD. A GPIIb/IIIa blocking antibody did not alter the blood cell-vessel wall interactions to HCD. Mice deficient in the NADPH oxidase subunit gp91 phox exhibited significantly blunted platelet and leukocyte recruitment responses to HCD. Focal I/R also elicited inflammatory and prothrombogenic responses in cerebral venules and these were exaggerated in mice on HCD. These results implicate an oxidant-dependent, P-selectin–mediated mechanism in the blood cell-vessel wall interactions induced by hypercholesterolemia in the brain and demonstrate that the deleterious effects of I/R on the brain are exacerbated by this cardiovascular risk factor.
The zonal distribution of megamitochondria with crystalline inclusions in nonalcoholic steatohepatitis
Authors: Tri H. Le, Stephen H. Caldwell, Jan A. Redick, Bonnie L. Sheppard, Christine A. Davis, Kristen O. Arseneau, Julia C. Iezzoni, Elizabeth E. Hespenheide, Abdullah Al-Osaimi, Theresa C. Peterson
Journal: Hepatology (2004)

Megamitochondria with crystalline inclusions (MMC) have been previously described in nonalcoholic fatty liver; however, their distribution within hepatic zones is unknown. We sought to determine this distribution from the core liver biopsy specimens of 31 patients: 8 males and 23 females, age range 21 to 72 years. Twenty-nine showed evidence of nonalcoholic steatohepatitis (NASH) on biopsy with steatosis, inflammation, varying degree of fibrosis, ballooned hepatocytes, and Mallory hyaline, and two patients had cryptogenic cirrhosis thought to represent "burned out" NASH. Identified by transmission electron microscopy, the abundance of MMC was compared between low-stage (fibrosis stages 1 and 2) and high-stage (fibrosis stages 3 and 4) groups and between zones with or without difference in fibrosis stage. Regardless of stage, the MMC were distributed equally in all zones and were abundant similarly in low- and high-stage groups. This abundance did not correlate with the degree of oxidative stress (4-hydroxynonenal staining) or with the abundance of ballooned hepatocytes. Consistent with age as a risk factor for more severe disease, the median age for the low-stage group was significantly lower than that of the high-stage group (P =.003). In conclusion, in NASH, the MMC seem to be distributed randomly among zones and without variation in abundance, regardless of the fibrosis stage. The exact function of these structures remains to be defined. In this study, their presence did not seem to correlate with the light microscopic injury pattern represented by ballooned hepatocytes or degree of oxidative stress defined by immunostaining for 4-hydroxynonenal.
Recruitment manoeuvres in acute lung injury/acute respiratory distress syndrome
Authors: I. Morán, E. Zavala, R. Fernández, L. Blanch, J. Mancebo
Journal: European Respiratory Journal (2003)

Acute respiratory distress syndrome/acute lung injury is characterised by profound hypoxaemia due to a permeability pulmonary oedema. In this setting, recruitment manoeuvres (RMs) can be a useful tool as adjuncts to lung protective ventilatory strategies to prevent cyclic alveolar stress and avoid alveolar collapse. Many experimental and physiological studies have discussed the use of RMs but only a few heterogeneous clinical experiences have demonstrated the beneficial and deleterious effects that can occur using these manoeuvres. Besides, a lot of questions remain to be answered to find the best way to perform optimal RMs. Further experimental and clinical trials are needed to understand the potential beneficial effects of recruitment manoeuvres when using a protective mechanical ventilation strategy. This paper is a general review of experimental works that support application of recruitment manoeuvres emphasising the clinical studies that have been published to date in acute respiratory distress syndrome patients.
Aromatase Expression in Stromal Cells of Endometrioid Endometrial Cancer Correlates with Poor Survival
Authors: Tomoya Segawa, Makio Shozu, Kouich Murakami, Tadayuki Kasai, Kazunori Shinohara, Kazuhito Nomura, Satoshi Ohno, Masaki Inoue
Journal: Clinical Cancer Research (2005)

