bluuebunny/crossref_metadata_2025 huggingface dataset:
Formation of the prismatic layer in the freshwater bivalveHyriopsis cumingii: the feedback of crystal growth on organic matrix
Authors: Liu Xiaojun , Li Jiale
Published: October 2013

The squeezing hypothesis and the organic frameworks preformation hypothesis propose two different mechanisms to explain the interaction between organic frameworks and crystals during biomineralization of the prismatic layer of the mollusk shell. In this study, we began to studyHyriopsis cumingiishell formation and discover that this species seemed to follow the squeezing hypothesis. During the formation of the aragonite prismatic layer in the freshwater bivalveH. cumingii, we found that crystal growth was involved in controlling initiation of formation of the interprismatic organic membranes. First, newly formed crystals were embedded in the periostracum. Next, the interprismatic organic membranes of the prismatic layer were produced via squeezing between neighboring crystals. The organic matrix secreted by the mantle continuously self‐assembled into the interprismatic organic membranes as the crystals grew. In the mature stage, the interprismatic organic membranes were shaped by crystal growth. These findings provide evidence to support the squeezing hypothesis and add to the existing knowledge about interactions that occur at the organic–inorganic interfaces during mollusk shell biomineralization.
Effectiveness of pharmaceutical care for patients with chronic obstructive pulmonary disease (PHARMACOP): a randomized controlled trial
Authors: Tommelein Eline , Mehuys Els , Van Hees Thierry , Adriaens Els , Van Bortel Luc , Christiaens Thierry , Van Tongelen Inge , Remon Jean‐Paul , Boussery Koen , Brusselle Guy
Published: October 2013

Aims

Few well‐designed randomized controlled trials have been conducted regarding the impact of community pharmacist interventions on pharmacotherapeutic monitoring of patients with chronic obstructive pulmonary disease (COPD). We assessed the effectiveness of a pharmaceutical care programme for patients with COPD.

Methods

The pharmaceutical care for patients with COPD (PHARMACOP) trial is a single‐blind 3 month randomized controlled trial, conducted in 170 community pharmacies in Belgium, enrolling patients prescribed daily COPD medication, aged ≥50 years and with a smoking history of ≥10 pack‐years. A computer‐generated randomization sequence allocated patients to an intervention group (n = 371), receiving protocol‐defined pharmacist care, or a control group (n = 363), receiving usual pharmacist care (1:1 ratio, stratified by centre). Interventions focusing on inhalation technique and adherence to maintenance therapy were carried out at start of the trial and at 1 month follow‐up. Primary outcomes were inhalation technique and medication adherence. Secondary outcomes were exacerbation rate, dyspnoea, COPD‐specific and generic health status and smoking behaviour.

Results

From December 2010 to April 2011, 734 patients were enrolled. Forty‐two patients (5.7%) were lost to follow‐up. At the end of the trial, inhalation score [mean estimated difference (Δ),13.5%; 95% confidence interval (CI), 10.8–16.1; P < 0.0001] and medication adherence (Δ, 8.51%; 95% CI, 4.63–12.4; P < 0.0001) were significantly higher in the intervention group compared with the control group. In the intervention group, a significantly lower hospitalization rate was observed (9 vs. 35; rate ratio, 0.28; 95% CI, 0.12–0.64; P = 0.003). No other significant between‐group differences were observed.

Conclusions

Pragmatic pharmacist care programmes improve the pharmacotherapeutic regimen in patients with COPD and could reduce hospitalization rates.
Pharmacological strategies for detoxification
Authors: Diaper Alison M. , Law Fergus D. , Melichar Jan K.
Published: October 2013

Detoxification refers to the safe discontinuation from a substance of dependence and is distinct from relapse prevention. Detoxification usually takes between a few days and a few weeks to complete, depending on the substance being misused, the severity of dependence and the support available to the user. Psychosocial therapies alongside pharmacological treatments are essential to improve outcome. The dependencies considered in this overview are detoxification from opioids (with methadone, buprenorphine, α2‐adrenoceptor agonists and adjunct medications), alcohol (with benzodiazepines, anti‐glutamatergics and γ‐aminobutyric acid (GABA)‐ergic drugs), stimulants and cannabis (with no clear recommended pharmacological treatments), benzodiazepines (with dose tapering) and nicotine (with nicotine replacement therapy, antidepressants and partial agonists). Evidence is limited by a lack of controlled trials robust enough for review bodies, and more research is required into optimal treatment doses and regimes, alone and in combination.
A model‐based approach for the evaluation of once daily dosing of lamivudine in HIV‐infected children
Authors: Piana Chiara , Zhao Wei , Adkison Kimberly , Burger David , Jacqz‐Aigrain Evelyne , Danhof Meindert , Della Pasqua Oscar
Published: October 2013

Aim

Little attention has been paid to the effects of compliance and prescription practice on treatment outcome in HIV‐infected children. In this context, an evaluation of the role of covariates on pharmacokinetics is required to establish the impact of differences in dosing regimens. Here we investigate whether a once daily dosing regimen of lamivudine provides comparable exposure to the currently approved paediatric regimen.

Methods

A hypothetical group of 180 patients between 3 months and 12 years old was used to evaluate the impact of body weight on systemic exposure to lamivudine. Simulation scenarios were evaluated using AUC and Cmax as parameters of interest. The analysis was performed using a population pharmacokinetic model previously implemented in nonmem v.6.2.

