bluuebunny/crossref_metadata_2025 huggingface dataset:
Parotid Tumours
Authors: Williams Stephen , Lamyman Abigail
Published: April 2012

The salivary glands act to produce and secrete saliva. They are grouped into the minor salivary glands (located throughout the mucosa of the mouth and throat) and the paired major salivary glands: the parotid, submandibular and sublingual glands. Salivary gland tumours, both benign and malignant, can arise from any of these glands but it is the parotid, which is the most commonly affected, representing around 70% of all salivary gland tumours.
Model analysis for plant disease dynamics co-mediated by herbivory and herbivore-borne phytopathogens
Authors: Nakazawa Takefumi , Yamanaka Takehiko , Urano Satoru
Published: April 2012

Plants are subject to diseases caused by pathogens, many of which are transmitted by herbivorous arthropod vectors. To understand plant disease dynamics, we studied a minimum hybrid model combining consumer–resource (herbivore–plant) and susceptible–infected models, in which the disease is transmitted bi-directionally between the consumer and the resource from the infected to susceptible classes. Model analysis showed that: (i) the disease is more likely to persist when the herbivore feeds on the susceptible plants rather than the infected plants, and (ii) alternative stable states can exist in which the system converges to either a disease-free or an endemic state, depending on the initial conditions. The second finding is particularly important because it suggests that the disease may persist once established, even though the initial prevalence is low (i.e. theR0rule does not always hold). This situation is likely to occur when the infection improves the plant nutritive quality, and the herbivore preferentially feeds on the infected resource (i.e. indirect vector–pathogen mutualism). Our results highlight the importance of the eco-epidemiological perspective that integration of tripartite interactions among host plant, plant pathogen and herbivore vector is crucial for the successful control of plant diseases.
A methodology for global-sensitivity analysis of time-dependent outputs in systems biology modelling
Authors: Sumner T. , Shephard E. , Bogle I. D. L.
Published: April 2012

One of the main challenges in the development of mathematical and computational models of biological systems is the precise estimation of parameter values. Understanding the effects of uncertainties in parameter values on model behaviour is crucial to the successful use of these models. Global sensitivity analysis (SA) can be used to quantify the variability in model predictions resulting from the uncertainty in multiple parameters and to shed light on the biological mechanisms driving system behaviour. We present a new methodology for global SA in systems biology which is computationally efficient and can be used to identify the key parameters and their interactions which drive the dynamic behaviour of a complex biological model. The approach combines functional principal component analysis with established global SA techniques. The methodology is applied to a model of the insulin signalling pathway, defects of which are a major cause of type 2 diabetes and a number of key features of the system are identified.
Single and mixed poloxamine micelles as nanocarriers for solubilization and sustained release of ethoxzolamide for topical glaucoma therapy
Authors: Ribeiro Andreza , Sosnik Alejandro , Chiappetta Diego A. , Veiga Francisco , Concheiro Angel , Alvarez-Lorenzo Carmen
Published: April 2012

Polymeric micelles of single and mixed poloxamines (Tetronic) were evaluated regarding their ability to host the antiglaucoma agent ethoxzolamide (ETOX) for topical ocular application. Three highly hydrophilic varieties of poloxamine (T908, T1107 and T1307) and a medium hydrophilic variety (T904), possessing a similar number of propylene oxide units but different contents in ethylene oxide, were chosen for the study. The critical micellar concentration and the cloud point of mixed micelles in 0.9 per cent NaCl were slightly greater than the values predicted from the additive rule, suggesting that the co-micellization is hindered. Micellar size ranged between 17 and 120 nm and it was not altered after the loading of ETOX (2.7–11.5 mg drug g
–1
poloxamine). Drug solubilization ability ranked in the order: T904 (50-fold increase in the apparent solubility) > T1107 ≅ T1307 > T908. Mixed micelles showed an intermediate capability to host ETOX but a greater physical stability, maintaining almost 100 per cent drug solubilized after 28 days. Furthermore, the different structural features of poloxamines and their combination in mixed micelles enabled the tuning of drug release profiles, sustaining the release in the 1–5 days range. These findings together with promising hen's egg test-chorioallantoic membrane biocompatibility tests make poloxamine micelles promising nanocarriers for carbonic anhydrase inhibitors in the treatment of glaucoma.
Host modulation of parasite competition in multiple infections
Authors: Ulrich Yuko , Schmid-Hempel Paul
Published: April 2012

Parasite diversity is a constant challenge to host immune systems and has important clinical implications, but factors underpinning its emergence and maintenance are still poorly understood. Hosts typically harbour multiple parasite genotypes that share both host resources and immune responses. Parasite diversity is thus shaped not only by resource competition between co-infecting parasites but also by host-driven immune-mediated competition. We investigated these effects in an insect–trypanosome system, combining
in vivo
and
in vitro
single and double inoculations.
In vivo
, a non-pathogenic, general immune challenge was used to manipulate host immune condition and resulted in a reduced ability of hosts to defend against a subsequent exposure to the trypanosome parasites, illustrating the costs of immune activation. The associated increase in available host space benefited the weaker parasite strains of each pair as much as the otherwise more competitive strains, resulting in more frequent multiple infections in immune-challenged hosts.
In vitro
assays showed that in the absence of a host, overall parasite diversity was minimal because the outcome of competition was virtually fixed and resulted in strain extinction. Altogether, this shows that parasite competition is largely host-mediated and suggests a role for host immune condition in the maintenance of parasite diversity.
Snail is an independent prognostic predictor for progression and patient survival of gastric cancer
Authors: He Hongyong , Chen Weidong , Wang Xuefei , Wang Cong , Liu Fenglin , Shen Zhenbin , Xu Jiejie , Gu Jianxin , Sun Yihong
Published: April 2012