To assess the prognostic significance of intratumoral aromatase in endometrioid endometrial cancer, sections from 55 patients with endometrial cancer were evaluated for expression of aromatase using immunohistochemistry, and the correlation between aromatase expression and clinicopathologic parameters were analyzed.Immunohistochemical staining for aromatase was positive for 32 (58%), 20 (36%), and 19 (34%) patients in cancer epithelial cells, stromal cells, and myometrial cells around the flank invasion, respectively. In situ hybridization also detected aromatase mRNA in all three types of cells. RT-PCR analysis revealed that aromatase mRNA was 2.5 +/- 1.0 amol/mug total RNA (mean +/- SE; n = 7) in tumor tissue. Western blot analysis detected the expected aromatase protein size of 58 kDa in cancer tissues more abundantly than in cancer-free endometrium (n = 3). The immunoreactivity in stromal cells correlated positively with advanced surgical stage and poor survival. Survival analysis revealed that the immunoreactivity of stromal cells was a significant prognostic factor, independent of histologic grade, muscular invasion, and lymph node metastasis, but dependent on surgical stage. By contrast, the immunoreactivity of aromatase both in cancer epithelial cells and myometrial cells did not correlate with prognosis.To the best of our knowledge, this is the first evidence associating intratumoral aromatase expression in stromal cells and poor survival in endometrioid endometrial cancer. This positive linkage indicates that local expression of aromatase plays a role in tumor progression through the formation of in situ estrogens. In situ expression of aromatase may offer a potential target for management of endometrial cancers.
Immunohistological observations in rat kidney allografts after local steroid administration.
Authors: T J Ruers, W A Buurman, C J van Boxtel, C J van der Linden, G Kootstra
Journal: The Journal of Experimental Medicine (1987)

In this report we investigated local regulatory mechanisms in graft rejection and their response to local immunosuppressive therapy. For this purpose local immunosuppression was induced in rat kidney allografts by intrarenal infusion of prednisolone. Intrarenal drug delivery resulted in high drug levels within the graft and low systemic drug levels. Systemic drug levels were by themselves not sufficiently immunosuppressive to induce graft survival, and local prednisolone levels within the graft proved to be responsible for prolongation of graft survival. During intrarenal drug delivery, systemic responsiveness to the renal allograft proved normal, since intrarenally treated grafts were infiltrated by MHC class II-positive host cells and, except for a somewhat lower percentage of macrophages, cellular infiltration in intrarenal treated grafts was comparable to untreated grafts. However, T cells and macrophages present in intrarenally treated grafts were not able to destroy the grafted tissue. Local immunosuppressive therapy resulted in inhibition of IL-2-R expression, absence of IFN-gamma, and prevention of MHC class II induction on grafted tissue. These observations strongly indicate the presence of local regulatory mechanisms in graft rejection. The experimental model described can be used for further analysis of these intragraft events. Moreover, the results demonstrate that local immunosuppressive therapy can contribute to effective inhibition of cellular immune response in graft rejection.
Undiagnosed chronic hepatitis B is prevalent in the british-chinese community of the north east (NE) of england
Authors: S. Mcpherson, M. Valappil, S. Moses, G. Eltringham, C. Miller, K. Baxter, B. Brown, P. Clapper, A. Chan, M. Hudson, M. Bassendine
Journal: Gut (2011)