Results

The simulations show that once daily dosing of lamivudine yields comparable exposure to historical values observed in children and adults, both for liquid and solid dosage forms. Simulated steady‐state AUC(0–24 h) and Cmax values after once daily doses ranged respectively from 9.95 mg l−1 h and 1.9 mg l−1 for children lighter than 14 kg to 13.75 mg l−1 h and 3.0 mg l−1 for children heavier than 30 kg. These values are comparable or higher than historical values observed after once daily dosing in children and adults.

Conclusions

Our findings illustrate how dosing regimens can be evaluated taking into account the effects of developmental growth on drug disposition. Most importantly, they suggest that the reduction in dosing frequency to once daily leads to comparable lamivudine exposure, as observed after administration of a twice daily dosing regimen.
Relationship between plasma, atrial and ventricular perhexiline concentrations in humans: insights into factors affecting myocardial uptake
Authors: Drury Nigel E. , Licari Giovanni , Chong Cher‐Rin , Howell Neil J. , Frenneaux Michael P. , Horowitz John D. , Pagano Domenico , Sallustio Benedetta C.
Published: October 2013

Aim

Little is known regarding the steady‐state uptake of drugs into the human myocardium. Perhexiline is a prophylactic anti‐anginal drug which is increasingly also used in the treatment of heart failure and hypertrophic cardiomyopathy. We explored the relationship between plasma perhexiline concentrations and its uptake into the myocardium.

Methods

Blood, right atrium ± left ventricle biopsies were obtained from patients treated with perhexiline for a median of 8.5 days before undergoing coronary surgery in the perhexiline arm of a randomized controlled trial. Perhexiline concentrations in plasma and heart tissue were determined by HPLC.

Results

Atrial biopsies were obtained from 94 patients and ventricular biopsies from 28 patients. The median plasma perhexiline concentration was within the therapeutic range at 0.24 mg l−1 (IQR 0.12–0.44), the median atrial concentration was 6.02 mg kg–1 (IQR 2.70–9.06) and median ventricular concentration was 10.0 mg kg–1 (IQR 5.76–13.1). Atrial (r2 = 0.76) and ventricular (r2 = 0.73) perhexiline concentrations were closely and directly correlated with plasma concentrations (both P < 0.001). The median atrial : plasma ratio was 21.5 (IQR 18.1–27.1), ventricular : plasma ratio was 34.9 (IQR 24.5–55.2) and ventricular : atrial ratio was 1.67 (IQR 1.39–2.22). Using multiple regression, the best model for predicting steady‐state atrial concentration included plasma perhexiline, heart rate and age (r2 = 0.83). Ventricular concentrations were directly correlated with plasma perhexiline concentration and length of therapy (r2 = 0.84).

Conclusions

This study demonstrates that plasma perhexiline concentrations are predictive of myocardial drug concentrations, a major determinant of drug effect. However, net myocardial perhexiline uptake is significantly modulated by patient age, potentially via alteration of myocardial:extracardiac drug uptake.
Cumulative Mitoxantrone‐Induced Haematological and Hepatic Adverse Effects in a Subchronic In vivo Study
Authors: Rossato Luciana G. , Costa Vera M. , Dallegrave Eliane , Arbo Marcelo , Dinis‐Oliveira Ricardo J. , Santos‐Silva Alice , Duarte José A. , de Lourdes Bastos Maria , Palmeira Carlos , Remião Fernando
Published: October 2013

Mitoxantrone (MTX) is an antineoplastic agent that can induce hepato‐ and haematotoxicity. This work aimed to investigate the occurrence of cumulative early and late MTX‐induced hepatic and haematological disturbances in an vivo model. A control group and two groups treated with three cycles of 2.5 mg/kg MTX at days 0, 10 and 20 were formed. One of the treated groups suffered euthanasia on day 22 (MTX22) to evaluate early MTX toxic effects, while the other suffered euthanasia on day 48 (MTX48), to allow the evaluation of MTX late effects. An early immunosuppression with a drop in the IgG levels was observed, causing a slight decrease in the plasma total protein content. The early bone marrow depression was followed by signs of recovery in MTX48. The genotoxic potential of MTX was demonstrated by the presence of several micronuclei in MTX22 leucocytes. Increases in plasma iron and cholesterol levels in the MTX22 rats were observed, while in both groups increases in the unconjugated bilirubin, C4 complement, and decreases in the triglycerides, alanine aminotransferase, alkaline phosphatase and transferrin were found in plasma samples. On MTX 48, the liver histology showed more hepatotoxic signs, the hepatic levels of reduced and oxidized glutathione were increased, and ATP hepatic levels were decreased. However, the hepatic total protein levels were decreased only in the livers of MTX22 group. Results demonstrated the MTX genotoxic effects, haemato‐ and direct hepatotoxicity. While the haematological toxicity is ameliorated with time, the same was not observed in the hepatic injury.
Nilotinib Interferes with the Signalling Pathways Implicated in Acetaminophen Hepatotoxicity
Authors: Shaker Mohamed E.
Published: October 2013

