bluuebunny/crossref_metadata_2025 huggingface dataset:
Onconase responsive genes in human mesothelioma cells: implications for an RNA damaging therapeutic agent
Authors: Altomare Deborah A , Rybak Susanna M , Pei Jianming , Maizel Jacob V , Cheung Mitchell , Testa Joseph R , Shogen Kuslima
Published: February 2010

Background

Onconase represents a new class of RNA-damaging drugs. Mechanistically, Onconase is thought to internalize, where it degrades intracellular RNAs such as tRNA and double-stranded RNA, and thereby suppresses protein synthesis. However, there may be additional or alternative mechanism(s) of action.

Methods

In this study, microarray analysis was used to compare gene expression profiles in untreated human malignant mesothelioma (MM) cell lines and cells exposed to 5 μg/ml Onconase for 24 h. A total of 155 genes were found to be regulated by Onconase that were common to both epithelial and biphasic MM cell lines. Some of these genes are known to significantly affect apoptosis (IL-24, TNFAIP3), transcription (ATF3, DDIT3, MAFF, HDAC9, SNAPC1) or inflammation and the immune response (IL-6, COX-2). RT-PCR analysis of selected up- or down-regulated genes treated with varying doses and times of Onconase generally confirmed the expression array findings in four MM cell lines.

Results

Onconase treatment consistently resulted in up-regulation of IL-24, previously shown to have tumor suppressive activity, as well as ATF3 and IL-6. Induction of ATF3 and the pro-apoptotic factor IL-24 by Onconase was highest in the two most responsive MM cell lines, as defined by DNA fragmentation analysis. In addition to apoptosis, gene ontology analysis indicated that pathways impacted by Onconase include MAPK signaling, cytokine-cytokine-receptor interactions, and Jak-STAT signaling.

Conclusions

These results provide a broad picture of gene activity after treatment with a drug that targets small non-coding RNAs and contribute to our overall understanding of MM cell response to Onconase as a therapeutic strategy. The findings provide insights regarding mechanisms that may contribute to the efficacy of this novel drug in clinical trials of MM patients who have failed first line chemotherapy or radiation treatment.
SNAI1 expression and the mesenchymal phenotype: an immunohistochemical study performed on 46 cases of oral squamous cell carcinoma
Authors: Schwock Joerg , Bradley Grace , Ho James C , Perez-Ordonez Bayardo , Hedley David W , Irish Jonathan C , Geddie William R
Published: February 2010

Background

SNAI1 can initiate epithelial-mesenchymal transition (EMT), leading to loss of epithelial characteristics and, in cancer, to invasion and metastasis. We hypothesized that SNAI1 reactivation occurs in oral squamous cell carcinoma (OSCC) where it might also be associated with focal adhesion kinase (FAK) expression and p63 loss.

Methods

Immunohistochemistry was performed on 46 tumors and 26 corresponding lymph node metastases. Full tissue sections were examined to account for rare and focal expression. Clinical outcome data were collected and analyzed.

Results

SNAI1-positivity (nuclear, ≥ 5% tumor cells) was observed in 10 tumors and 5 metastases (n = 12 patients). Individual SNAI1(+) tumor cells were seen in primary tumors of 30 patients. High level SNAI1 expression (>10% tumor cells) was rare, but significantly associated with poor outcome. Two cases displayed a sarcomatoid component as part of the primary tumor with SNAI1(+)/FAK(+)/E-cadherin(-)/p63(-) phenotype, but disparate phenotypes in corresponding metastases. All cases had variable SNAI1(+) stroma. A mesenchymal-like immunoprofile in primary tumors characterized by E-cadherin loss (n = 29, 63%) or high cytoplasmic FAK expression (n = 10, 22%) was associated with N(+) status and tumor recurrence/new primary, respectively.

Conclusions

SNAI1 is expressed, although at low levels, in a substantial proportion of OSCC. High levels of SNAI1 may herald a poor prognosis and circumscribed SNAI1 expression can indicate the presence of a sarcomatoid component. Absence of p63 in this context does not exclude squamous tumor origin. Additional EMT inducers may contribute to a mesenchymal-like phenotype and OSCC progression.
Evaluation of a community pharmacy-based intervention for improving patient adherence to antihypertensives: a randomised controlled trial
Authors: Lau Rosalind , Stewart Kay , McNamara Kevin P , Jackson Shane L , Hughes Jeffery D , Peterson Gregory M , Bortoletto Diana A , McDowell Jenny , Bailey Michael J , Hsueh Arthur , George Johnson
Published: February 2010

Background

The majority of patients using antihypertensive medications fail to achieve their recommended target blood pressure. Poor daily adherence with medication regimens and a lack of persistence with medication use are two of the major reasons for failure to reach target blood pressure. There is no single intervention to improve adherence with antihypertensives that is consistently effective. Community pharmacists are in an ideal position to promote adherence to chronic medications. This study aims to test a specific intervention package that could be integrated into the community pharmacy workflow to enable pharmacists to improve patient adherence and/or persistence with antihypertensive medications - Hypertension Adherence Program in Pharmacy (HAPPY).

