bluuebunny/crossref_metadata_2025 huggingface dataset:
DURATION‐2: efficacy and safety of switching from maximum daily sitagliptin or pioglitazone to once‐weekly exenatide
Authors: Wysham C. , Bergenstal R. , Malloy J. , Yan P. , Walsh B. , Malone J. , Taylor K.
Published: March 2011

Diabet. Med. 28, 705–714 (2011)

Aims  In the initial 26‐week, double‐blind, double‐dummy assessment period of the DURATION‐2 trial in patients with Type 2 diabetes on metformin, the once‐weekly glucagon‐like peptide 1 (GLP‐1) receptor agonist exenatide once‐weekly resulted in greater HbA1c improvement and weight reduction compared with maximum approved daily doses of sitagliptin or pioglitazone. This subsequent, 26‐week, open‐label, uncontrolled assessment period evaluated the safety and efficacy of (i) continued exenatide once‐weekly treatment and (ii) switching from sitagliptin or pioglitazone to exenatide once‐weekly.

Methods  Randomised oral medications were discontinued and all patients received exenatide once‐weekly. Of the 364 patients [original baseline HbA1c 8.5 ± 1.1% (70 mmol/mol), fasting plasma glucose 9.0 ± 2.5 mmol/l, weight 88 ± 20 kg) who continued into the open‐label period, 319 patients (88%) completed 52 weeks.

Results  Evaluable patients who received only exenatide once‐weekly demonstrated significant 52‐week improvements (least square mean ± se) in HbA1c (−1.6 ± 0.1%), fasting plasma glucose (−1.8 ± 0.3 mmol/l) and weight (−1.8 ± 0.5 kg). Evaluable patients who switched from sitagliptin to exenatide once‐weekly demonstrated significant incremental improvements in HbA1c (−0.3 ± 0.1%), fasting plasma glucose (−0.7 ± 0.2 mmol/l) and weight (−1.1 ± 0.3 kg). Patients who switched from pioglitazone to exenatide once‐weekly maintained HbA1c and fasting plasma glucose improvements (week 52: −1.6 ± 0.1%, −1.7 ± 0.3 mmol/l), with significant weight reduction (−3.0 ± 0.3 kg). Exenatide once‐weekly was generally well tolerated and adverse events were predominantly mild or moderate in intensity. Nausea was the most frequent adverse event in this assessment period (intent‐to‐treat: exenatide once‐weekly‐only 5%; sitagliptin → exenatide once‐weekly 11%; pioglitazone → exenatide once‐weekly 10%). No major hypoglycaemia was observed.

Conclusions  Patients who switched to once‐weekly exenatide from daily sitagliptin or pioglitazone had improved or sustained glycaemic control, with weight loss.
Mobile phone support is associated with reduced ketoacidosis in young adults
Authors: Farrell K. , Holmes–Walker D. J.
Published: March 2011

Diabet. Med. 28, 1001–1004 (2011)

Aims  To determine if access to mobile phone support for sick‐day management is associated with reduced hospital admissions with diabetic ketoacidosis in young adults aged 15–25 with Type 1 diabetes.

Methods  This was an observational study with data collected prospectively from January 2005 to December 2008. A mobile phone support service for sick‐day management began in May 2005. Data from clinic attendees (group 1), including age, sex, diabetes duration, referral age, insulin therapy delivery, clinic attendance and HbA1c, were compared with clinic attendees with diabetic ketosis accessing sick‐day management phone support (group 2), clinic attendees not accessing phone support and admitted with diabetic ketoacidosis (group 3) and non‐clinic attendees admitted with diabetic ketoacidosis (group 4).

Results  Age was similar in all groups. Patients in group 3 had significantly shorter duration of diabetes (6.8 ± 3.1 years) than groups 1 or 2 (10.1 and 9.8 years, respectively). Diabetes control was poor in all presentations of diabetic ketoacidosis (groups 2–4, HbA1c > 97 mmol/mol, > 11%) and was significantly higher than clinic attendees without ketosis (HbA1c 70 mmol/mol, 8.6%; P < 0.001). There was similar attendance at the clinic across all three groups, 2.9 compared with 2.4 compared with 2.1 visits/year, respectively. Thirty‐one patients accessed phone support on 83 occasions for sick‐day management (mean 2.7 contacts/episode); two patients progressed to admission with diabetic ketoacidosis. Diabetic ketoacidosis admission rates in the clinic population fell significantly from baseline, 0.10 to 0.05 admissions per patient per year (P < 0.05) in the third year.

Conclusion  Mobile phone support is associated with reduced progression of ketosis to diabetic ketoacidosis in young adults despite poor diabetes control.
Retention, early dropout and treatment completion among therapeutic community admissions
Authors: DARKE SHANE , CAMPBELL GABRIELLE , POPPLE GARTH
Published: March 2011

Introduction and Aims. The study aimed to ascertain the association between baseline client characteristics, drug use and psychopathology on length of stay, treatment completion and early separation in drug free therapeutic communities.

Design and Methods. Prospective longitudinal follow up of 191 treatment admissions to We Help Ourselves drug free treatment services.