The present study investigated the clinical significance of Snail, a zinc‐finger transcription factor, in the development and progression of gastric cancer. To elucidate the relationship between Snail expression and dedifferentiation status with cancer stem cell phenotype in gastric cancer cells, we used western blot analysis, RT‐PCR, quantitative real‐time PCR and flow cytometry. Immunohistochemistry staining and evaluation of Snail expression in 10 human normal gastric samples versus 103 clinicopathologically characterized gastric cancer tissues followed by statistical analyses were applied to evaluate the prognostic value of Snail expression for progression and patient survival of gastric carcinomas. The results showed that functional Snail expression interlinks dedifferentiation status with cancer stem cell phenotype in gastric cancer cells. In addition, expression levels of Snail in gastric cancer tissues were significantly associated with tumor cell differentiation, local tumor growth, lymph node status, distant metastasis and tumor stage. The overall survival rate of gastric cancer patients with high Snail expression was significantly lower than for those patients with low Snail expression. Multivariate Cox regression analyses showed that Snail expression is an independent prognostic predictor for patient survival of gastric carcinomas. Thus, our data suggest that Snail expression could be a reliable independent prognostic factor to predict gastric carcinoma progression, which might open a new avenue for potential clinical intervention with functional Snail expression in gastric cancer patients. (Cancer Sci 2012; 103: 1296–1303)
Pleomorphic lobular carcinoma: a distinctive clinical and molecular breast cancer type
Authors: Monhollen Laketa , Morrison Carl , Ademuyiwa Foluso O , Chandrasekhar Rameela , Khoury Thaer
Published: April 2012

Monhollen L, Morrison C, Ademuyiwa F O, Chandrasekhar R, Khoury T  (2012) Histopathology 61, 365–377

Pleomorphic lobular carcinoma: a distinctive clinical and molecular breast cancer type

Aims:  Pleomorphic lobular carcinoma (PLC) is an aggressive variant of invasive lobular carcinoma. The aim of this study was to redefine PLC in terms of molecular classification.

Methods and results:  Cases of PLC were selected between 1995 and 2010. Key clinicopathological features were recorded for most of the patients. A panel of immunohistochemical stains including E‐cadherin, oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin (CK)5/6, CK14, CK17, anti‐cytokeratin (CAM) 5.2, CD117, vimentin, epidermal growth factor receptor (EGFR), p53 and gross cystic disease fluid protein‐15 (GCDFP‐15) were performed. HER2 test by fluorescence in‐situ hybridization (FISH) was also performed. The log‐rank test was used for statistical analyses. Forty cases fulfilled the criteria for PLC (26 with available tissue). The median age was 61 years and median tumour size was 2.0 cm. There were five of 38 (13.2%) triple‐negative cases. The basal type was seen in one of 25 cases (4%), which had a triple‐negative phenotype. HER2 was amplified in 14 of 38 cases (35%). Older patients and negative hormonal receptor status correlated significantly with worse clinical outcome (P < 0.03). The 5‐year recurrence‐free and overall survival was 54.9% and 76.2%, respectively.

Conclusions:  Pleomorphic lobular carcinoma is a distinctive breast cancer subtype. It has hybrid clinicopathological characteristics of ductal and lobular carcinoma.
The relevance of the epidemiology of human sex ratios at birth to some medical problems
Authors: James William H.
Published: April 2012

James WH. The relevance of the epidemiology of human sex ratios at birth to some medical problems. Paediatric and Perinatal Epidemiology 2012; 26: 181–189.

The human sex ratio (proportion male at birth) shows considerable variation which is central to reproductive epidemiology. For example, it has reportedly shown significant secular trends and wartime variation, and it has shown replicated variation with parental exposure to several deleterious chemicals. However, scientific progress in identifying the causes of these forms of variation has been very slow and, as described here, this has elicited some scepticism. Benefits may be expected from identifying these causes. Two (non‐competing) hypotheses have emerged, the first relating to the hormonal regulation of sex ratio at conception, and the second to the sex‐selective effects of stressors during pregnancy. It is shown here that if the first of these hypotheses was substantially correct, it would illuminate a number of scientific and medical problems, for example, the causes of autism and of selected sex‐related congenital malformations and obstetric pathologies.
The outcome of critical illness in decompensated alcoholic liver cirrhosis
Authors: KAVLI M. , STRØM T. , CARLSSON M. , DAHLER‐ERIKSEN B. , TOFT P.
Published: April 2012

Background

The mortality of patients suffering from acute decompensated liver disease treated in the intensive care unit (ICU) varies between 50% and 100%. Previously published data suggest that liver‐specific score systems are less accurate compared with the ICU‐specific scoring systems acute physiology and chronic health evaluation II (APACHE II) and simplified organ failure assessment (SOFA) in predicting outcome. We hypothesized that in a Scandinavian cohort of ICU patients, APACHE II, SOFA, and simplified acute physiology score (SAPS II) were superior to predict outcome compared with the Child–Pugh score.