Nilotinib, a second‐generation tyrosine kinase inhibitor, has been recently approved for the treatment for chronic myeloid leukaemia. The objective of this study was to explore the potential effects of clinically relevant doses of nilotinib against acetaminophen (APAP)‐induced hepatotoxicity in mice. To simulate the clinical application in human beings, nilotinib (25 and 50 mg/kg) was administered to mice 2 hr after APAP intoxication (500 mg/kg). The results indicated that nilotinib (25 mg/kg) (i) abolished APAP‐induced liver injury and necro‐inflammation, (ii) increased hepatic‐reduced glutathione (GSH) and its related enzymes synthesis, (iii) suppressed hepatic oxidative/nitrosative stress cascades, (iv) decreased neutrophil accumulation in the liver, and (v) prevented the over‐expression of B‐cell lymphoma‐2 (bcl‐2), cyclin‐D1 and stem cell factor receptor (c‐Kit) proteins in the liver. Although nilotinib (50 mg/kg) acted through the same mechanisms, there was severe depletion in hepatic GSH content by nilotinib itself at that dose level, rather than the potent stimulation observed by using a dose of 25 mg/kg. Consequently, the mortality rate after 18 hr was 100% for nilotinib (50 mg/kg) + APAP (750 mg/kg) versus 60% for APAP (750 mg/kg) and 40% for nilotinib (25 mg/kg) + APAP (750 mg/kg) in the survival analysis experiment. In conclusion, nilotinib can counteract the hepatotoxicity produced by a non‐lethal dose of APAP. However, there is a risk of aggravating the mortality for a lethal dose of APAP when nilotinib is co‐administered at doses relatively high, or near to the clinical range because of hepatic GSH depletion and c‐kit inhibition.
Microdialysis as a Tool for Drug Quantification in the Bronchioles of Anaesthetized Pigs
Authors: Rottbøll Lisa A. H. , Friis Christian
Published: October 2013

Target site drug determinations are crucial for optimizing treatment of infectious diseases. There is limited knowledge of antibiotic drug penetration into the pulmonary epithelial lining fluid (PELF) and a lack of easily performed methods for continuous drug sampling hereof. The aim of this study was to develop a readily accessible microdialysis (MD) method for antibiotic drug quantification inPELFof pigs. The fluoroquinolone danofloxacin was administered to anaesthetized pigs allocated to three groups: intravenous injection, intravenous infusion and intramuscular injection.MDprobes were guided through a tracheostomy into the distal bronchioles using an insertion tube. Intravenously administered inulin served as a marker of extracellular fluid contamination ofPELF. Concentrations of free drug inMDfractions were compared to total and non‐protein‐bound drug concentrations in plasma. Rising and declining danofloxacin plasma concentrations were rapidly reflected inPELF, suggesting an efficient drug transport across the blood bronchial barrier. TheAUCFREE DRUG PELF/AUCFREE DRUG PLASMAratio was 1.8 (S.D. 0.4, 95%CL1.4–2.3). Although the probes were placed without fiberscopic or other special equipment, the danofloxacin concentrations inPELFwere consistent within the different administration groups. The describedMDmethod for drug quantification inPELFis easily accessible and provides repeatable results. However, trace amount of inulin was detected in theMDfractions, suggesting a local tissue reaction induced by theMDmembrane. The significance of this finding needs to be clarified in future studies.
Antiproliferative Activity of King Cobra (Ophiophagus hannah) Venom l‐Amino Acid Oxidase
Authors: Li Lee Mui , Chung Ivy , Yee Fung Shin , Kanthimathi M.S. , Hong Tan Nget
Published: October 2013

King cobra (Ophiophagus hannah) venom l‐amino acid oxidase (LAAO), a heat‐stable enzyme, is an extremely potent antiproliferative agent against cancer cells when compared with LAAO isolated from other snake venoms. King cobra venom LAAO was shown to exhibit very strong antiproliferative activities against MCF‐7 (human breast adenocarcinoma) and A549 (human lung adenocarcinoma) cells, with an IC50 value of 0.04 ± 0.00 and 0.05 ± 0.00 μg/mL, respectively, after 72‐hr treatment. In comparison, its cytotoxicity was about 3–4 times lower when tested against human non‐tumourigenic breast (184B5) and lung (NL 20) cells, suggesting selective antitumour activity. Furthermore, its potency in MCF‐7 and A549 cell lines was greater than the effects of doxorubicin, a clinically established cancer chemotherapeutic agent, which showed an IC50 value of 0.18 ± 0.03 and 0.63 ± 0.21 μg/mL, respectively, against the two cell lines. The selective cytotoxic action of the LAAO was confirmed by phycoerythrin (PE) annexin V/7‐amino‐actinomycin (AAD) apoptotic assay, in which a significant increase in apoptotic cells was observed in LAAO‐treated tumour cells than in their non‐tumourigenic counterparts. The ability of LAAO to induce apoptosis in tumour cells was further demonstrated using caspase‐3/7 and DNA fragmentation assays. We also determined that this enzyme may target oxidative stress in its killing of tumour cells, as its cytotoxicity was significantly reduced in the presence of catalase (a H2O2 scavenger). In view of its heat stability and selective and potent cytotoxic action on cancer cells, king cobra venom LAAO can be potentially developed for treating solid tumours.
Am I My Profession's Keeper?
Authors: Kolers Avery
Published: October 2013