Results. The median length of stay was 39 days. A total of 17% of treatment entrants dropped out in the first week, and 34% successfully completed the treatment program. Length of stay was independently associated with a previous history of treatment completion (β = 0.21, P < 0.001), higher Short Form‐12 physical health scores (β = 0.16, P < 0.05) and lifetime prison history (β = −0.15, P < 0.05). Independent predictors of early separation were recent prison release [odds ratio (OR) 2.64, confidence interval (CI) 1.08–6.42] and a lower perception of the likeliness of completing treatment (OR 2.38, CI 1.01–5.46), with independent predictors of treatment completion being male gender (OR 2.56, CI 1.19–5.51) and fewer stressful life events (OR 0.84, CI 0.72–0.97). Drug use and psychopathology were not related to length of stay, early separation or treatment completion.

Discussion and Conclusions. Different parameters of treatment stay were predicted by different variables. The fact that neither psychopathology nor primary problem drug was related to treatment indicates that these should not be seen as poor prognostic indicators for treatment success in a drug free treatment setting.[Darke S, Campbell G, Popple G. Retention, early dropout and treatment completion among therapeutic community admissions. Drug Alcohol Rev 2012;31:64–71]
Gold loans in the Australian gold mining industry: Do gold loans allow gold producers to increase leverage?
Authors: Heaney Richard , Wai Nicholas , Walker Julie
Published: March 2011

This paper tests the hypothesis that gold producers exhibit greater leverage where gold loans are used. As the choice of gold producers and the study period essentially avoids debt tax shield effects, the paper focuses on information asymmetry and agency costs explanations for leverage. Theory suggests hedging can reduce the cost of debt but it has little impact if management is not committed to adopting the promised hedging policy. The implicit hedge in gold loans commits management to hedging and so greater leverage is expected for producers adopting gold loans. Results from the analysis are consistent with this hypothesis.
The role of current and non‐current accruals in the relation between stock returns and earnings
Authors: Loftus Janice A. , Sin Samantha
Published: March 2011

This study examines the role of accruals in the relation between stock returns and earnings for intervals of one to four years. We argue that the roles of current and non‐current accruals differ because the former turn over more frequently while the latter include long term timing differences and permanent differences. Accordingly, the roles of both categories of accruals are examined over intervals within and beyond the cycle of current accruals. The results suggest that accruals strengthen the association between stock returns and earnings and that they are more important for shorter intervals. Further, non‐current accruals play a dominant role in the relation between stock returns and earnings while the effect of current accruals is negligible for all intervals examined.
Distortion effects and extreme observations in empirical research: An analysis of the incremental information content of cash flows
Authors: Wilson Cynthia R.
Published: March 2011

Linear regression models are used in a number of studies examining the presence or absence of incremental information content in cash flows. The results of these studies are not consistent. This paper provides evidence of the impact that extreme observations can exert on parameter estimates in a regression model. Two techniques commonly used to address the problem of extreme observations are considered. These techniques, winsorising the data and trimming the data, are compared to a regression diagnostic technique, Cook's distance. The comparison of these techniques provides evidence that the choice of technique can determine the significance or otherwise of regression results. This paper concludes that the inconsistency in reported results examining the incremental information content in cash flows may be attributed to the techniques adopted to address the issue of extreme observations.
Cross‐sectional determinants of New Zealand share market returns
Authors: Bryant Paul S. , Eleswarapu Venkat R.
Published: March 2011

We present evidence of the cross‐sectional relation between security returns, beta, firm size and book‐to‐market ratio over the period 1971 to 1993 on the New Zealand sharemarket. Our results suggest that the NZSE‐40 market index is not a mean‐variance efficient market proxy—the betas calculated with respect to it being of little use for explaining expected returns cross‐sectionally. Also, there is a significant positive relation between book‐to‐market ratio and average return.
Establishing specialty jurisdictions in medicine: the case of American obstetrics and gynaecology
Authors: Zetka Jr. James R.
Published: March 2011

The profession of medicine has evolved into an extremely specialised occupation. Yet, recent research has neglected the intra‐occupational processes influencing medical specialisation. This article aims to correct this oversight. It develops an historical account of intra‐occupational factors influencing the decision to establish gynaecologic oncology as American ob/gyn’s surgical subspecialty in 1972. Working within the framework initially developed by Everett C. Hughes and his students, the article examines this development as the outcome of a three‐party relationship among gynaecologic oncologists, American ob/gyns, and gynaecologic pelvic surgeons. Aggressive movement by the gynaecologic pelvic surgeons challenging the established élite’s identity definition for the ob/gyn specialty helped spur official recognition of gynaecologic oncology, a less threatening subspecialty. The article draws theoretical implications from the case regarding the role of a threatening other in influencing the specialisation process.
Comparing Playful and Nonplayful Incidental Attention to Form
Authors: Bell Nancy
Published: March 2011

Current evidence demonstrating the importance of language play in second‐language (L2) development rests largely on qualitative analyses of L2 discourse. Although these rich descriptions have illustrated a number of important functions of language play, further study of the phenomenon is necessary to understand its potential to facilitate learning. This article reports on research designed to compare learner recall of items that have been the focus of serious versus playful attention. Forty‐four hours of interaction by 16 adult English‐as‐a‐second‐language learners in an 8‐week conversation class were observed and audio‐recorded. All instances in which they spontaneously engaged in metalinguistic reflection or discussion about their language use or knowledge (i.e., Swain & Lapkin's, 1995, language‐related episodes, or LREs) were identified and coded for whether this was done playfully (PLREs) or seriously (LREs). Each student received tailor‐made tests to assess recall of those items. Statistical analysis showed significantly stronger recall of items occurring in PLREs than in LREs.
In Defense of Relational Direct Realism
Authors: Hobson Kenneth
Published: March 2011

