bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetics of exenatide
Authors: Cirincione Brenda , Mager Donald E. 
Published: September 2016

AimThe aim of the present analysis was to develop a core population pharmacokinetic model for the pharmacokinetic properties of immediate‐release (IR) exenatide, which can be used in subsequent analyses of novel sustained‐release formulations.MethodsData from eight clinical trials, evaluating a wide range of doses and different administration routes, were available for analysis. All modelling and simulations were conducted using the nonlinear mixed‐effect modelling program NONMEM. External model validation was performed using data from the phase III clinical trials programme through standard visual predictive checks.ResultsThe pharmacokinetics of IR exenatide was described by a two‐compartment model, and the absorption of subcutaneous exenatide was described with a sequential zero‐order rate constant followed by a saturable nonlinear absorption process. Drug elimination was characterized by two parallel routes (linear and nonlinear), with significant relationships between renal function and the linear elimination route, and between body weight and volume of distribution. For a subject with normal renal function, the linear clearance was estimated to be 5.06 l hr−1. The nonlinear elimination was quantified with a Michaelis–Menten constant (Km) of 567 pg ml−1 and a maximum rate of metabolism (Vmax) of 1.6 μg h−1. For subcutaneous administration, 37% of the subcutaneous dose is absorbed via the zero‐order process, and the remaining 63% via the nonlinear pathway.ConclusionsThe present analysis provides a comprehensive population pharmacokinetic model for exenatide, expanding the elimination process to include both linear and nonlinear components, providing a suitable platform for a broad range of concentrations and patient conditions that can be leveraged in future modelling efforts of sustained‐release exenatide formulations.
The effect of renal dysfunction and haemodialysis on circulating liver specific miR‐122
Authors: Rivoli Laura , Vliegenthart A. D. Bastiaan , de Potter Carmelita M. J. , van Bragt Job J. M. H. , Tzoumas Nikolaos , Gallacher Peter , Farrah Tariq E. , Dhaun Neeraj , Dear James W. 
Published: September 2016

AimsmicroRNA‐122 (miR‐122) is a hepatotoxicity biomarker with utility in the management of paracetamol overdose and in drug development. Renal dysfunction and haemodialysis have been associated with a reduction in circulating microRNA. The objective of this study was to determine their effect on miR‐122.MethodsBlood samples were collected from 17 patients with end‐stage renal disease (ESRD) on haemodialysis, 22 healthy controls, 30 patients with chronic kidney disease (CKD) and 15 patients post‐kidney transplantation. All had normal standard liver function tests. Samples from ESRD patients were collected immediately pre‐ and post‐haemodialysis. Serum alanine transaminase activity (ALT), miR‐122 and miR‐885 (liver enriched) were compared.ResultsCirculating miR‐122 was substantially reduced in ESRD patients pre‐haemodialysis compared with the other groups (19.0‐fold lower than healthy controls; 21.7‐fold lower than CKD). Haemodialysis increased miR‐122 from a median value of 6.7 × 103 (2.3 × 103–1.4 × 104) to 1.6 × 104 (5.4 × 103–3.2 × 104) copies ml−1. The increase in miR‐122 did not correlate with dialysis adequacy. miR‐122 was reduced in the argonaute 2 bound fraction pre‐haemodialysis; this fraction was increased post‐dialysis. There was no change in miR‐122 associated with extracellular vesicles. miR‐885 was also reduced in ESRD patients (4‐fold compared to healthy subjects) and increased by haemodialysis.ConclusionmiR‐122 is substantially lower in ESRD compared to healthy controls, patients with CKD and transplanted patients. Haemodialysis increases the concentration of miR‐122. These data need to be considered when interpreting liver injury using miR‐122 in patients with ESRD on dialysis, and specific reference ranges that define normal in this setting may need to be developed.
Anabolic Effect of Insulin Therapy on the Bone: Osteoprotegerin and Osteocalcin Up‐Regulation in Streptozotocin‐Induced Diabetic Rats
Authors: Bortolin Raul Hernandes , Freire Neto Francisco Paulo , Arcaro Carlos Alberto , Bezerra João Felipe , da Silva Flávio Santos , Ururahy Marcela Abbott Galvão , Souza Karla Simone da Costa , Lima Valeria Morgiana Gualberto Duarte Moreira , Luchessi André Ducati , Lima Francisco Pignataro , Lia Fook Marcus Vinicius , da Silva Bartolomeu Jorge , Almeida Maria das Graças , Abreu Bento João , de Rezende Luciana Augusto , de Rezende Adriana Augusto 
Published: September 2016