Methods

A single‐centre retrospective cohort analysis was conducted in a university‐affiliated ICU. Eighty‐seven adult patients with decompensated liver alcoholic cirrhosis were admitted from January 2007 to January 2010.

Results

The patients were severely ill with median scores: SAPS II 60, SOFA (day 1) 11, APACHE II 31, and Child–Pugh 12. Receiver operating characteristic curves area under curve was 0.79 for APACHE II, 0.83 for SAPS II, and 0.79 for SOFA (day1) compared with 0.59 for Child–Pugh. In patients only in need of mechanical ventilation, the 90‐day mortality was 76%. If respiratory failure was further complicated by shock treated with vasopressor agents, the 90‐day mortality increased to 89%. Ninety‐day mortality for patients in need of mechanical ventilation, vasoactive medication, and renal replacement therapy because of acute kidney injury was 93%.

Conclusion

APACHE II, SAPS II, and SOFA were better at predicting mortality than the Child–Pugh score. With three or more organ failures, the ICU mortality was > 90%. APACHE II > 30, SAPS II > 60, and SOFA at day 1 > 12 were all associated with a mortality of > 90%. Referral criteria of patients suffering from decompensated alcoholic liver disease should be revised.
Micafungin in haematology
Authors: Gamaletsou Maria N. , Sipsas Nikolaos V. , Kontoyiannis Dimitrios P.
Published: April 2012

Invasive fungal infections have emerged as a major cause of increased morbidity and mortality among severely immunosuppressed patients with haematological malignancy. Micafungin, a new member of the echinocandin class, is a valuable addition to the antifungal armamentarium of the 21st century as it is active against Candida species, Aspergillus species, and other unusual mycoses that frequently affect these high risk patients. Available data on the safety and efficacy of micafungin as prophylaxis, preemptive/empirical treatment, or treatment of documented invasive fungal infection in patients with haematological malignancies are summarized in this review.
Azole‐resistant Candida spp. – emerging pathogens?
Authors: Tobudic Selma , Kratzer Christina , Presterl Elisabeth
Published: April 2012

Invasive fungal infections cause significant morbidity and mortality in immunocompromised patients. Azoles, and fluconazole in particular, are very active against Candida albicans, and are used widely because of their good tolerability. However, the increasing use of azole antifungals for the treatment of mucosal and systemic Candida infections has resulted in the selection and/or emergence of resistant Candida strains. The main mechanisms of azole resistance among Candida species are the development of bypass pathways, alterations in the ERG 11 gene encoding the azole target enzyme, and the up‐regulation of genes encoding efflux pumps. A better understanding of the mechanisms and clinical impact of antifungal resistance is essential to prompt and efficient treatment of patients with invasive mycoses and to improve the outcome of such infections.
Candida biofilms associated with CVC and medical devices
Authors: Chandra Jyotsna , Mukherjee Pranab K. , Ghannoum Mahmoud A.
Published: April 2012

Intravascular device‐related infections are often associated with biofilms (microbial communities encased within polysaccharide‐rich extracellular matrix) formed by pathogens on surfaces of these devices. Candida species are the most common fungi isolated from catheter, denture and voice prosthesis‐associated infections, and also are commonly isolated from contact lens‐related infections (e.g. fungal keratitis). These biofilms exhibit decreased susceptibility to most antimicrobial agents, which contributes to the persistence of infection. Drug resistance in fungal biofilms is multifactorial and phase‐dependent, e.g. efflux pumps mediate resistance in biofilms during early phase whereas altered membrane sterol composition contributes to resistance in mature phase. Both substrate type and surface coatings play an important role in the pathogenesis of device‐related fungal biofilms. Microarray and proteomic analyses have identified the differentially expressed genes and proteins in Candida biofilms, and recent studies demonstrate that microbial biofilms interact with host immune cells. In this review, we will summarise recent advances in research on fungal biofilms and their relevance to device‐associated infections.
Clinical feature of asymptomatic reflux esophagitis in patients who underwent upper gastrointestinal endoscopy
Authors: Nagahara Akihito , Hojo Mariko , Asaoka Daisuke , Sasaki Hitoshi , Oguro Masako , Mori Hiroki , Matsumoto Kenshi , Osada Taro , Yoshizawa Takashi , Watanabe Sumio
Published: April 2012

Background and Aim:  Prevalence of gastroesophageal reflux disease (GERD) varies in regions, but few reports on clinical features and quality of life (QOL) of asymptomatic GERD exist in Japan.

Methods:  Endoscopy was performed in our department between April 2008 and September 2010. Among 6409 cases answering Frequency of Scale for the Symptoms of GERD (FSSG) and SF8 QOL (PCS: physical component summary; MCS: mental component summary), proton pump inhibitor or histamine 2 receptor antagonist users were excluded, and 388 cases diagnosed as reflux esophagitis (RE) (Los Angeles Classification grade A, B, C, D) were analyzed. Asymptomatic cases with FSSG total score = 0 were defined as asymptomatic RE (AsymRE) and FSSG total score ≥ 1 as symptomatic RE (SymRE). Each clinical feature was analyzed.