Conscientious refusal is distinguished by its peculiar attitude towards the obligations that the objector refuses: the objector accepts the authority of the institution in general, but claims a right of conscience to refuse some particular directive. An adequate ethics of conscientious objection will, then, require an account of the institutional obligations that the objector claims a right to refuse. Yet such an account must avoid two extremes: ‘anarchism,’ where obligations apply only insofar as they match individual conscience; and ‘totalitarianism,’ where even immoral obligations bind us. The challenge is to explain institutional obligations in such a way that an agent can be obligated to act against conscience, yet can object if the institution's orders go too far. Standard accounts of institutional obligations rely on individual autonomy, expressed through consent. This paper rejects the Consent model; a better understanding of institutional obligations emerges from reflecting on the intersecting goods produced by institutions and the intersecting autonomy of numerous distinct agents rather than only one. The paper defends ‘Professionalism’ as a grounding of professional obligations. The professional context can justify acting against conscience but more often that context partly shapes the professional conscience. Yet Professionalism avoids totalitarianism by distinguishing between (mere) injustice and abuse. When institutions are – or we conscientiously believe them to be – merely unjust, their directives still obligate us; when they are abusive, however, they do not. Finally, the paper applies these results to the problem of conscientious refusal in general and specifically to controversial reproduction cases.
Welcome to the Wild, Wild North: Conscientious Objection Policies Governing Canada's Medical, Nursing, Pharmacy, and Dental Professions
Authors: Shaw Jacquelyn , Downie Jocelyn
Published: October 2013

In Canada, as in many developed countries, healthcare conscientious objection is growing in visibility, if not in incidence. Yet the country's health professional policies on conscientious objection are in disarray. The article reports the results of a comprehensive review of policies relevant to conscientious objection for four Canadian health professions: medicine, nursing, pharmacy and dentistry. Where relevant policies exist in many Canadian provinces, there is much controversy and potential for confusion, due to policy inconsistencies and terminological vagueness. Meanwhile, in Canada's three most northerly territories with significant Aboriginal populations, whose already precarious health is influenced by funding and practitioner shortages, there are major policy gaps applicable to conscientious objection. In many parts of the country, as a result of health professionals' conscientious refusals, access to some legal health services – including but not limited to reproductive health services such as abortion – has been seriously impeded. Although policy reform on conscientious conflicts may be difficult, and may generate strenuous opposition from some professional groups, for the sake of both patients and providers, such policy change must become an urgent priority.
Conscientious Refusal and Health Professionals: Does Religion Make a Difference?
Authors: Weinstock Daniel
Published: October 2013

Freedom of Conscience and Freedom of Religion should be taken to protect two distinct sets of moral considerations. The former protects the ability of the agent to reflect critically upon the moral and political issues that arise in her society generally, and in her professional life more specifically. The latter protects the individual's ability to achieve secure membership in a set of practices and rituals that have as a moral function to inscribe her life in a temporally extended narrative. Once these grounds are distinguished, it becomes more difficult to grant healthcare professionals' claims to religious exemptions on the basis of the latter than it is on the basis of the former. While both sets of considerations generate ‘internal reasons’ for rights to accommodation, the relevant ‘external’ reasons present in the case of claims of moral conscience do not possess analogues in the case of claims of religious conscience. However, the argument applies only to ‘irreducibly religious’ claims, that is to claims that cannot be translated into moral vocabulary. What's more, there may be reasons to grant the claims of religious persons to exemptions that have to do not with the nature of the claims, but with the beneficial effects that the presence of religious persons may have in the context of the healthcare institutions of multi‐faith societies.
Two-Stage Hierarchical Group Testing for Multiple Infections with Application to the Infertility Prevention Project
Authors: Tebbs Joshua M. , McMahan Christopher S. , Bilder Christopher R.
Published: October 2013

Screening for sexually transmitted diseases (STDs) has benefited greatly from the use of group testing (pooled testing) to lower costs. With the development of assays that detect multiple infections, screening practices now involve testing pools of individuals for multiple infections simultaneously. Building on the research for single infection group testing procedures, we examine the performance of group testing for multiple infections. Our work is motivated by chlamydia and gonorrhea testing for the infertility prevention project (IPP), a national program in the United States. We consider a two-stage pooling algorithm currently used to perform testing for the IPP. We first derive the operating characteristics of this algorithm for classification purposes (e.g., expected number of tests, misclassification probabilities, etc.) and identify pool sizes that minimize the expected number of tests. We then develop an expectation–maximization (EM) algorithm to estimate probabilities of infection using both group and individual retest responses. Our research shows that group testing can offer large cost savings when classifying individuals for multiple infections and can provide prevalence estimates that are actually more efficient than those from individual testing.
Hybrid Pairwise Likelihood Analysis of Animal Behavior Experiments
Authors: Cattelan Manuela , Varin Cristiano
Published: October 2013

The study of the determinants of fights between animals is an important issue in understanding animal behavior. For this purpose, tournament experiments among a set of animals are often used by zoologists. The results of these tournament experiments are naturally analyzed by paired comparison models. Proper statistical analysis of these models is complicated by the presence of dependence between the outcomes of fights because the same animal is involved in different contests. This paper discusses two different model specifications to account for between-fights dependence. Models are fitted through the hybrid pairwise likelihood method that iterates between optimal estimating equations for the regression parameters and pairwise likelihood inference for the association parameters. This approach requires the specification of means and covariances only. For this reason, the method can be applied also when the computation of the joint distribution is difficult or inconvenient. The proposed methodology is investigated by simulation studies and applied to real data about adult male Cape Dwarf Chameleons.
Early changes, attrition, and dose–response in low intensity psychological interventions
Authors: Delgadillo Jaime , McMillan Dean , Lucock Mike , Leach Chris , Ali Shehzad , Gilbody Simon
Published: October 2013

Objectives

To investigate if early symptom changes in brief low intensity psychological interventions (guided self‐help and psycho‐education using cognitive behavioural therapy principles) are predictive of final treatment outcome.