AbstractType 1 diabetes mellitus (T1DM) is associated with several skeletal alterations, particularly in conditions of poor glycaemic control. Insulin therapy is the major conservative treatment for T1DM; however, the effects of this hormone on bone markers of T1DM rats are limited, and the regulatory mechanisms remain elusive. Therefore, the evaluation of molecular and non‐molecular parameters in a chronic animal model of T1DM‐induced bone loss, treated with and without insulin, may help in elucidating the insulin mechanisms. Male Wistar rats were assigned into three groups: control, T1DM (T1DM rats induced with streptozotocin [STZ] at 40 mg/kg intravenously) and T1DM plus insulin therapy (T1DMI). After 8 weeks, we evaluated the serum biochemical, tibia histomorphometric and biomechanical parameters, as well as the gene expression of the receptor activator of nuclear factor kappa‐B ligand (RANKL), osteoprotegerin (OPG) and osteocalcin (OC) of femur mRNA. Compared with T1DM, the T1DMI group showed less bone loss, which was revealed by the increased trabecular width (TbWi, p < 0.001) and trabecular bone area (BAr, p < 0.01), reduced trabecular separation (TbSp, p < 0.01) and increased Young's modulus (p < 0.05). Moreover, molecular analyses indicated that the expression of OPG and OC was up‐regulated (p < 0.001 and p < 0.05, respectively). In summary, the up‐regulation of OPG and OC in the T1DMI group supports an anabolic effect of insulin, which was demonstrated by the maintenance of bone architecture and flexibility. These results suggest that insulin therapy may prevent T1DM‐induced bone loss via the effects on the bone formation.
The effects of cigarette smoking behavior and psychosis history on general and social cognition in bipolar disorder
Authors: Ospina Luz H , Russo Manuela , Nitzburg George M , Cuesta‐Diaz Armando , Shanahan Megan , Perez‐Rodriguez Mercedes M , Mcgrath Meaghan , Levine Hannah , Mulaimovic Sandra , Burdick Katherine E 
Published: September 2016

ObjectivesSeveral studies have documented the prevalence and effects of cigarette smoking on cognition in psychotic disorders; fewer have focused on bipolar disorder (BD). Cognitive and social dysfunction are common in BD, and the severity of these deficits may be related both to illness features (e.g., current symptoms, psychosis history) and health‐related behaviors (e.g., smoking, alcohol use). The current study assessed the influence of cigarette smoking on general and social cognition in a BD cohort, accounting for illness features with a focus on psychosis history.MethodsWe assessed smoking status in 105 euthymic patients with BD, who completed a comprehensive battery including social (facial affect recognition, emotional problem‐solving, and theory of mind) and general (the MATRICS Consensus Cognitive Battery and executive functioning) cognitive measures. We compared smokers vs nonsmokers on cognitive performance and tested for the effects of psychosis history, premorbid intellectual functioning, substance use, and current affective symptoms.ResultsWithin the nonpsychotic subgroup with BD (n=45), smokers generally outperformed nonsmokers; by contrast, for subjects with BD with a history of psychosis (n=41), nonsmokers outperformed smokers. This pattern was noted more globally using a general composite cognitive score and on social/affective measures assessing patients’ ability to identify emotions of facial stimuli and solve emotional problems.ConclusionsCigarette smoking differentially affects performance on both general and social cognition in patients with BD as a function of psychosis history. These results suggest that there may be at least partially divergent underlying neurobiological causes for cognitive dysfunction in patients with BD with and without psychosis.
Comparative clinical effectiveness of azacitidine versus decitabine in older patients with myelodysplastic syndromes
Authors: Zeidan Amer M. , Davidoff Amy J. , Long Jessica B. , Hu Xin , Wang Rong , Ma Xiaomei , Gross Cary P. , Abel Gregory A. , Huntington Scott F. , Podoltsev Nikolai A. , Hajime Uno , Prebet Thomas , Gore Steven D. 
Published: September 2016