Abstract: According to proponents of relational direct realism, veridical perceptual experiences are irreducibly relational mental states that include as constituents perceived physical objects or intrinsic aspects of them. One consequence of the theory is the rejection of the causal theory of perception. This paper defends the relational theory against several objections recently developed by Paul Coates. He argues that the required experiential relation is incoherent and unmotivated. The argument that it is incoherent commits a fallacy. In reply to the argument that it is unmotivated, I suggest that the relational theorist's appeal to transparency provides sufficient motive and, when properly clarified, defeasibly justifies the theory as well. Coates also argues that rejection of the causal theory leaves relational theorists without any way of determining which object is perceived or of accommodating our scientific understanding of perceptual experiences as causally dependent on physical objects. I reply that relational theorists are able to provide the required explanations and discuss how the relational theory is consistent with this scientific understanding of perceptual experience.
Bodily Thought and the Corpse Problem
Authors: Árnadóttir Steinvör Thöll
Published: March 2011

Abstract:A key consideration in favour of animalism—the thesis that persons like you and me are identical to the animals we walk around with—is that it avoids a too many thinkers problem that arises for non‐animalist positions. The problem is that it seems that any person‐constituting animal would itself be able to think, but if wherever there is a thinking person there is a thinking animal distinct from it then there are at least two thinkers wherever there is a thinking person. Most find this result unacceptable, and some think it provides an excellent reason for accepting animalism. It has been argued, however, that animalists face an analogous problem of too many thinkers, the so‐called corpse problem, as they must accept both 1) that we are distinct from our bodies, as our bodies can and we cannot persist through death as corpses and 2) that our bodies can think. I argue that the best reasons animalists have for accepting the two claims that generate the distinctness part of the problem double up as reasons to reject the claim that our bodies can think, and vice versa. I argue further that Lockeans cannot similarly get around their problem of too many thinkers.
Frailty in elderly persons with essential tremor: a population‐based study (NEDICES)
Authors: Louis E. D. , Benito‐León J. , Vega S. , Bermejo‐Pareja F. ,   On behalf of the Neurological Disorders in Central Spain (NEDICES) Study Group
Published: March 2011

Background and purpose:  Essential tremor (ET), one of the most prevalent neurological diseases, has been associated with a variety of comorbidities and, in some studies, a modest increase in risk of mortality. The mechanisms underlying this possible increased mortality have yet to be explored, although one possibility is increased frailty. Frailty has not been studied in ET, and our objective was to address this gap in knowledge. We hypothesized that frailty would be greater in ET cases than in controls.

Methods:  A 20‐item frailty score assessed comorbid conditions, number of medications, and functional activity. The frailty score was compared in 237 non‐demented elderly ET cases and 3903 non‐demented age‐matched controls from a population‐based study in central Spain.

Results:  The frailty score was higher in ET cases than in controls (8.6 ± 5.2 vs. 6.8 ± 4.6, P < 0.001). Stratifying the frailty score into quartiles and tertiles similarly revealed case–control differences (both P < 0.001). The frailty score also increased with age (r = 0.25, P < 0.001), was higher in women than men (P = 0.02), was correlated with subjective rating of health status (r = 0.42, P < 0.001), and was inversely correlated with body weight (r = −0.06, P < 0.001) and hours/day that participants performed moderate or intensive physical activities (r = −0.16, P < 0.001).

Conclusion:  Essential tremor cases had increased frailty compared to their counterparts without this disease. Whether this increased frailty is a contributor to the increased risk of mortality that has been observed in some studies is a question that deserves further scrutiny.
Clinical and genetic analysis of spinocerebellar ataxia in Mali
Authors: Traoré M. , Coulibaly T. , Meilleur K. G. , La Pean A. , Sangaré M. , Landouré G. , Mochel F. , Karambé M. , Guinto C. O. , Fischbeck K. H.
Published: March 2011

Background:  Autosomal dominant cerebellar ataxia, currently denominated spinocerebellar ataxia (SCAs), represents a heterogeneous group of neurodegenerative disorders affecting the cerebellum and its connections. We describe the clinical and molecular findings in 16 patients originating from Malian families, who suffer from progressive cerebellar ataxia syndrome.

Methods and results:  Molecular analysis allows genetic profiles of SCA to be distinguished. In seven patients, SCA type 2 (CAG) mutation was expanded from 39 to 43 repeats. SCA type 7 (CAG) mutation was confirmed in six patients. Mutations were expanded from 49 to 59 repeats. In three patients, SCA type3 was diagnosed and CAG mutation was expanded to 73 repeats.

Conclusions:  Our data suggest that the most frequent types of SCA are SCA2 and SCA7. However, further studies are needed to confirm these preliminary results.
Association of HLA‐DRB1*15 allele and CSF oligoclonal bands in a Spanish multiple sclerosis cohort
Authors: Romero‐Pinel L. , Martínez‐Yélamos S. , Bau L. , Matas E. , Gubieras L. , María Pujal J. , Morandeira F. , Bas J. , Arbizu T.
Published: March 2011

Background and objective:  The HLA‐DRB1*15 allele is consistently associated with multiple sclerosis (MS) susceptibility in most studied populations. This study investigated the association between HLA‐DRB1 alleles and the presence of oligoclonal immunoglobulin G bands (OCB) in the cerebrospinal fluid (CSF) in a Spanish population with MS.