Results:  The frequency of AsymRE was 11.6% of RE (AsymRE, n = 45; SymRE, n = 343). Patient characteristics in AsymRE, SymRE were male/female = 35/10; 239/104 (not significant), mean age (year) = 63.5 ± 14.3; 58.3 ± 12.7 (P < 0.01), body mass index = 23.9 ± 4.3; 23.5 ± 3.7 (ns), respectively. Regarding the grade of RE, grade A 80.0%, B 17.8%, C 2.2% and D 0% in AsymRE, and grade A 72.6%, B 24.8%, C 2.0% and D 0.6% in SymRE (ns). PCS in SF8 was AsymRE; SymRE = 51.8 ± 9.8; 49.0 ± 7.7 (P < 0.01) and MCS in SF8 was AsymRE; SymRE = 51.4 ± 9.4; 48.2 ± 7.6 (P < 0.01), respectively.

Conclusion:  The prevalence of asymptomatic RE was high, particularly in elderly subjects. Unlike symptomatic RE, QOL was not impaired at all with asymptomatic RE. No differences were seen between groups in clinical features such as endoscopic severity of RE, indicating that asymptomatic RE is a condition that should not be overlooked clinically.
Utility and problems of endoscopic submucosal dissection for early gastric cancer in elderly patients
Authors: Tokioka Satoshi , Umegaki Eiji , Murano Mitsuyuki , Takeuchi Nozomi , Takeuchi Toshihisa , Kawakami Ken , Yoda Yukiko , Kojima Yuichi , Higuchi Kazuhide
Published: April 2012

Background and Aim:  Endoscopic submucosal dissection (ESD) is reported to be a safe and reliable procedure for the elderly, but these reports could have already had a bias at the time ESD was performed. However, the reports have not clearly stated the criteria of indications. In the present study, we retrospectively elucidated the usefulness and problems of ESD for early gastric cancer in elderly patients (≥ 65 years) in comparison with non‐elderly patients.

Methods:  The subjects were selected from 412 consecutive patients with early gastric cancer (515 lesions) for which ESD was performed between June 2002 and February 2010. The following were used for analysis between groups: pre‐ and postoperative performance status (PS) of subjects, prevalence rates of pre‐existing comorbidities, characteristics of lesions, treatment outcomes, durations of hospitalization, operating times, incidence rates of complications and durations of hospitalization, and postoperative hemorrhage rates, and duration of hospitalization in patients with anticoagulant therapy.

Results:  Of the lesions in the elderly, four patients (1.0%) were elderly with a PS of 3. The PS increased to six patients (1.6%) after the procedure. None of the non‐elderly had a PS of 3 before or after the procedure. The ratio of patients with a pre‐existing comorbidity was higher in the elderly than in the non‐elderly. There were no differences between the two groups in the characteristics of the lesions, their duration of hospitalization, their operating times, or the incidence rates of complications. However, the elderly with perforations had a significantly longer hospitalization than the comparable non‐elderly. The percentage of the patients taking anticoagulant drugs was significantly higher among the elderly. Of the patients on anticoagulant therapy, the duration of hospitalization tended to be longer in the elderly but no significant difference was found. None of the non‐elderly with postoperative hemorrhage had received anticoagulant therapy. In the elderly with postoperative hemorrhage, 15.8% of the lesions were in those who had received anticoagulant therapy, indicating a significantly higher percentage of such lesions in the elderly group.

Conclusion:  We conclude that ESD is useful in elderly patients because there is a similar risk as for the non‐elderly if the approach is individualized, and the following are taken into consideration when making the final decision of performing ESD in an elderly patient: patients should have a PS of 0, 1, or 2; determine whether or not anticoagulant therapy can be discontinued and whether or not treatment can be performed reliably without complications.
Effect of ecabet sodium treatment on urea breath test and stool antigen tests in volunteers with Helicobacter pylori infection
Authors: Okuda Masumi , Yamamoto Noriyasu , Fukuda Nobuhisa , Maekawa Kohei , Kusaka Takeshi , Hashimoto Manabu , Kotake Junichiro , Koizuka Hiromasa , Fukuda Yoshihiro
Published: April 2012

Background and Aim:  Ecabet sodium is reported to have a bactericidal effect on Helicobacter pylori and inhibit urease activity in vitro.

Methods:  Seven male volunteers (mean age, 51.3 years; range, 45–55 years) with H. pylori infection were medicated with 1 g ecabet sodium t.i.d. for 4 weeks. The urea breath test (UBT) was performed 10 times per person: before medication, seven times in 2 weeks, and once in the third and fourth weeks. Stool antigen tests (HpSA PLUS and Testmate pylori antigen) were performed five times per person: before medication and weekly during medication.

Results:  The premedication UBT value ranged from 4.9‰ to 77.4‰ and from 2.9‰ to 44‰ at the end of the treatment period. Not one of the subjects had a negative UBT result during medication. The optical densities of the HpSA and Testmate pylori antigen tests ranged from 0.4 to > 3.0 premedication and from 0.0 to > 3.0 at the end of treatment. HpSA and Testmate pylori antigen were negative in two cases.

Conclusions:  In this study, ecabet sodium did not effect the results of UBT in volunteers with H. pylori infection. Ecabet sodium may influence stool antigens because in two of seven cases the H. pylori stool antigen tests returned negative results.
Effect of gastric acid suppression with pantoprazole on the efficacy of calcium carbonate as a phosphate binder in haemodialysis patients
Authors: CERVELLI MATTHEW J , SHAMAN AHMED , MEADE ANTHONY , CARROLL ROBERT , MCDONALD STEPHEN P
Published: April 2012

Aim:  Metallic phosphate binders require acidity to dissociate to the free metallic ion and bind phosphorus. Altered gastric acidity may, therefore, influence phosphate‐binding efficacy. We evaluated the clinical effect of pantoprazole on the efficacy of calcium carbonate phosphate binders in haemodialysis patients.