SummaryThe hypomethylating agents (HMAs) azacitidine and decitabine are both approved for treatment of myelodysplastic syndromes (MDS) in the USA. In Europe, decitabine is not approved due to lack of survival advantage in randomized trials. The two drugs have not been compared in clinical trials. We identified patients diagnosed with MDS between 2004 and 2011 from the Surveillance, Epidemiology, and End Results (SEER)‐Medicare linked database in the USA who received ≥ 10 doses of either HMA. We estimated survival from HMA initiation with Kaplan–Meier methods and used multivariate Cox proportional hazards models to adjust for covariates. Analyses controlled for histological subtype and we conducted a subset analysis limited to patients with refractory anaemia with excess blasts (RAEB). In 2025 HMA‐treated patients, median survival was 15 months with no difference in survival based on the HMA received in adjusted analysis (decitabine versus azacitidine, hazard ratio = 1·06, 95% confidence interval: 0·94–1·19, P = 0·37). For RAEB patients (n = 523), median survival was 12 months, with no significant difference based on HMA received. No significant survival difference was found between azacitidine and decitabine in patients with MDS, including RAEB. Importantly, population‐based survival of azacitidine‐treated RAEB patients was substantially shorter than in the AZA‐001 clinical trial (11 versus 24·5 months).
Decreased WNT3 expression in chronic lymphocytic leukaemia is a hallmark of disease progression and identifies patients with worse prognosis in the subgroup with mutated IGHV
Authors: Poppova Lucie , Janovska Pavlina , Plevova Karla , Radova Lenka , Plesingerova Hana , Borsky Marek , Kotaskova Jana , Kantorova Barbara , Hlozkova Michaela , Figulova Jana , Brychtova Yvona , Machalova Michaela , Urik Milan , Doubek Michael , Kozubik Alois , Pospisilova Sarka , Pavlova Sarka , Bryja Vitezslav 
Published: September 2016

SummaryThe canonical Wnt pathway, dependent on β‐catenin‐controlled transcription, is the most explored Wnt pathway, known to drive the malignant transformation of multiple cell types. Several reports have suggested that this pathway also participates in chronic lymphocytic leukaemia (CLL) pathogenesis. To get a better insight into the role of the Wnt/β‐catenin pathway in CLL we analysed in detail the expression of the most overexpressed Wnt ligand, encoded by the WNT3 gene, in a well‐defined cohort of 137 CLL patients. Our analysis demonstrated that (i) untreated patients with more aggressive disease (with a notable exception of patients with 11q deletion) express less WNT3, (ii) WNT3 declines with disease progression in a significant proportion of patients and (iii) low WNT3 was identified as a strong independent marker indicating shorter treatment‐free survival in CLL patients with IGHV mutation. Interestingly, CLL‐related lymphoid cell lines, but not stromal cells, failed to respond to the ligand‐induced activation of the Wnt/β‐catenin pathway. This opens the possibility that CLL cells use Wnt‐3 to communicate with the cells in the microenvironment. We thus propose that the Wnt/β‐catenin pathway plays a more complex role in CLL pathogenesis than previously anticipated.
Rates and risk factors of hypertension in adolescents and adults with sickle cell anaemia in Tanzania: 10 years’ experience
Authors: Makubi Abel , Mmbando Bruno P. , Novelli Enrico M. , Lwakatare Johnson , Soka Deogratius , Marik Harvest , Tibarazwa Kemi , Ngaeje Mariam , Newton Charles R. , Gladwin Mark T. , Makani Julie 
Published: September 2016

SummaryData on the magnitude and risk factors for hypertension in sickle cell anaemia (SCA) are limited. A retrospective analysis of individuals with SCA aged ≥15 years enrolled from 2004–2014 at Muhimbili National Hospital, Tanzania was conducted to determine the prevalence, incidence and risk factors for hypertension. A total of 1013 individuals with SCA were analysed, of whom 571(56%) were females. The median age [interquartile range] was 17 [15–22] years. Four hundred and forty‐one (44%) of the patients had relative hypertension [systolic blood pressure (SBP) 120–139 mmHg or diastolic blood pressure (DBP) 70–89 mmHg], and 79 (8%) had hypertension (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg). The incidence of hypertension was 64/1000 person years of observation and the 5‐year survival rate was 0·71 [95% confidence interval (CI): 0·67–0·75]. In multivariate analysis, age>18 years, Hazard ratio (HR) 1·50 (95% CI: 1·03–2·18); pulse pressure, HR 0·64 (95% CI: 0·42 to 0·98); pulse rate, 1·02 (95% CI: 1·01–1·03); body mass index (BMI), HR 1·08 (95% CI: 1·03–1·13); blood transfusion, HR 2·50 (95% CI: 1·01–6·21) and haemoglobin, HR 1·12 (95% CI: 1·05–1·33) were independently associated with hypertension. In conclusion, despite the younger age, hypertension in this population was higher than that reported in others studies. Age, BMI, pulse pressure and haemoglobin were independently associated with hypertension in SCA.
99mTc‐anti‐epidermal growth factor receptor nanobody for tumor imaging
Authors: Piramoon Majid , Hosseinimehr Seyed Jalal , Omidfar Kobra , Noaparast Zohreh , Abedi Seyed Mohammad 
Published: September 2016