Design

Retrospective cohort data analysis.

Method

Clinical records for 1,850 patients who screened positive for depression and/or an anxiety disorder were analysed. Reliable and clinically significant improvement (RCSI) on depression (Patient Health Questionnaire‐9: PHQ‐9) or anxiety (generalized anxiety disorder‐7: GAD‐7) outcome measures after treatment was the primary outcome. Change scores ≥6 on PHQ‐9 and ≥5 on GAD‐7 were taken as indicative of reliable improvement (RI). The model assumed that RI in the earliest treatment sessions would be predictive of RCSI post‐treatment. Predictive accuracy was assessed by calculating the area under the curve (AUC), as well as positive and negative predictive values. Diagnostic odds ratios were also estimated, adjusting for confounders such as baseline severity, use of medication, and pre‐treatment symptom change.

Results

The AUC estimates for session‐to‐session change scores ranged between .62 and .88, indicative of modest to high predictive reliability. Predictive accuracy was higher for patients who had four or more treatment sessions, with more than 70% of patients with RCSI being accurately identified as early as sessions 1–3. Attrition rates were significantly associated with poor outcomes. Results suggest that at least four therapy sessions are necessary to achieve more than 50% RCSI rates, and the dose–response effect appears to decline in treatments longer than six sessions.

Conclusions

Patients showing RI early in treatment were at least twice as likely to fully recover compared to those without early RI.

Practitioner points

Patients showing early response to low intensity therapy are at least twice as likely to recover at the end of treatment.

Dropout from treatment is associated with poor clinical outcomes.

Optimal recovery rates were observed for treatments with a total length of between four and six sessions; the dose–response declined in lengthier treatments.

Randomization to different treatment lengths is necessary to confirm this dose–response effect with greater certainty.
A person‐centred analysis of teacher–child relationships in early childhood
Authors: Hughes Kathleen , Bullock Amanda , Coplan Robert J.
Published: October 2013

Background

Previously, the nature of teacher–child relationships (TCRs) has been explored through dimensions of close, conflicted, and dependent. However, this variable‐centred approach is limited, as many relationships can be characterized by more than one characteristic or trait. A person‐centred approach would allow for a greater understanding of the types of relationships that are formed and improved interpretation of the students' socio‐emotional outcomes associated with that relationship.

Aims

The primary goal of this study was to examine the socio‐emotional functioning of young children who formed distinct types of TCRs.

Sample

Participants were n = 202 kindergarten children (98 girls, 104 boys, Mage = 64.12 months, SD = 4.86).

Method

Multi‐source assessment was employed with data collected from parent ratings, teacher reports, child interviews, and naturalistic observations in the classroom. Using quartile cut‐offs, we identified children who formed conflicted, dependent, and ‘combined’ (conflicted and dependent) TCRs.

Results

Results indicated distinct patterns of socio‐emotional functioning for each TCR group. For example, whereas children in conflicted TCRs evidenced greater externalizing difficulties, children with dependent TCRs had greater internalizing difficulties. Children who evidenced high levels of both conflicted and dependent TCRs displayed the most pervasive socio‐emotional difficulties.

Conclusions

Children who form TCRs characterized by high levels of both conflict and dependency displayed the most pervasive adjustment difficulties. Further investigation is needed to improve our understanding of this group and to assess the plausibility of early intervention strategies.
Transformed non‐Hodgkin lymphoma in the rituximab era: analysis of the NCCN outcomes database
Authors: Ban‐Hoefen Makiko , Vanderplas Ann , Crosby‐Thompson Allison L. , Abel Gregory A. , Czuczman Myron S. , Gordon Leo I. , Kaminski Mark S. , Kelly Jennifer , Millenson Michael , Nademanee Auayporn P. , Rodriguez Maria A. , Zelenetz Andrew D. , Niland Joyce , LaCasce Ann S. , Friedberg Jonathan W.
Published: October 2013