Methods:  The study had two parts: a cross‐sectional study (n = 67), and an interventional, crossover, double‐blind, randomized, placebo‐controlled trial in 26 patients given pantoprazole 40 mg daily or placebo for two consecutive 6‐week periods.

Results:  The cross‐sectional study showed no difference between those on and off acid suppressants in phosphate (1.43 ± 0.45 vs 1.46 ± 0.31 mmol/L, P = 0.782) or other parameters except age (72.2 ± 9.8 vs 63.8 ± 14.8 years, P = 0.01). In the interventional study, phosphate was higher during pantoprazole than placebo (1.59 ± 0.3 vs 1.42 ± 0.3 mmol/L, P = 0.005). Serum calcium (2.37 ± 0.2 vs 2.46 ± 0.2 mmol/L, P = 0.012) and ionized calcium (1.17 ± 0.1 vs 1.22 ± 0.1 mmol/L, P = 0.013) were lower during pantoprazole treatment. CaxPO4 (3.76 ± 0.7 vs 3.48 ± 0.7 mmol2/L2, P = 0.032) and intact parathyroid hormone (31.9 ± 21.4 vs 23.6 ± 17.7 pmol/L, P = 0.004) were higher on pantoprazole.

Conclusion:  These results demonstrate clinical evidence for an adverse effect of gastric acid suppression on the effectiveness of calcium carbonate phosphate binders. Given their frequent co‐prescription, this interaction may be a minor but common reason why some patients fail to control hyperphosphataemia. Clinicians should regularly assess the need for acid suppressants. Further studies are needed to investigate interactions with other phosphate binders.
Relationship between serum levels of tumour necrosis factor‐related apoptosis‐inducing ligand and the survival of Chinese peritoneal dialysis patients
Authors: POON PETER YAM‐KAU , SZETO CHEUK‐CHUN , KWAN BONNIE CHING‐HA , CHOW KAI‐MING , LEUNG CHI‐BON , LI PHILIP KAM‐TAO
Published: April 2012

Aim:  Tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) can counteract inflammation and atherosclerosis, both common causes of morbidity in peritoneal dialysis (PD) patients. We examined the relation between serum soluble TRAIL (sTRAIL) levels and the outcome of Chinese PD patients.

Methods:  We studied 116 new PD patients (67 males, age 56.7 ± 13.4 years). Baseline serum sTRAIL level was determined and grouped to tertiles 1 (lowest) to 3 (highest). All patients were followed for 20.9 ± 7.0 months.

Results:  Patient survival was 83.4%, 74.2% and 100% for tertiles 1 to 3, respectively, at 24 months (P = 0.021). Multivariate Cox regression analysis showed that serum sTRAIL level was an independent predictor of patient survival after adjusting for confounding factors (adjusted hazard ratio 0.962, 95% confidence interval [CI] 0.935–0.991, P = 0.010).

Conclusion:  A higher baseline serum sTRAIL level was associated with a better survival of PD patients. The detailed mechanism deserves further investigation.
Impact of renal function on cardiovascular events in patients undergoing radical nephrectomy for renal cancer
Authors: Takeshita Hideki , Yokoyama Minato , Fujii Yasuhisa , Chiba Koji , Ishioka Junichiro , Noro Akira , Kihara Kazunori
Published: April 2012

Objective:  To examine the actual impact of renal dysfunction on cardiovascular events in Japanese patients undergoing radical nephrectomy for renal cancer.

Methods:  This retrospective study included 178 Japanese patients who underwent radical nephrectomy between 1980 and 2010. Kaplan–Meier survival curves with a log–rank test and the Cox proportional hazards model were used to investigate the impact of the estimated glomerular filtration rate at 1 month after the radical nephrectomy on cardiovascular‐event‐free, cancer‐specific and overall survivals.

Results:  During a median follow up of 68 months, 23 patients experienced cardiovascular events and 32 died. Postoperative renal dysfunction (estimated glomerular filtration rate <45 mL/min/1.73 m2 1 month after radical nephrectomy) was a significant risk factor for postoperative cardiovascular events in addition to age and history of cardiovascular disease. After adjustment for preoperative characteristics, postoperative renal dysfunction increased the risk of cardiovascular events by 3.48‐fold (95% confidence interval 1.28–8.66). For overall and cancer‐specific survivals, postoperative renal dysfunction did not represent an independent risk factor.

Conclusion:  Renal dysfunction has a significant impact on cardiovascular events in patients undergoing radical nephrectomy for renal cancer.
Explaining failure through success: a critical analysis of reduction in road and stroke deaths as an explanation for Australia's low deceased organ donation rates
Authors: Bendorf A. , Kerridge I. H. , Kelly P. J. , Pussell B. , Guasch X.
Published: April 2012

Background/Aim:  During the past two decades, Australian federal and state governments have funded many initiatives to bolster organ donation. Despite large investments of time, effort and money, Australia's deceased donation rate is in the bottom half of the Organisation for Economic Co‐operation and Development countries and has only marginally increased from 11.9 donors per million people (pmp) in 1990 to 14.9 donors pmp in 2011. An often‐cited explanation for this situation is that Australia's success in increasing levels of public health and safety through reduced traffic and stroke fatalities has reduced its number of potential deceased organ donors. We refer to this as the ‘Failure Because of Success’ hypothesis. Although commonly accepted, this hypothesis is largely untested.