<h3>Introduction</h3> Chronic hepatitis B (HBV) is highly prevalent in China and the Far East (&gt;8% seroprevalence). AASLD guidelines1 recommend HBV screening and vaccination in subjects born in high (&gt;8%) or intermediate (2–7%) endemic areas. However, there are no current UK guidelines. The study aim was to apply AASLD recommendations locally to the community with the highest endemicity – British Chinese (estimated population 430 000). <h3>Methods</h3> Members of the NE Chinese community were invited to attend screening sessions at the Newcastle Chinese Healthy Living Centre. Dry blood spots were obtained by finger prick and tested for HBsAg and HBcAb (Abbott ARCHITECT). HBsAg positive individuals were advised to undergo confirmatory testing and be referred for specialist assessment. <h3>Results</h3> 315 subjects were screened (mean age 52±18 years, 63% female). 31 (10%) were HBsAg positive (48% female) indicating chronic HBV. Of these, 7 reported being previously diagnosed with HBV, but were not under follow-up. When previously diagnosed individuals were excluded the prevalence of HBsAg positivity was 8%. 50 (16%) subjects were HBsAg negative and HBcAb positive indicating past HBV infection. HBsAg positive individuals were significantly younger than HBcAb and negative subjects (44±12 vs 59±15 vs 52±19 years, p&lt;0.001). HBsAg individuals were most commonly born in China (52%), followed by Hong Kong (19%), Vietnam (13%), UK (10%), Macau (3%) and Malaysia (3%). The prevalence of HBsAg positivity for subjects born in China was 12% (16/129), Hong Kong 5% (6/126), Vietnam 18% (4/22) and UK 18% (3/17). Only 8% of subjects in the study reported previous vaccination against HBV. <h3>Conclusion</h3> (1) Undiagnosed chronic Hepatitis B is highly prevalent in British-Chinese in NE England, including subjects born in the UK. (2) The frequency of previous HBV vaccination was low in this high risk group. (3) These results provide evidence for a UK HBV screening and vaccination program for the British Chinese community, which is the largest in Europe and is the fastest growing non-European ethnic group in the UK.
New insights into the cell biology of ischemic acute renal failure.
Authors: B A Molitoris
Journal: Journal of the American Society of Nephrology (1991)

Proximal tubule cells play an essential role in the reabsorption of ions, water, and solutes from the glomerular filtrate. This is accomplished, in large part, by having a surface membrane polarized into structurally, biochemically, and physiologically distinct apical and basolateral membrane domains separated by cellular junctional complexes. Establishment and maintenance of these unique membrane domains are essential for the normal functioning of the cell. Ischemia results in the duration-dependent loss of apical and basolateral surface membrane lipid and protein polarity. Loss of surface membrane polarity is preceded by disruption of the microfilament network and opening of cellular tight junctions. Surface membrane lipids and proteins are then free to diffuse laterally within the bilayer into the alternate membrane domain. Functionally, ischemia-induced loss of epithelial polarity has been shown to be responsible for reduced sodium and glucose reabsorption. Reduced Na+ reabsorption has been related to redistribution of Na+, K(+)-ATPase into the apical membrane. During recovery from ischemic injury, proximal tubule cells undergo remodeling of the surface membrane such that the unique apical and basolateral membrane domains are reestablished, allowing for the return of normal cellular function.
Lobar pressure-volume characteristics of excised human lungs.
Authors: N Berend, C Skoog, W M Thurlbeck
Journal: Thorax (1981)

The pressure-volume (P-V) characteristics were investigated in 14 excised left human lungs and their individual lobes. Comparison of the upper and lower lobar P-V curves of the emphysema-free and emphysematous lungs showed no significant difference when plotted as per cent lobar volume at a transpulmonary pressure (PL) of 30 cm H2O (V30). However, when in the emphysematous lungs the more severely involved lobes were compared with the less severely involved lobes, significant differences in the PL 60-90% V30 were found, the more severely involved lungs exhibited a higher PL. The mean linear intercepts were identical in the upper and lower lobes of the emphysema-free lungs indicating equal distension and validating expression of the P-V data as per cent V30. However, in he emphysematous lungs, in which the upper lobes were more severely involved, the linear intercepts tended to be larger in the upper lobes and the ratio of upper to lower lobe V30 tended to be larger than in the emphysema-free lungs. Thus, in the emphysematous lungs, comparison of the lobar P-V curves expressed as per cent V30 may not be valid.
Deficiency in Lymphotoxin β Receptor Protects From Atherosclerosis in apoE-Deficient Mice
Authors: Maria Grandoch, Kathrin Feldmann, Joachim R. Göthert, Lena S. Dick, Susanne Homann, Christina Klatt, Julia K. Bayer, Jan N. Waldheim, Berit Rabausch, Nadine Nagy, Alexander Oberhuber, René Deenen, Karl Köhrer, Stefan Lehr, Bernhard Homey, Klaus Pfeffer, Jens W. Fischer
Journal: Circulation Research (2015)