Histological transformation (HT) is a major cause of morbidity and mortality in patients with indolent non‐Hodgkin lymphoma (NHL). The multicentre National Cancer Comprehensive Network database for NHL provides a unique opportunity to investigate the natural history of HT in the rituximab era. 118 patients with biopsy‐confirmed indolent lymphoma and subsequent biopsy‐confirmed HT were identified. Treatments for HT included autologous stem‐cell transplant (auto‐SCT) (n = 50), allogeneic SCT (allo‐SCT) (n = 18), and treatment without transplant (n = 50). The 2‐year overall survival (OS) for the entire cohort was 68%. For auto‐SCT patients aged ≤60 years (n = 24), the 2‐year OS was 74%. For non‐transplanted patients aged ≤60 years (n = 19), the 2‐year OS was 59%. The 2‐year OS of patients naïve to chemotherapy prior to HT was superior to patients who were exposed to chemotherapy prior to HT (100% vs. 35%, P = 0·03). In this largest prospective cohort of patients of strictly defined HT in the rituximab era, the natural history of HT appears more favourable than historical studies. Younger patients who were not exposed to chemotherapy prior to HT experienced a prolonged survival even without transplantation. This study serves as a benchmark for future trials of novel approaches for HT in the Rituximab era.
Genetics on a WHIM
Authors: Al Ustwani Omar , Kurzrock Razelle , Wetzler Meir
Published: October 2013

We initially described the WHIM syndrome based on the combination of Warts, Hypogammaglobulinaemia, Infections and Myelokathexis (neutrophil retention in the bone marrow). Translational research led to the discovery that this rare immunodeficiency disease is caused by a heterozygous mutation in the CXCR4 gene. Recently, Plerixafor has been suggested as a treatment for WHIM syndrome due to its efficacy as a CXCR4 antagonist, closing the translational research loop. In this review, we will focus on the clinical manifestations, pathophysiology, diagnosis and possible therapies for this rare entity.
An investigation into the relevance of action planning, theory of planned behaviour concepts, and automaticity for fruit intake action control
Authors: de Bruijn Gert‐Jan , Wiedemann Amelie , Rhodes Ryan E.
Published: October 2013

Objectives

In the action control framework, intention–behaviour discordance is studied around public health guidelines. Although this framework has been applied to physical activity behaviours, it has only seen very limited attention regarding fruit intake. The purpose of this study was therefore to investigate distributions and predictors of fruit intake intention–behaviour discordance.

Design

Prospective correlational design.

Methods

Data were obtained from undergraduate students (n = 413) using validated questionnaires. Variables from the theory of planned behaviour, automaticity, and action planning were assessed at baseline, and fruit intake was assessed 2 weeks later. Data were analysed using discriminant function analyses and analyses of variance.

Results

The proportion of unsuccessful intenders ranged from 39.2% to 80.8%. There was a larger proportion of fruit intake intenders amongst those who reported strong automatic fruit intake. Action control was predicted by fruit intake automaticity and affective attitudes, but the strongest predictor was perceived behavioural control. No action planning items were related to fruit intake action control.

Conclusions

There is considerable asymmetry in the intention–fruit intake relationship. An application of the action control framework may stimulate debate on the applicability of intention‐based models at the public health level.

Statement of contribution

What is already known on this subject?

Intention is theorized to be a key construct in fruit intake.

Studies in the physical activity domain indicate that nearly half of the people with positive intentions fail to subsequently act.

What does this study add?

The proportion of unsuccessful intenders ranged from 39.2% to 80.8%.

Holding positive intentions is not sufficient to consume fruit at suggested public health guidelines.

Perceived behavioural control is the most important predictor of fruit intake action control.
Urinary saturation: casual or causal risk factor in urolithiasis?
Authors: Rodgers Allen L.
Published: October 2013

Objective

To assess (i) the extent to which urinary supersaturation (SS) has successfully discriminated between stone formers and healthy individuals (N), (ii) whether absolute SS has diagnostic worth and (iii) whether high SS is the fundamental cause of stone formation per se.

Materials and Methods

Google Scholar was used to identify studies in which urinary compositional data had been determined.

In those cases where SS values were not given, or where other risk indices had been reported, they were (re‐)calculated.

Collected data were termed ‘global’ but were then ‘filtered’ according to stone type and protocols used for SS calculations.

SS distribution plots for calcium oxalate, brushite and uric acid were constructed.

Data were statistically analysed using the unpaired t‐test and Mann–Whitney test.

Results

In all, 47 studies yielded 123 SS values for healthy individuals and 122 values for stone formers.

The mean and median SS values were significantly greater in stone formers compared with healthy individuals in all but one of the comparisons.

Wide variations in SS occurred for healthy individuals and stone formers. The two groups could not be separated.

Conclusions

Absolute SS has no diagnostic worth. It is impossible to quantify the meaning of a ‘high’ SS value. Urines cannot be identified as originating from healthy individuals or stone formers based on their SS.

SS should be determined in clinical and research settings for relative comparisons during the assessment of treatment efficacies.

This study provides a compelling argument for SS being a casual factor rather than a causal one.
A high‐resolution Lateglacial and Holocene palaeoceanographic record from the Greenland Sea
Authors: Telesiński Maciej M. , Spielhagen Robert F. , Lind Ewa M.
Published: October 2013