Methods:  The HLA‐DRB1 typing was performed in 268 patients with sporadic MS and the detection of OCB in CSF. HLA‐DRB1 allelic frequencies were compared between OCB‐positive and OCB‐negative patients, and both groups were also compared with 1088 unrelated healthy controls. Moreover, we correlated the various HLA‐DRB1 genotypes, considering all the combinations of both parental alleles found with the presence or absence of OCB.

Results:  We found 206 OCB‐positive and 62 OCB‐negative patients. The HLA‐DRB1*15 allele in OCB‐positive patients had a higher frequency when compared with OCB‐negative patients (39.3% in OCB‐positive vs. 16.1% in OCB‐negative, OR = 1.38 95% CI = 1.18–1.61, P < 0.001). The other alleles did not show differences. When we compared with controls, the HLA‐DRB1*15 allele was associated with the disease only in the OCB‐positive patients group. None of the 55 genotypes found showed any association with the presence or absence of OCB.

Conclusions:  HLA‐DRB1*15 allele is associated with OCB‐positive patients with MS when studying a Spanish MS population.
Neuropathy and paraproteins: review of a complex association
Authors: Rajabally Y. A.
Published: March 2011

Coexistence of neuropathy and monoclonal gammopathy represents a common but complex problem in clinical practice. This association is here reviewed considering latest available literature. The association is not infrequent, and various possible syndromes need to be distinguished. However, coincidental co‐occurrence also needs to be recognized. The monoclonal gammopathy may be a ‘monoclonal gammopathy of uncertain significance’ (MGUS) or occur in a context of malignancy such as multiple myeloma or Waldenström’s macroglobulinaemia. IgM paraproteins can bind to myelin‐associated glycoprotein (MAG) in peripheral nerve. In this case, the paraprotein is directly linked to the neuropathy, causing a specific phenotype. One randomized controlled trial of this (‘Anti‐MAG’) neuropathy showed possible moderate effect of rituximab on disability. Results of another trial are awaited. IgM/G/A paraproteins can be associated with a polyneuropathy indistinguishable from chronic inflammatory demyelinating polyneuropathy. Axonal neuropathies may coexist with IgM/G/A MGUS. There is insufficient evidence about causality or effective treatment in such cases. Pain/dysautonomia with an axonal neuropathy and serum paraprotein raises the possibility of amyloidosis. Specific haematological treatment is required for malignant disorders, although caution is required with neurotoxic agents. Polyneuropathy, organomegaly, endocrinopathy, M‐protein, skin changes syndrome and chronic ataxic neuropathy with ophthalmoplegia, M‐protein, cold agglutinins and disialosyl antibodies represent rare separate entities for which evidence‐based treatment options are still lacking. The association of monoclonal gammopathy and neuropathy requires the appropriate neurological/haematological investigations for a precise diagnosis. Causality is only established in few cases. Adequate management ideally requires joint neurological/haematological input for diagnosis, monitoring and treatment.
The telomerase activator TA‐65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence
Authors: de Jesus Bruno Bernardes , Schneeberger Kerstin , Vera Elsa , Tejera Agueda , Harley Calvin B. , Blasco Maria A.
Published: March 2011

Here, we show that a small‐molecule activator of telomerase (TA‐65) purified from the root of Astragalus membranaceus is capable of increasing average telomere length and decreasing the percentage of critically short telomeres and of DNA damage in haploinsufficient mouse embryonic fibroblasts (MEFs) that harbor critically short telomeres and a single copy of the telomerase RNA Terc gene (G3 Terc+/− MEFs). Importantly, TA‐65 does not cause telomere elongation or rescue DNA damage in similarly treated telomerase‐deficient G3 Terc−/− littermate MEFs. These results indicate that TA‐65 treatment results in telomerase‐dependent elongation of short telomeres and rescue of associated DNA damage, thus demonstrating that TA‐65 mechanism of action is through the telomerase pathway. In addition, we demonstrate that TA‐65 is capable of increasing mouse telomerase reverse transcriptase levels in some mouse tissues and elongating critically short telomeres when supplemented as part of a standard diet in mice. Finally, TA‐65 dietary supplementation in female mice leads to an improvement of certain health‐span indicators including glucose tolerance, osteoporosis and skin fitness, without significantly increasing global cancer incidence.
The case for peripheral CB1 receptor blockade in the treatment of visceral obesity and its cardiometabolic complications
Authors: Kunos George , Tam Joseph
Published: March 2011

In this review, we consider the role of endocannabinoids and cannabinoid‐1 (CB1) cannabinoid receptors in metabolic regulation and as mediators of the thrifty phenotype that underlies the metabolic syndrome. We survey the actions of endocannabinoids on food intake and body weight, as well as on the metabolic complications of visceral obesity, including fatty liver, insulin resistance and dyslipidemias. Special emphasis is placed on weighing the relative importance of CB1 receptors located in peripheral tissues versus the central nervous system in mediating the metabolic effects of endocannabinoids. Finally, we review recent observations that indicate that peripherally restricted CB1 receptor antagonists retain efficacy in reducing weight and improving metabolic abnormalities in mouse models of obesity without causing behavioural effects predictive of neuropsychiatric side effects in humans.

LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue‐7
Protein kinase A and the exchange protein directly activated by cAMP (Epac) modulate phenotype plasticity in human airway smooth muscle
Authors: Roscioni Sara S , Prins Alwin G , Elzinga Carolina RS , Menzen Mark H , Dekkers Bart GJ , Halayko Andrew J , Meurs Herman , Maarsingh Harm , Schmidt Martina
Published: March 2011

BACKGROUND AND PURPOSE Platelet‐derived growth factor (PDGF) modulates the airway smooth muscle (ASM) ‘contractile’ phenotype to a more ‘proliferative’ phenotype, resulting in increased proliferation and reduced contractility. Such phenotypic modulation may contribute to airway remodelling in asthma. We have previously shown that the cAMP effector molecules, protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac) inhibited PDGF‐induced phenotypic modulation in bovine ASM. Here, we investigated these mechanisms in human ASM strips and cells.

EXPERIMENTAL APPROACH ASM strips were incubated with PDGF in the absence or presence of the activators of Epac (8‐pCPT‐2′‐O‐Me‐cAMP) or of PKA (6‐Bnz‐cAMP) for 4 days. Strips were mounted for isometric contraction experiments or analysed for the expression of contractile markers. Cell proliferation was measured and proliferative markers were analysed under similar conditions.

KEY RESULTS Activation of Epac and PKA prevented PDGF‐induced ASM strip hypocontractility, and restored the expression of smooth muscle actin, myosin and calponin, which had been markedly diminished by PDGF. Epac and PKA activation inhibited the PDGF‐induced ASM cell proliferation and G1/S phase transition and the expression and phosphorylation of cell cycle regulators.

CONCLUSIONS AND IMPLICATIONS Epac and PKA maintain a normally contractile ASM phenotype in a mitogenic environment, suggesting that specific activators of Epac and PKA may be beneficial in the treatment of airway remodelling in asthma.
Moxonidine improves cardiac structure and performance in SHR through inhibition of cytokines, p38 MAPK and Akt
Authors: Aceros H , Farah G , Cobos‐Puc L , Stabile AM , Noiseux N , Mukaddam‐Daher S
Published: March 2011

BACKGROUND AND PURPOSE Regression of left ventricular hypertrophy by moxonidine, a centrally acting sympatholytic imidazoline compound, results from a sustained reduction of DNA synthesis and transient stimulation of DNA fragmentation. Because apoptosis of cardiomyocytes may lead to contractile dysfunction, we investigated in spontaneously hypertensive rats (SHR), time‐ and dose‐dependent effects of in vivo moxonidine treatment on cardiac structure and function as well as on the inflammatory process and signalling proteins involved in cardiac cell survival/death.

EXPERIMENTAL APPROACH 12 week old SHR received moxonidine at 0, 100 and 400 µg·kg−1·h−1, s.c., for 1 and 4 weeks. Cardiac function was evaluated by echocardiography; plasma cytokines were measured by elisa and hearts were collected for histological assessment of fibrosis and measurement of cardiac proteins by Western blotting. Direct effects of moxonidine on cardiac cell death and underlying mechanisms were investigated in vitro by flow cytometry and Western blotting.

KEY RESULTS After 4 weeks, the sub‐hypotensive dose of moxonidine (100 µg) reduced heart rate and improved global cardiac performance, reduced collagen deposition, regressed left ventricular hypertrophy, inhibited Akt and p38 MAPK phosphorylation, and attenuated circulating and cardiac cytokines. The 400 µg dose resulted in similar effects but of a greater magnitude, associated with blood pressure reduction. In vitro, moxonidine inhibited norepinephrine‐induced neonatal cardiomyocyte mortality but increased fibroblast mortality, through I1‐receptor activation and differential effects on downstream Akt and p38 MAPK.

CONCLUSIONS AND IMPLICATIONS While the antihypertensive action of centrally acting imidazoline compounds is appreciated, new cardiac‐selective I1‐receptor agonists may confer additional benefit.
PGE2‐EP2 signalling in endothelium is activated by haemodynamic stress and induces cerebral aneurysm through an amplifying loop via NF‐κB
Authors: Aoki T. , Nishimura M. , Matsuoka T. , Yamamoto K. , Furuyashiki T. , Kataoka H. , Kitaoka S. , Ishibashi R. , Ishibazawa A. , Miyamoto S. , Morishita R. , Ando J. , Hashimoto N. , Nozaki K. , Narumiya S.
Published: March 2011

BACKGROUND AND PURPOSE Cerebral aneurysm is a frequent cerebrovascular event and a major cause of fatal subarachnoid haemorrhage, but there is no medical treatment for this condition. Haemodynamic stress and, recently, chronic inflammation have been proposed as major causes of cerebral aneurysm. Nevertheless, links between haemodynamic stress and chronic inflammation remain ill‐defined, and to clarify such links, we evaluated the effects of prostaglandin E2 (PGE2), a mediator of inflammation, on the formation of cerebral aneurysms.

EXPERIMENTAL APPROACH Expression of COX and prostaglandin E synthase (PGES) and PGE receptors were examined in human and rodent cerebral aneurysm. The incidence, size and inflammation of cerebral aneurysms were evaluated in rats treated with COX‐2 inhibitors and mice lacking each prostaglandin receptor. Effects of shear stress and PGE receptor signalling on expression of pro‐inflammatory molecules were studied in primary cultures of human endothelial cells (ECs).