Lymphotoxin β receptor (LTbR) regulates immune cell trafficking and communication in inflammatory diseases. However, the role of LTbR in atherosclerosis is still unclear.The aim of this study was to elucidate the role of LTbR in atherosclerosis.After 15 weeks of feeding a Western-type diet, mice double-deficient in apolipoprotein E and LTbR (apoE(-/-)/LTbR(-/-)) exhibited lower aortic plaque burden than did apoE(-/-) littermates. Macrophage content at the aortic root and in the aorta was reduced, as determined by immunohistochemistry and flow cytometry. In line with a decrease in plaque inflammation, chemokine (C-C motif) ligand 5 (Ccl5) and other chemokines were transcriptionally downregulated in aortic tissue from apoE(-/-)/LTbR(-/-) mice. Moreover, bone marrow chimeras demonstrated that LTbR deficiency in hematopoietic cells mediated the atheroprotection. Furthermore, during atheroprogression, apoE(-/-) mice exhibited increased concentrations of cytokines, for example, Ccl5, whereas apoE(-/-)/LTbR(-/-) mice did not. Despite this decreased plaque macrophage content, flow cytometric analysis showed that the numbers of circulating lymphocyte antigen 6C (Ly6C)(low) monocytes were markedly elevated in apoE(-/-)/LTbR(-/-) mice. The influx of these cells into atherosclerotic lesions was significantly reduced, whereas apoptosis and macrophage proliferation in atherosclerotic lesions were unaffected. Gene array analysis pointed to chemokine (C-C motif) receptor 5 as the most regulated pathway in isolated CD115(+) cells in apoE(-/-)/LTbR(-/-) mice. Furthermore, stimulating monocytes from apoE(-/-) mice with agonistic anti-LTbR antibody or the natural ligand lymphotoxin-α1β2, increased Ccl5 mRNA expression.These findings suggest that LTbR plays a role in macrophage-driven inflammation in atherosclerotic lesions, probably by augmenting the Ccl5-mediated recruitment of monocytes.
From numerical concepts to concepts of number
Authors: Lance J Rips, Amber Bloomfield, Jennifer Asmuth
Journal: Behavioral and Brain Sciences (2008)

Many experiments with infants suggest that they possess quantitative abilities, and many experimentalists believe that these abilities set the stage for later mathematics: natural numbers and arithmetic. However, the connection between these early and later skills is far from obvious. We evaluate two possible routes to mathematics and argue that neither is sufficient: (1) We first sketch what we think is the most likely model for infant abilities in this domain, and we examine proposals for extrapolating the natural number concept from these beginnings. Proposals for arriving at natural number by (empirical) induction presuppose the mathematical concepts they seek to explain. Moreover, standard experimental tests for children's understanding of number terms do not necessarily tap these concepts. (2) True concepts of number do appear, however, when children are able to understand generalizations over all numbers; for example, the principle of additive commutativity (a+b=b+a). Theories of how children learn such principles usually rely on a process of mapping from physical object groupings. But both experimental results and theoretical considerations imply that direct mapping is insufficient for acquiring these principles. We suggest instead that children may arrive at natural numbers and arithmetic in a more top-down way, by constructing mathematical schemas.
Pay settlement next year is not likely to exceed 2%, Johnson says
Authors: Adrian O’Dowd
Journal: BMJ (2007)

An acceptable pay settlement for NHS staff next year should be achievable, despite the fact that an increase will probably be only around 2%, the health secretary has said.

Alan Johnson told MPs last week he was optimistic about the current “difficult” pay discussions taking place.

Mr Johnson was giving evidence as part of the parliamentary health select committee’s inquiry into public expenditure.

The committee tackled him on the government’s recent call for a 2% pay rise in 2008-9 for most NHS staff and asked whether pay rises below the rate of inflation were going to be the norm.

“It depends on how you measure inflation,” …