We present an unprecedented multicentennial sediment record from the foot of Vesterisbanken Seamount, central Greenland Sea, covering the past 22.3 thousand years (ka). Based on planktic foraminiferal total abundances, species assemblages, and stable oxygen and carbon isotopes, the palaeoenvironments in this region of modern deepwater renewal were reconstructed. Results show that during the Last Glacial Maximum the area was affected by harsh polar conditions with only episodic improvements during warm summer seasons. Since 18 ka extreme freshwater discharges from nearby sources occurred, influencing the surface water environment. The last major freshwater event took place during the Younger Dryas. The onset of the Holocene was characterized by an improvement of environmental conditions suggesting warming and increasing ventilation of the upper water layers. The early Holocene saw a stronger Atlantic waters advection to the area, which began around 10.5 and ended quite rapidly at 5.5 ka, followed by the onset of Neoglacial cooling. Surface water ventilation reached a maximum in the middle Holocene. Around 3 ka the surface water stratification increased leading to subsequent amplification of the warming induced the North Atlantic Oscillation at 2 ka.
Plasminogen‐stimulated airway smooth muscle cell proliferation is mediated by urokinase and annexin A2, involving plasmin‐activated cell signalling
Authors: Stewart A G , Xia Y C , Harris T , Royce S , Hamilton J A , Schuliga M
Published: October 2013

Background and Purpose

The conversion of plasminogen into plasmin by interstitial urokinase plasminogen activator (uPA) is potentially important in asthma pathophysiology. In this study, the effect of uPA‐mediated plasminogen activation on airway smooth muscle (ASM) cell proliferation was investigated.

Experimental Approach

Human ASM cells were incubated with plasminogen (0.5–50 μg·mL−1) or plasmin (0.5–50 mU·mL−1) in the presence of pharmacological inhibitors, including UK122, an inhibitor of uPA. Proliferation was assessed by increases in cell number or MTT reduction after 48 h incubation with plasmin(ogen), and by earlier increases in [3H]‐thymidine incorporation and cyclin D1 expression.

Key Results

Plasminogen (5 μg·mL−1)‐stimulated increases in cell proliferation were attenuated by UK122 (10 μM) or by transfection with uPA gene‐specific siRNA. Exogenous plasmin (5 mU·mL−1) also stimulated increases in cell proliferation. Inhibition of plasmin‐stimulated ERK1/2 or PI3K/Akt signalling attenuated plasmin‐stimulated increases in ASM proliferation. Furthermore, pharmacological inhibition of cell signalling mediated by the EGF receptor, a receptor trans‐activated by plasmin, also reduced plasmin(ogen)‐stimulated cell proliferation. Knock down of annexin A2, which has dual roles in both plasminogen activation and plasmin‐signal transduction, also attenuated ASM cell proliferation following incubation with either plasminogen or plasmin.

Conclusions and Implications

Plasminogen stimulates ASM cell proliferation in a manner mediated by uPA and involving multiple signalling pathways downstream of plasmin. Targeting mediators of plasminogen‐evoked ASM responses, such as uPA or annexin A2, may be useful in the treatment of asthma.
Effects of 3,4‐methylenedioxymethamphetamine (MDMA) and its main metabolites on cardiovascular function in conscious rats
Authors: Schindler Charles W , Thorndike Eric B , Blough Bruce E , Tella Srihari R , Goldberg Steven R , Baumann Michael H
Published: October 2013

Background and Purpose

The cardiovascular effects produced by 3,4‐methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) contribute to its acute toxicity, but the potential role of its metabolites in these cardiovascular effects is not known. Here we examined the effects of MDMA metabolites on cardiovascular function in rats.

Experimental Approach

Radiotelemetry was employed to evaluate the effects of s.c. administration of racemic MDMA and its phase I metabolites on BP, heart rate (HR) and locomotor activity in conscious male rats.

Key Results

MDMA (1–20 mg·kg−1) produced dose‐related increases in BP, HR and activity. The peak effects on HR occurred at a lower dose than peak effects on BP or activity. The N‐demethylated metabolite, 3,4‐methylenedioxyamphetamine (MDA), produced effects that mimicked those of MDMA. The metabolite 3,4‐dihydroxymethamphetamine (HHMA; 1–10 mg·kg−1) increased HR more potently and to a greater extent than MDMA, whereas 3,4‐dihydroxyamphetamine (HHA) increased HR, but to a lesser extent than HHMA. Neither dihydroxy metabolite altered motor activity. The metabolites 4‐hydroxy‐3‐methoxymethamphetamine (HMMA) and 4‐hydroxy‐3‐methoxyamphetamine (HMA) did not affect any of the parameters measured. The tachycardia produced by MDMA and HHMA was blocked by the β‐adrenoceptor antagonist propranolol.

Conclusions and Implications

Our results demonstrate that HHMA may contribute significantly to the cardiovascular effects of MDMA in vivo. As such, determining the molecular mechanism of action of HHMA and the other hydroxyl metabolites of MDMA warrants further study.
The expression and function of histamine H3 receptors in pancreatic beta cells
Authors: Nakamura T , Yoshikawa T , Noguchi N , Sugawara A , Kasajima A , Sasano H , Yanai K
Published: October 2013

Background and Purpose

Histamine and its receptors in the CNS play important roles in energy homeostasis. Here, we have investigated the expression and role of histamine receptors in pancreatic beta cells, which secrete insulin.

Experimental Approach

The expression of histamine receptors in pancreatic beta cells was examined by RT‐PCR, Western blotting and immunostaining. Insulin secretion assay, ATP measurement and calcium imaging studies were performed to determine the function and signalling pathway of histamine H3 receptors in glucose‐induced insulin secretion (GIIS) from MIN6 cells, a mouse pancreatic beta cell line. The function and signalling pathway of H3 receptors in MIN6 cell proliferation were examined using pharmacological assay and Western blotting.