KEY RESULTS COX‐2, microsomal PGES‐1 and prostaglandin E receptor 2 (EP2) were induced in ECs in the walls of cerebral aneurysms. Shear stress applied to primary ECs induced COX‐2 and EP2. Inhibition or loss of COX‐2 or EP2in vivo attenuated each other's expression, suppressed nuclear factor κB (NF‐κB)‐mediated chronic inflammation and reduced incidence of cerebral aneurysm. EP2 stimulation in primary ECs induced NF‐κB activation and expression of the chemokine (C‐C motif) ligand 2, essential for cerebral aneurysm.

CONCLUSIONS AND IMPLICATIONS These results suggest that shear stress activated PGE2‐EP2 pathway in ECs and amplified chronic inflammation via NF‐κB. We propose EP2 as a therapeutic target in cerebral aneurysm.
The role of underlying structural cause for epilepsy classification: Clinical features and prognosis in mesial temporal lobe epilepsy caused by hippocampal sclerosis versus cavernoma
Authors: Menzler Katja , Thiel Patricia , Hermsen Anke , Chen Xu , Benes Ludwig , Miller Dorothea , Sure Ulrich , Knake Susanne , Rosenow Felix
Published: March 2011

Purpose: The recent “Report of the ILAE Commission on Classification and Terminology” recommends an epilepsy classification that gives more emphasis to the underlying structural or metabolic cause rather than to the localization of the epileptogenic zone. The aim of the present study was to investigate differences in clinical features, treatment response, and prognosis in patients with mesial temporal lobe epilepsy (MTLE) caused by hippocampal sclerosis (MTLE‐HS) or singular mesiotemporal cavernomas (MTLE‐C) in order to evaluate the impact of underlying pathology on the course of the disease while controlling for localization.

Methods: Age at onset, age at surgery, seizure frequency and semiology, pharmacoresistance, psychiatric comorbidities, memory deficits, or initial precipitating insults (e.g., febrile seizures, traumatic brain injury, infection of the central nervous system, birth complications) as well as postoperative outcome were compared in eleven patients with MTLE‐C and 33 patients with MTLE‐HS using nonparametric statistical methods.

Key Findings: The postoperative outcome was significantly better in patients with MTLE‐C, even after controlling for preoperative epilepsy duration. Patients with MTLE‐HS more frequently were drug resistant (88% vs. 36%) and more often presented with an initial precipitating insult (70% vs. 27%) and with automotor seizures (79% vs. 46%).

Significance: The results suggest that patients with MTLE‐C show a more favorable postoperative outcome, supporting the commission’s suggestion to put more emphasis on the underlying cause in future epilepsy classifications.
Hippocampal sclerosis and a second focal lesion—How often is it ipsilateral?
Authors: Hofman Paul A. M. , Fitt Gregory , Mitchell L. Anne , Jackson Graeme D.
Published: March 2011

Purpose:  Hippocampal sclerosis (HS) is the most common pathologic finding in intractable temporal lobe epilepsy (TLE). In many patients, HS is accompanied by an extrahippocampal lesion (EHL). We sought to assess the lobar distribution and side of EHLs in relation to HS in a large consecutive series of patients presenting to our epilepsy surgery program.

Methods:  The inclusion criterion was the presence of both definite HS and an unequivocal EHL on magnetic resonance imaging (MRI) studies in patients evaluated for potential epilepsy surgery at our tertiary epilepsy center.

Key Findings:  Fifty‐eight patients were identified over a 7‐year period. This represented about one‐third of all patients with HS. The mean age was 32 years (SD 18.4), and the mean age of seizure onset 13 years (SD 16.4). Fifty‐four percent of the EHLs could be classified as acquired and 36% as developmental. In 98% of patients HS was found on the same side as EHL.

Significance:  Our findings support the hypothesis that HS may be a secondary event from seizures generated initially by another focal lesion. However, HS and EHL may also originate from the same insult to the brain.
Clinical experience with generic levetiracetam in people with epilepsy
Authors: Chaluvadi Siresha , Chiang Sharon , Tran Larry , Goldsmith Corey E. , Friedman David E.
Published: March 2011

Purpose:  To describe the clinical outcomes of a compulsory switch from branded to generic levetiracetam (LEV) among people with epilepsy (PWE) in an outpatient setting.

Methods:  We conducted a retrospective chart review of 760 unduplicated consecutive adult patients attending a tertiary care epilepsy clinic at Ben Taub General Hospital. On November 1, 2008 hospital policy required all patients receiving branded LEV to be automatically switched to generic LEV. We calculated the proportion of patients switching back to branded LEV and reasons for the switch back.

Key Findings:  Of the 260 patients (34%) being prescribed LEV (generic and brand name) during the study period, 105 (42.9%) were switched back to brand name LEV by their treating physicians. Reasons for switch back included increase in seizure frequency (19.6% vs. 1.6%; p < 0.0001) and adverse effects (AEs) (3.3%). AEs included headache, fatigue, and aggression. Patient age was associated with switchback when controlling for gender, epilepsy classification, and treatment characteristics [relative risk (RR) 2.44; 95% confidence interval (CI) 2.09–2.84; p < 0.05)]. An increase in seizure frequency subsequent to generic substitution was associated with polytherapy compared to monotherapy (3.225; 1.512–6.880; p < 0.05).