Nanobodies are important biomolecules for tumor targeting. In this study, we synthesized and labeled anti‐epidermal growth factor receptor (EGFR) nanobody OA‐cb6 with 99mTc(CO)3+ and evaluated its characteristics for targeting the EGFR in the A431 human epidermal carcinoma cell line. Nanobody radiolabeling was achieved with high yield and radiochemical purity, and the radioconjugate was stable. Biodistribution results in nude mice exhibited a favorable tumor‐to‐muscle ratio at 4‐hr postinjection, and tumor location was visualized at 4 hr after injection of radiolabeled nanobody. Our result showed that the OA‐cb6‐99mTc‐tricarbonyl radiolabeled nanobody is a promising radiolabeled biomolecule for tumor imaging in cancers with high EGFR overexpression.
The impact of smoking on marginal bone loss in a 10‐year prospective longitudinal study
Authors: Bahrami Golnosh , Væth Michael , Kirkevang Lise‐Lotte , Wenzel Ann , Isidor Flemming 
Published: September 2016

AbstractObjectivesThe aim of this epidemiologic study was to determine the impact of smoking on marginal bone loss in a subsample derived from an original randomly selected adult sample, after adjusting for oral and general factors.MethodsThe number of participants at baseline in this 10‐year longitudinal study was 616 (mean age: 42 years, range 21–63 years). The participants underwent a full‐mouth radiographic survey. After recall in 2003, 473 (77%) of the participants accepted and completed an identical survey. In 2008, the survey was repeated, and 301 (48.9%) individuals were included in this study. The marginal bone level of each tooth was measured in mm. Age, gender, smoking habits, number of teeth, apical periodontitis, crowns and initial marginal bone level were also recorded for each individual. Only individuals who did not report a change in smoking habits during the 10‐year period were included in the study. Multiple regression analyses were used to evaluate crude and adjusted associations between smoking and marginal bone loss.ResultsAt the first, radiographic survey smokers had a statistically significantly more reduced marginal bone level (in average 0.9 mm) than nonsmokers. After 10 years, a progression of a mean marginal bone loss of > 2 mm was statistically significantly more common in smokers than in nonsmokers (7.1% and 0%, respectively). Furthermore, a marginal bone loss of 1–2 mm was observed in 29% of the smokers and 19% of the nonsmokers, and ≤ 1 mm marginal bone loss was found in 69% of smokers and 81% of nonsmokers. Even after adjusting for initial marginal bone level, gender, age, and also presence of apical periodontitis and crowns, the difference in progression of marginal bone loss was still statistically higher in smokers (on average 0.36 mm).ConclusionsThe smokers started out with a more reduced marginal bone level than nonsmokers. However, even after adjusting for the initial marginal bone level, the progression of marginal bone loss in smokers was more pronounced than in nonsmokers. This shows that smoking is a factor with significant impact on the marginal bone level and can be assumed to be a true risk factor for marginal bone loss.
Total thyroidectomy: a clue to understanding the metabolic changes induced by subclinical hyperthyroidism?
Authors: Bel Lassen Pierre , Kyrilli Aglaia , Lytrivi Maria , Ruiz Patino Maria , Corvilain Bernard 
Published: September 2016