Methods:  By analysing data from international donation and transplantation organisations and international public health and safety organisations, we compared historical deceased organ donation rates with traffic and stroke fatality rates in Australia and the seven countries with the world's highest deceased organ donation rates (Spain, Portugal, France, USA, Belgium, Austria and Italy).

Results:  Traffic fatality rates across all countries in the study have fallen dramatically during the time period, with Spain having the lowest traffic fatality rates. Stroke fatality rates demonstrate similar reductions, with France showing the lowest cerebral vascular accident mortality rates.

Conclusion:  When compared with countries with the world's highest deceased donation rates, Australia's improvements to public health and safety through reductions in traffic and stroke fatalities were neither unique nor exemplary and do not provide an adequate explanation for its low organ donor rates.
Single centre experience with pegylated interferon and ribavirin for hepatitis C: looking back before moving forward
Authors: Muller K. , Rodgers A. , Wundke R. , Waddell V. , Altus R. , Gordon D. L. , Wigg A.
Published: April 2012

Background:  Hepatitis C treatment is successful in 40–80% of patients in drug sponsored registration trials. However, few studies have examined treatment outcomes in non‐trial, routine clinical practice settings.

Aim:  The aim of this study was to investigate the treatment outcomes and predictors of a sustained virological response in a routine clinical setting.

Methods:  Data were collected retrospectively on patients treated for hepatitis C between January 2004 and March 2010 in a tertiary hospital setting. Demographics, treatment outcomes and potential predictors of outcome (viral genotype, viral load, virological response, platelet count, alanine transaminase level, glucose, ferritin, weight, fibrosis and cirrhosis, compliance, dose reductions, adverse events, psychiatric and alcohol history) were recorded. Univariate and multiple logistic regressions were performed.

Results:  A total of 405 patients was treated during the study period. On an intention to treat basis, sustained virological response rates were 55%, 82% and 72% in genotypes 1, 2 and 3 respectively. Predictors of response were gender, age, genotype, weight, fibrosis, cirrhosis, platelet count and alanine transaminase on univariate analysis. Age, genotype, cirrhosis and platelet count were independently associated with sustained virological response on multiple logistic regression.

Conclusion:  In our cohort, treatment outcomes for genotype 1 and 2 were similar to results from clinical trials but results for genotype 3 were inferior. Clinicians should not assume that results from registration trials are transferable to their own clinical practice. This has particular relevance for the new era of triple therapy regimens containing direct antivirals.
Strategic control in decision‐making under uncertainty
Authors: Venkatraman Vinod , Huettel Scott A.
Published: April 2012

Complex economic decisions – whether investing money for retirement or purchasing some new electronic gadget – often involve uncertainty about the likely consequences of our choices. Critical for resolving that uncertainty are strategic meta‐decision processes, which allow people to simplify complex decision problems, evaluate outcomes against a variety of contexts, and flexibly match behavior to changes in the environment. In recent years, substantial research has implicated the dorsomedial prefrontal cortex (dmPFC) in the flexible control of behavior. However, nearly all such evidence comes from paradigms involving executive function or response selection, not complex decision‐making. Here, we review evidence that demonstrates that the dmPFC contributes to strategic control in complex decision‐making. This region contains a functional topography such that the posterior dmPFC supports response‐related control, whereas the anterior dmPFC supports strategic control. Activation in the anterior dmPFC signals changes in how a decision problem is represented, which in turn can shape computational processes elsewhere in the brain. Based on these findings, we argue for both generalized contributions of the dmPFC to cognitive control, and specific computational roles for its subregions depending upon the task demands and context. We also contend that these strategic considerations are likely to be critical for decision‐making in other domains, including interpersonal interactions in social settings.
Generalization of value in reinforcement learning by humans
Authors: Wimmer G. Elliott , Daw Nathaniel D. , Shohamy Daphna
Published: April 2012

Research in decision‐making has focused on the role of dopamine and its striatal targets in guiding choices via learned stimulus–reward or stimulus–response associations, behavior that is well described by reinforcement learning theories. However, basic reinforcement learning is relatively limited in scope and does not explain how learning about stimulus regularities or relations may guide decision‐making. A candidate mechanism for this type of learning comes from the domain of memory, which has highlighted a role for the hippocampus in learning of stimulus–stimulus relations, typically dissociated from the role of the striatum in stimulus–response learning. Here, we used functional magnetic resonance imaging and computational model‐based analyses to examine the joint contributions of these mechanisms to reinforcement learning. Humans performed a reinforcement learning task with added relational structure, modeled after tasks used to isolate hippocampal contributions to memory. On each trial participants chose one of four options, but the reward probabilities for pairs of options were correlated across trials. This (uninstructed) relationship between pairs of options potentially enabled an observer to learn about option values based on experience with the other options and to generalize across them. We observed blood oxygen level‐dependent (BOLD) activity related to learning in the striatum and also in the hippocampus. By comparing a basic reinforcement learning model to one augmented to allow feedback to generalize between correlated options, we tested whether choice behavior and BOLD activity were influenced by the opportunity to generalize across correlated options. Although such generalization goes beyond standard computational accounts of reinforcement learning and striatal BOLD, both choices and striatal BOLD activity were better explained by the augmented model. Consistent with the hypothesized role for the hippocampus in this generalization, functional connectivity between the ventral striatum and hippocampus was modulated, across participants, by the ability of the augmented model to capture participants’ choice. Our results thus point toward an interactive model in which striatal reinforcement learning systems may employ relational representations typically associated with the hippocampus.
Instrumental vigour in punishment and reward
Authors: Dayan Peter
Published: April 2012