Significance:  A significant proportion of patients in our cohort on generic LEV required switch back to the branded drug. Careful monitoring is imperative because a compulsory switch from branded to generic LEV may lead to poor clinical outcomes, with risk of AEs and increased seizure frequency.
Competitive Lending with Partial Knowledge of Loan Repayment: Some Positive and Normative Analysis
Authors: BROCK WILLIAM A. , MANSKI CHARLES F.
Published: March 2011

We study a credit market where lenders with partial knowledge of repayment use one of several criteria to make lending decisions. Supposing that a public Authority wants to maximize the social return to borrowing, we study interventions that manipulate the return on the safe asset or guarantee a minimum loan return. Manipulating the return on the safe asset is effective if lender beliefs about the return to lending are not too pessimistic relative to those of the Authority. Guaranteeing a minimum return is effective if lender beliefs are not too optimistic relative to those of the Authority.
Dynamic Limited Dependent Variable Modeling and U.S. Monetary Policy
Authors: MONOKROUSSOS GEORGE
Published: March 2011

I estimate a forward‐looking, dynamic, discrete‐choice monetary policy reaction function for the U.S. economy that accounts for the fact that there are substantial restrictions in the period‐to‐period changes of the policy instrument. I find a substantial contrast between the periods before and after Paul Volcker's appointment as Fed chairman in 1979, both in terms of the Fed's response to expected inflation and in terms of its response to the (perceived) output gap. In the pre‐Volcker era, the Fed's response to inflation was substantially weaker than in the Volcker–Greenspan era; conversely, the Fed seems to have been more responsive to (inaccurate real‐time estimates of) the output gap in the pre‐Volcker era than later. These results, which carry through a series of extensions and robustness checks, provide support for the “policy mistakes” hypothesis as an explanation of the stark contrast in U.S. macroeconomic performance between the pre‐Volcker and the Volcker–Greenspan periods.
The Failure of Woodford's Model of the Channel System in the Cashless Economy
Authors: ROGERS COLIN
Published: March 2011

Woodford claims to present a cashless and frictionless model of the channel system of interest rate control. This note explains why Woodford's frictionless model omits an essential feature of channel systems: the need for clearing e‐cash balances at the central bank. Without the existence of some form of final settlement on the books of the central bank channel systems collapse. Woodford makes this conceptual error because he assumes that moneyless accounting systems of exchange can be applied to model e‐cash economies.
Two Who Called the Great Depression: An Initial Formulation of the Monetary‐Origins View
Authors: TAVLAS GEORGE S.
Published: March 2011

The consensus view in the economics profession today is that the genesis of the Great Depression was the tightening of policy by the Fed in 1928 and 1929, mainly to stem the stock market boom. Nevertheless, monetary historians have not provided evidence that any economist writing prior to the stock market crash of October 1929 foresaw that the Fed's actions would lead to a major depression. This paper shows that two economists, William Foster and Waddill Catchings, co‐authored a paper in July 1929 containing arguments strikingly similar to the present consensus view. Their critique of Fed policy supports the view that the genesis of the Great Depression had monetary origins and was preventable.
Taylor Rules and the Euro
Authors: MOLODTSOVA TANYA , NIKOLSKO‐RZHEVSKYY ALEX , PAPELL DAVID H.
Published: March 2011

This article uses real‐time data to show that inflation and either the output gap or unemployment, variables which normally enter central banks’ Taylor rules, can provide evidence of out‐of‐sample predictability for the U.S. dollar/euro exchange rate from 1999 to 2007. The strongest evidence is found for specifications that constrain the coefficients on inflation and real economic activity to be the same for the United States and the Euro Area, do not incorporate interest rate smoothing, and do not include the real exchange rate in the forecasting regression. Evidence of predictability is found with both one‐quarter‐ahead and longer‐horizon forecasts.
Prostate needle biopsies: interobserver variation and clinical consequences of histopathological re‐evaluation
Authors: BERG KASPER DRIMER , TOFT BIRGITTE GRØNKÆR , RØDER MARTIN ANDREAS , BRASSO KLAUS , VAINER BEN , IVERSEN PETER
Published: March 2011

Berg KD, Toft BG, Røder MA, Brasso K, Vainer B, Iversen P. Prostate needle biopsies: interobserver variation and clinical consequences of histopathological re‐evaluation. APMIS 2011; 119: 239–46.

Histopathological grading of prostate cancer (PCa) is associated with significant interobserver variability. This, as well as clinical consequences of histopathological re‐evaluation, was investigated. In 350 patients, histopathological re‐evaluations of prostate biopsies were compared with primary pathology reports and with histopathology of the radical prostatectomy specimen. The consequences of re‐evaluation for clinical workup and treatment of patients according to local algorithms were determined. For Gleason score (GS), complete agreement between primary report and re‐evaluation was found in 76.9%. The cancers were assessed with higher GS at re‐evaluation in 25.0% of patients in cases with primary GS ≤ 6, while scores were devaluated in 3.0% and 10.3% of the patients with primary GS = 7 and ≥8, respectively. Strategies for clinical evaluation and treatment were changed as a result of the biopsy re‐evaluations in 19.7% and 13.1% of patients, respectively. Gleason scoring based on the radical prostatectomy specimen was higher than in both primary reports and re‐evaluation of biopsies. Although a relatively high degree of concordance was found between biopsy assessments, the significant trend towards higher Gleason scoring at re‐evaluation, leading to frequent changes in clinical assessments and surgical strategy, justifies re‐evaluation of PCa biopsies in patients with primary GS ≤ 6.
Interaction between linezolid and Mycobacterium tuberculosis in an experimental in vitro model
Authors: CREMADES ROSA , RODRÍGUEZ JUAN CARLOS , GARCIA‐PACHÓN EDUARDO , GALIANA ANTONIO , RUIZ‐GARCÍA MONTSERRAT , LÓPEZ PILAR , ROYO GLORIA
Published: March 2011

Cremades R, Rodríguez JC, Garcia‐Pachón E, Galiana A, Ruiz‐García M, López P, Royo G. Interaction between linezolid and Mycobacterium tuberculosis in an experimental in vitro model. APMIS 2011; 119: 304–8.