Key Results

Histamine H3 receptors were expressed in pancreatic beta cells. A selective H3 receptor agonist, imetit, and a selective inverse H3 receptor agonist, JNJ‐5207852, had inhibitory and facilitatory effects, respectively, on GIIS in MIN6 cells. Neither imetit nor JNJ‐5207852 altered intracellular ATP concentration, or intracellular calcium concentration stimulated by glucose and KCl, indicating that GIIS signalling was affected by H3 receptor signalling downstream of the increase in intracellular calcium concentration. Moreover, imetit attenuated bromodeoxyuridine incorporation in MIN6 cells. The phosphorylation of cAMP response element‐binding protein (CREB), which facilitated beta cell proliferation, was inhibited, though not significantly, by imetit, indicating that activated H3 receptors inhibited MIN6 cell proliferation, possibly by decreasing CREB phosphorylation.

Conclusions and Implications

Histamine H3 receptors were expressed in mouse beta cells and could play a role in insulin secretion and, possibly, beta cell proliferation.
Mitochondrial protein quality control in health and disease
Authors: Baker Michael J , Palmer Catherine S , Stojanovski Diana
Published: October 2013

Progressive mitochondrial dysfunction is linked with the onset of many age‐related pathologies and neurological disorders. Mitochondrial damage can come in many forms and be induced by a variety of cellular insults. To preserve organelle function during biogenesis or times of stress, multiple surveillance systems work to ensure the persistence of a functional mitochondrial network. This review provides an overview of these processes, which collectively contribute to the maintenance of a healthy mitochondrial population, which is critical for cell physiology and survival.

Linked Articles

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue‐8
Unravelling mitochondrial pathways to Parkinson's disease
Authors: Celardo I , Martins L M , Gandhi S
Published: October 2013

Mitochondria are essential for cellular function due to their role in ATP production, calcium homeostasis and apoptotic signalling. Neurons are heavily reliant on mitochondrial integrity for their complex signalling, plasticity and excitability properties, and to ensure cell survival over decades. The maintenance of a pool of healthy mitochondria that can meet the bioenergetic demands of a neuron, is therefore of critical importance; this is achieved by maintaining a careful balance between mitochondrial biogenesis, mitochondrial trafficking, mitochondrial dynamics and mitophagy. The molecular mechanisms that underlie these processes are gradually being elucidated. It is widely recognized that mitochondrial dysfunction occurs in many neurodegenerative diseases, including Parkinson's disease. Mitochondrial dysfunction in the form of reduced bioenergetic capacity, increased oxidative stress and reduced resistance to stress, is observed in several Parkinson's disease models. However, identification of the recessive genes implicated in Parkinson's disease has revealed a common pathway involving mitochondrial dynamics, transport, turnover and mitophagy. This body of work has led to the hypothesis that the homeostatic mechanisms that ensure a healthy mitochondrial pool are key to neuronal function and integrity. In this paradigm, impaired mitochondrial dynamics and clearance result in the accumulation of damaged and dysfunctional mitochondria, which may directly induce neuronal dysfunction and death. In this review, we consider the mechanisms by which mitochondrial dysfunction may lead to neurodegeneration. In particular, we focus on the mechanisms that underlie mitochondrial homeostasis, and discuss their importance in neuronal integrity and neurodegeneration in Parkinson's disease.

Linked Articles

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue‐8
Platelet P2Y12 receptors are involved in the haemostatic effect of notoginsenoside Ft1, a saponin isolated from Panax notoginseng
Authors: Gao B , Huang L , Liu H , Wu H , Zhang E , Yang L , Wu X , Wang Z
Published: October 2013

Background and Purpose

Saponins isolated from Panax notoginseng (Burk.) F.H. Chen have been shown to relieve thrombogenesis and facilitate haemostasis. However, it is not known which saponin accounts for this haemostatic effect. Hence, in the present study we aimed to identify which saponins contribute to its haemostatic activity and to elucidate the possible underlying mechanisms.

Experimental Approach

Platelet aggregation was analysed using a platelet aggregometer. Prothrombin time, activated partial thromboplastin time and thrombin time were measured using a blood coagulation analyser, which was further corroborated with bleeding time and thrombotic assays. The interaction of notoginsenoside Ft1 with the platelet P2Y12 receptor was determined by molecular docking analysis, cytosolic Ca2+ and cAMP measurements, and phosphorylation of PI3K and Akt assays.

Key Results

Among the saponins examined, Ft1 was the most potent procoagulant and induced dose‐dependent platelet aggregation. Ft1 reduced plasma coagulation indexes, decreased tail bleeding time and increased thrombogenesis. Moreover, it potentiated ADP‐induced platelet aggregation and increased cytosolic Ca2+ accumulation, effects that were attenuated by clopidogrel. Molecular docking analysis suggested that Ft1 binds to platelet P2Y12 receptors. The increase in intracellular Ca2+ evoked by Ft1 in HEK293 cells overexpressing P2Y12 receptors could be blocked by ticagrelor. Ft1 also affected the production of cAMP and increased phosphorylation of PI3K and Akt downstream of P2Y12 signalling pathways.

Conclusion and Implications

Ft1 enhanced platelet aggregation by activating a signalling network mediated through P2Y12 receptors. These novel findings may contribute to the effective utilization of this compound in the therapy of haematological disorders.