Recent notions about the vigour of responding in operant conditioning suggest that the long‐run average rate of reward should control the alacrity of action in cases in which the actual cost of speed is balanced against the opportunity cost of sloth. The average reward rate is suggested as being reported by tonic activity in the dopamine system and thereby influencing all actions, including ones that do not themselves lead directly to the rewards. This idea is syntactically problematical for the case of punishment. Here, we broaden the scope of the original suggestion, providing a two‐factor analysis of obviated punishment in a variety of operant circumstances. We also consider the effects of stochastically successful actions, which turn out to differ rather markedly between appetitive and aversive cases. Finally, we study how to fit these ideas into nascent treatments that extend concepts of opponency between dopamine and serotonin from valence to invigoration.
Different dorsal striatum circuits mediate action discrimination and action generalization
Authors: Hilario Mónica , Holloway Terrell , Jin Xin , Costa Rui M.
Published: April 2012

Generalization is an important process that allows animals to extract rules from regularities of past experience and apply them to analogous situations. In particular, the generalization of previously learned actions to novel instruments allows animals to use past experience to act faster and more efficiently in an ever‐changing environment. However, generalization of actions to a dissimilar instrument or situation may also be detrimental. In this study, we investigated the neural bases of action generalization and discrimination in mice trained on a lever‐pressing task. Using specific schedules of reinforcement known to bias animals towards habitual or goal‐directed behaviors, we confirmed that action generalization is more prominent in animals using habitual rather than goal‐directed strategies. We discovered that selective excitotoxic lesions of the dorsolateral and dorsomedial striatum have opposite effects on the generalization of a previously learned action to a novel lever. Whereas lesions of the dorsolateral striatum impair action generalization, dorsomedial striatum lesions affect action discrimination and bias subjects towards action generalization. Importantly, these lesions do not affect the ability of animals to explore or match their lever‐pressing rate to the reinforcement rate, or the ability to distinguish between different levers. The data presented here reveal that dorsolateral and dorsomedial striatal circuits have opposing roles in the generalization of previously learned actions to novel instruments, and suggest that these circuits compete for the expression of generalization in novel situations.
Decision value computation in DLPFC and VMPFC adjusts to the available decision time
Authors: Sokol‐Hessner Peter , Hutcherson Cendri , Hare Todd , Rangel Antonio
Published: April 2012

It is increasingly clear that simple decisions are made by computing decision values for the options under consideration, and then comparing these values to make a choice. Computational models of this process suggest that it involves the accumulation of information over time, but little is known about the temporal course of valuation in the brain. To examine this, we manipulated the available decision time and observed the consequences in the brain and behavioral correlates of choice. Participants were scanned with functional magnetic resonance imaging while they chose to eat or not eat basic food items, in two conditions differing in the amount of time provided for choice. After identifying valuation‐related regions with unbiased whole‐brain general linear models, we analyzed two regions of interest: ventromedial prefrontal cortex (VMPFC) and dorsolateral prefrontal cortex (DLPFC). Finite impulse response models of the upsampled estimated neural activity from those regions allowed us to examine the onset, duration and termination of decision value signals, and to compare across regions. We found evidence for the immediate onset of value computation in both regions, but an extended duration with longer decision time. However, this was not accompanied by behavioral changes in either the accuracy or determinants of choice. Finally, there was modest evidence that DLPFC computation correlated with, but lagged behind, VMPFC computation, suggesting the sharing of information across these regions. These findings have important implications for models of decision value computation and choice.
Is ethnicity associated with morphine’s side effects in children? Morphine pharmacokinetics, analgesic response, and side effects in children having tonsillectomy
Authors: Jimenez Nathalia , Anderson Gail D. , Shen Danny D. , Nielsen Susan S. , Farin Federico M. , Seidel Kristy , Lynn Anne M.
Published: April 2012

Objectives/Aims:  To examine whether morphine pharmacokinetics (PK) and/or genetic polymorphisms in opioid‐related genes, underlie differences in analgesic response and side effects to morphine in Latino (L) vs non‐Latino Caucasian (NL) children.

Background:  Morphine has high interindividual variability in its analgesic response and side effects profile. Earlier studies suggest that morphine response may vary by race and ethnicity.

Methods:  Prospective cohort study in L and NL children, 3–17 years of age comparing pain scores, occurrence of side effects, plasma morphine, morphine‐6‐ and morphine‐3‐glucuronide concentrations measured after a single morphine IV bolus administration. Noncompartmental pharmacokinetic analysis and genotyping for 28 polymorphisms in eight genes (UGT1A8, UGT2B7, ABCB1, COMT, STAT6, MC1R, OPRM1, and ARRB2) were performed.