As linezolid is emerging as a useful alternative in the treatment of multi‐resistant tuberculosis, we developed an in vitro model to elucidate certain aspects of the interaction that takes place between the microorganism and the antibiotic. We found that the drug does not generate resistant mutants following repeated exposure at subinhibitory concentrations and that it exhibits bactericidal activity against most of the susceptible strains in vitro at high concentrations (83.3% of the strains at concentrations of 50 μg/mL) in the exponential growth phase. This bactericidal activity is much less if the microorganism is in nonreplicating phase, even in the case of susceptible strains in vitro. Therefore, linezolid appears to be an alternative as far as generation of resistance is concerned in the treatment of multi‐resistant tuberculosis. However, it has limited bactericidal capacity against strains in nonreplicant phase, which makes it necessary to use linezolid in combination with other drugs that act on these microorganisms.
The presence of Epstein–Barr virus (EBV) in diffuse large B‐cell lymphomas (DLBCLs) in Turkey: special emphasis on ‘EBV‐positive DLBCL of the elderly’
Authors: UNER AYSEGUL , AKYUREK NALAN , SAGLAM ARZU , ABDULLAZADE SAMIR , UZUM NUKET , ONDER SEVGEN , BARISTA IBRAHIM , BENEKLI MUSTAFA
Published: March 2011

Uner A, Akyurek N, Saglam A, Abdullazade S, Uzum N, Onder S, Barista I, Benekli M. The presence of Epstein–Barr virus (EBV) in diffuse large B‐cell lymphomas (DLBCLs) in Turkey: special emphasis on ‘EBV‐positive DLBCL of the elderly’. APMIS 2011; 119: 309–16.

Accumulated evidence has shown the importance of Epstein–Barr virus in the pathogenesis of various lymphomas. This study aimed to determine the prevalence of Epstein–Barr virus expression and its effect on survival amongst diffuse large B‐cell lymphoma (DLBCL) cases from two large tertiary care centres in Turkey with a particular interest in identifying cases of ‘Epstein–Barr virus‐positive DLBCL of the elderly’. Diffuse large B‐cell lymphoma cases diagnosed between 1999 and 2009 were retrieved and 340 cases were used to construct tissue microarrays. The presence of Epstein–Barr virus small ribonucleic acids was examined by in situ hybridization using Epstein‐Barr virus (EBV)‐encoded small RNA (EBER) oligonucleotides. A total of 18 cases (5.3%) showed Epstein–Barr virus expression. Twelve cases were classified as Epstein–Barr virus‐positive DLBCL of the elderly. Epstein–Barr virus‐positive DLBCL cases showed a significantly inferior overall survival as compared with Epstein–Barr virus‐negative cases (p < 0.001). In our study group Epstein–Barr virus expression is not prevalent in DLBCLs. Epstein–Barr virus‐positive DLBCL of the elderly is also rare in the Turkish population. The presence of Epstein–Barr virus, however, is associated with poor prognosis.
A comparison of computer‐ and hand‐generated clinical dental notes with statutory regulations in record keeping
Authors: McAndrew R. , Ban J. , Playle R.
Published: March 2011

Introduction:  Dental patient records should be of high quality, contain information to allow for good continuity of care and clinical defence (should the need ever arise) and, ideally, facilitate clinical audit. Handwritten dental records have been assessed for their compliance to statutory regulations, but the same cannot be levelled at computer‐generated notes. This study aimed to compare and analyse the compliance of both methods of data recording with statutory regulations.

Method:  Fifty consecutive sets of handwritten notes and 50 sets of computer‐generated notes were audited for compliance with a number of legal requirements and desirable characteristics for dental records and the results compared. The standard set for compliance with all characteristics was 100%.

Results:  The computer‐generated notes satisfied the set standard for 8 of the 11 legal requirements and three of six desirable characteristics. The handwritten notes satisfied the set standard for 1 of 11 legal requirements and none of the desirable characteristics. A statistical difference (using a 95% confidence interval) between the two methods was observed in 5 of 11 legal characteristics and three of six desirable characteristics, all of which were in favour of computer‐generated notes.

Conclusions:  Within the limitations of this study, computer‐generated notes achieved a much higher compliance rate with the set parameters, making defence in cases of litigation, continuity of care and clinical audit easier and more efficient.
Assessing professionalism within dental education; the need for a definition
Authors: Zijlstra‐Shaw S. , Robinson P. G. , Roberts T.
Published: March 2011

Professionalism is a broad competency needed by dentists to act effectively and efficiently and is seen as a central part of both undergraduate and postgraduate curricula. Assessment is vital in education to assess progress and direct future learning. It is also an essential part of good professional regulation, which depends upon high quality assessment to maintain credibility. Educators must produce clear expectations that students can strive for. Thus dental educators are required to understand precisely what is meant by “professionalism” in relation to dentistry in order to both teach and assess it. The aim of this paper is to explain the importance of professionalism, explore its features and its assessment as described in the literature. The paper concludes that without a validated definition of this construct, assessment of professionalism within dental education will be compromised.