SummaryObjectiveThe effects of endogenous subclinical hyperthyroidism (eSCH) on heart and bone have been well documented. There are only limited data available regarding the impact of eSCH on weight regulation and lipid metabolism. Our aim was to evaluate the changes in body weight and metabolic parameters after total thyroidectomy in patients with pre‐operative eSCH compared with pre‐operative patients with euthyroid (EUT).DesignA retrospective study of 505 patients who underwent total thyroidectomy for benign multinodular goitre in an academic hospital in Brussels (Belgium) was performed.Patient's MeasurementsTwo hundred and 25 patients were included (eSCH group: n = 74; EUT group: n = 151). The mean follow‐up time was 26·1 ± 0·8 months and was similar in both groups.ResultsAbsolute BMI gain was significantly greater in the eSCH group than in the EUT group (1·11 ± 0·17 vs 0·33 ± 0·13 kg/m2; P = 0·003). A significant increase in LDL cholesterol was observed in the eSCH group (16·1 ± 3·8 mg/dl; P < 0·001) but not in the EUT group (0·0 ± 3·0 mg/dl; P = 0·88). In a multivariate model, pre‐operative TSH levels were the main factor significantly associated with increases in BMI or LDL cholesterol. Post‐operative median TSH levels and L‐thyroxine substitution were similar in both groups.ConclusionAfter total thyroidectomy, increases in weight and serum cholesterol were observed in the eSCH group. Given that post‐operative TSH levels were similar in the two groups, these observations are probably due to the correction of eSCH, suggesting a direct effect of eSCH on body weight regulation and lipid metabolism.
Effect of sham feeding with gum chewing on postoperative ileus after liver transplantation—a randomized controlled trial
Authors: Lee Hannah , Cho Chan Woo , Yoon Susie , Suh Kyung‐Suk , Ryu Ho Geol 
Published: September 2016

AbstractPostoperative ileus (POI) is a common complication after major abdominal surgery. Gum chewing has been shown to stimulate bowel motility and decrease duration of POI after abdominal surgery. We evaluated the effect of gum chewing in reducing the time to first flatus and on oral calorie intake in patients undergoing living or deceased donor liver transplantation. Patients were randomized into the sham feeding group or the control group. The sham feeding group chewed two pieces of xylitol flavored gum for 15 minutes, three times a day after extubation until oral nutrition was tolerated. The control group received the same routine care except for the gum chewing. Fifty‐nine patients were randomized into the sham feeding group (n=30) or the control group (n=29). There was no difference in the time to first flatus (72 [66.1‐82.9] hours vs 69.0 [57.6‐77.2] hours, P=.422). Cumulative energy intake (2.8 [5.8‐23.2] % vs 10.0 [8.5‐15.9] %, P=.695) and length of intensive care unit stay (4.2 [3.9‐5.3] days vs 4.0 [6.7‐4.5] days, P=.077) were also similar. In conclusion, sham feeding with gum chewing did not shorten the duration of POI nor facilitate oral intake after liver transplantation. (Clinicaltrials.gov number: NCT 01956643).
Cytology training in the UK: a training centre prospective
Authors: Dudding N. 
Published: September 2016

AbstractTraining in both cervical and non‐gynaecological cytology in the UK has never faced a more challenging environment. A national reconfiguration of cervical cytology services has focussed resources on large centres and damaged the traditional links and overlapping roles within non‐gynaecological cytology. The UK is now at significant risk of falling behind most European countries in the use of non‐gynaecological cytology. The UK currently has five training centres which are approved by the NHS Screening programme for training in cervical cytology; the planned introduction of HPV primary screening and the subsequent dramatic reduction in cervical cytology workload will increase pressure on the remaining training schools. Funding is variable across the country as is the degree of diversification that training schools have undertaken to try to ensure a viable future. It is vital for the future of cytology in the UK that the strong network of training schools remain to ensure the quality of the laboratory service as the UK moves towards HrHPV primary screening. There is no doubt that the training school roles will change and new technology embraced to deliver training fit for the changing role of cytology in healthcare but this will require funding and recognition of the vital role the training centres play in the delivery of high quality training in both cervical and non‐gynaecological cytology.
Stages of Supply Chain Disruption Response: Direct, Constraining, and Mediating Factors for Impact Mitigation
Authors: Bode Christoph , Macdonald John R. 
Published: September 2016

ABSTRACTIt is well established that supply chain disruptions can have a severe negative impact on firms and general wisdom suggests that this impact can be mitigated by quick responses. Aside from a few anecdotes, however, little is known about the decision‐making process that leads to speedy responses and about its impeding and supporting antecedents. Using the organizational information‐processing perspective, this empirical study unravels the disruption management process along a sequence of four stages—disruption recognition, disruption diagnosis, response development, and response implementation—and hypothesizes constraining and mediating effects of these stages. The findings contribute to an improved understanding of the role that the decision stages play in mitigating supply chain disruptions, and confirm the prediction that the speed with which information is processed and the stages are worked through positively affects supply chain performance. In addition, the findings suggest that one of the stages, diagnosis, acts as a constraining factor to the other stages. The stages also play a mediating role between the impact that the disruption has and a firm's readiness (prior to a disruption), dependence on a key supplier, and supply chain complexity. This provides guidance to decision makers in the application of resources both prior to a negative event and during a disruption recovery.