Results:  We enrolled 68 children (33 L, 35 NL). There were no differences in pain scores or need for rescue analgesia. Statistically significant differences in the occurrence of side effects were documented: While 58% of L children experienced at least one side effect only 20% of NL did (P = 0.001). Pruritus was four times (P = 0.006) and emesis seven times (P = 0.025) more frequent in L compared with NL. PK parameters were similar between groups. None of the assessed polymorphisms mediated the association between ethnicity and side effects.

Conclusions:  We found statistically significant differences in the occurrence of side effects after morphine administration between L and NL children. Neither differences in morphine or metabolite concentrations, nor the genetic polymorphisms examined explain these findings. Studies are needed to further investigate reasons for the increase in morphine side effects by Latino ethnicity.
Treating renal calculi 1–2 cm in diameter with minipercutaneous or retrograde intrarenal surgery: a prospective comparative study
Authors: Sabnis Ravindra B. , Jagtap Jitendra , Mishra Shashikant , Desai Mahesh
Published: April 2012

Study Type – Therapy (pattern of practice survey)

Level of Evidence 2b

What's known on the subject? and What does the study add?

Miniperc and RIRS are commonly used modality for treating non‐bulky renal urolithiasis. Both the treatment options are invasive and are associated with inherent complications. There are only a few studies that compare these two treatment modalities.

Both the modalities are effective to render patient stone free with minimal complications. Immediate stone free rate is higher with miniperc but comparable in both the modalities at 1 month. RIRS is associated with favourable pain scores and lower hemoglobin drop.

OBJECTIVE

To plan a prospective comparative case–control designed study aiming to compare minipercutaneous (miniperc) and retrograde intrarenal surgery (RIRS) for a renal calculus of size 1–2 cm.

PATIENTS AND METHODS

A total of 64 cases (32 in each arm) underwent miniperc and RIRS during the study period from March 2009 to April 2011.

The primary and secondary outcome objective was stone‐free rate and retreatment rate, complications, operation duration, patient visual pain scores, analgesic requirement, haemoglobin drop and hospital stay, respectively.

RESULTS

Miniperc and RIRS had stone clearance rates of 100% and 96.88%, respectively.

In the RIRS group, one patient required retreatment at 1 month.

Hospital stay (0.24) and intra‐operative (0.99) and postoperative complications (0.60) were similar in both groups.

Operation duration (P= 0.003) was lower in the miniperc group.

Haemoglobin drop (P < 0.001), patient pain and visual analogue scale score (each P < 0.001) at 6, 24 and 48 h, as well as analgesic requirement (P < 0.003), were all lower in the RIRS group.

CONCLUSIONS

The stone clearances in both modalities are high and complications are low.

RIRS requires a larger operation duration, although it is associated with favourable pain scores and a lower haemoglobin drop.
High normal HbA1c levels were associated with impaired insulin secretion without escalating insulin resistance in Japanese individuals: the Toranomon Hospital Health Management Center Study 8 (TOPICS 8)
Authors: Heianza Y. , Arase Y. , Fujihara K. , Tsuji H. , Saito K. , Hsieh S. D. , Kodama S. , Shimano H. , Yamada N. , Hara S. , Sone H.
Published: April 2012

Diabet. Med. 29, 1285–1290 (2012)

Aims  We aimed to characterize the association of insulin resistance, impaired insulin secretion and β‐cell dysfunction in relation to HbA1c levels in a non‐diabetic range in Japanese individuals without clinically diagnosed diabetes.

Methods  This cross‐sectional study included 1444 individuals without a history of outpatient treatment of diabetes or use of insulin or oral hypoglycaemic agents. The homeostasis model assessment of insulin resistance and beta‐cell function, insulinogenic index, Matsuda index and disposition index were calculated using data from 75‐g oral glucose tolerance tests and compared across quintile (Q) categories of HbA1c levels.

Results  Fasting plasma glucose and 30‐min and 60‐min plasma glucose (PG) levels were significantly higher when HbA1c exceeded 36 mmol/mol (5.4%). A HbA1c concentration of 36–37 mmol/mol (5.4–5.5%) (Q3) was significantly associated with a 15% lower homeostasis model assessment of β‐cell function value and 31% lower insulinogenic index value compared with HbA1c ≤ 32 mmol/mol (≤ 5.1%) (Q1) (P <0.01). Further, a HbA1c concentration of 38–40 mmol/mol (5.6–5.8%) (Q4) was associated with 17% (P <0.01) and 24% (P <0.05) reductions in those indexes, respectively. However, the homeostasis model assessment of insulin resistance was not significantly elevated and the Matsuda index was not significantly lower unless HbA1c exceeded 41 mmol/mol (5.9%). Individuals with HbA1c ≥ 41 mmol/mol (≥ 5.9%) (Q5) had a 69% lower disposition index than those with a HbA1c concentration of ≤ 32 mmol/mol (≤ 5.1%) (Q1).

Conclusions  Elevated HbA1c levels ≥ 41 mmol/mol (≥ 5.9%) were associated with substantial reductions in insulin secretion, insulin sensitivity and β‐cell dysfunction in Japanese individuals not treated for diabetes. High normal HbA1c levels of 36–40 mmol/mol (5.4–5.8%) were also associated with impaired insulin secretion without marked insulin resistance in Japanese individuals.