Methods/Design

The HAPPY trial is a multi-centre prospective randomised controlled trial. Fifty-six pharmacies have been recruited from three Australian states. To identify potential patients, a software application (MedeMine CVD) extracted data from a community pharmacy dispensing software system (FRED Dispense®). The pharmacies have been randomised to either 'Pharmacist Care Group' (PCG) or 'Usual Care Group' (UCG). To check for 'Hawthorne effect' in the UCG, a third group of patients 'Hidden Control Group' (HCG) will be identified in the UCG pharmacies, which will be made known to the pharmacists at the end of six months. Each study group requires 182 patients. Data will be collected at baseline, three and six months in the PCG and at baseline and six months in the UCG. Changes in patient adherence and persistence at the end of six months will be measured using the self-reported Morisky score, the Tool for Adherence Behaviour Screening and medication refill data.

Discussion

To our knowledge, this is the first research testing a comprehensive package of evidence-based interventions that could be integrated into the community pharmacy workflow to enable pharmacists to improve patient adherence and/or persistence with antihypertensive medications. The unique features of the HAPPY trial include the use of MedeMine CVD to identify patients who could potentially benefit from the service, control for the 'Hawthorne effect' in the UCG and the offer of the intervention package at the end of six months to patients in the UCG, a strategy that is expected to improve retention.

Trial Registration

Australian New Zealand Clinical Trial Registry ACTRN12609000705280
Regulations of the key mediators in inflammation and atherosclerosis by Aspirin in human macrophages
Authors: Lu Li , Liu Hong , Peng Jiahe , Gan Lin , Shen Lili , Zhang Qian , Li Liangpeng , Zhang Li , Su Chang , Jiang Yu
Published: February 2010

Although its role to prevent secondary cardiovascular complications has been well established, how acetyl salicylic acid (ASA, aspirin) regulates certain key molecules in the atherogenesis is still not known. Considering the role of matrix metalloproteinase-9 (MMP-9) to destabilize the atherosclerotic plaques, the roles of the scavenger receptor class BI (SR-BI) and ATP-binding cassette transporter A1 (ABCA1) to promote cholesterol efflux in the foam cells at the plaques, and the role of NF-κB in the overall inflammation related to the atherosclerosis, we addressed whether these molecules are all related to a common mechanism that may be regulated by acetyl salicylic acid. We investigated the effect of ASA to regulate the expressions and activities of these molecules in THP-1 macrophages. Our results showed that ASA inhibited MMP-9 mRNA expression, and caused the decrease in the MMP-9 activities from the cell culture supernatants. In addition, it inhibited the nuclear translocation of NF-κB p65 subunit, thus the activity of this inflammatory molecule. On the contrary, acetyl salicylic acid induced the expressions of ABCA1 and SR-BI, two molecules known to reduce the progression of atherosclerosis, at both mRNA and protein levels. It also stimulated the cholesterol efflux out of macrophages. These data suggest that acetyl salicylic acid may alleviate symptoms of atherosclerosis by two potential mechanisms: maintaining the plaque stability via inhibiting activities of inflammatory molecules MMP-9 and NF-κB, and increasing the cholesterol efflux through inducing expressions of ABCA1 and SR-BI.
High incidence of severe cyclosporine neurotoxicity in children affected by haemoglobinopaties undergoing myeloablative haematopoietic stem cell transplantation: early diagnosis and prompt intervention ameliorates neurological outcome
Authors: Noè Anna , Cappelli Barbara , Biffi Alessandra , Chiesa Robert , Frugnoli Ilaria , Biral Erika , Finizio Valentina , Baldoli Cristina , Vezzulli Paolo , Minicucci Fabio , Fanelli Giovanna , Fiori Rossana , Ciceri Fabio , Roncarolo Maria Grazia , Marktel Sarah
Published: February 2010

Background

Neurotoxicity is a recognized complication of cyclosporine A (CSA) treatment. The incidence of severe CSA-related neurological complications following hematopoietic stem cell transplantation (HSCT) is 4-11%.

Methods

We describe 6 cases of CSA related neurotoxicity out of 67 matched related HSCT performed in paediatric Middle East patients affected by haemoglobinopaties (5 beta thalassemia major, 1 sickle cell disease-SCD). Conditioning regimen consisted of iv busulphan, cyclophosphamide and graft-versus-host-disease (GvHD) prophylaxis with CSA, methylprednisolone, methotrexate and ATG.

Results

All 6 patients presented prodromes such as arterial hypertension, headache, visual disturbances and vomiting, one to two days before overt CSA neurotoxicity. CSA neurotoxicity consisted of generalized seizures, signs of endocranial hypertension and visual disturbances at a median day of onset of 11 days after HSCT (range +1 to +40). Brain magnetic resonance imaging (MRI) performed in all subjects showed reversible leukoencephalopathy predominantly in the posterior regions of the brain (PRES) in 5/6 patients. EEG performed in 5/6 patients was always abnormal. Neurotoxicity was not explainable by high CSA blood levels, as all patients had CSA in the therapeutic range with a median of 178 ng/ml (range 69-250). CSA was promptly stopped and switched to tacrolimus with disappearance of clinical and radiological findings. All patients are symptoms-free at a median follow up of 882 days (range 60-1065).

Conclusions

Our experience suggests that paediatric patients with haemoglobinopaties have a high incidence of CSA related neurological events with no correlation between serum CSA levels and neurotoxicity. Prognosis is good following CSA removal. Specific prodromes such as arterial hypertension, headache or visual disturbances occurring in the early post-transplant period should be carefully evaluated with electrophysiological and MRI-based imaging in order to intervene promptly and avoid irreversible sequels.
Maternal Vitamin D Status Determines Bone Variables in the Newborn
Authors: Viljakainen H. T. , Saarnio E. , Hytinantti T. , Miettinen M. , Surcel H. , Mäkitie O. , Andersson S. , Laitinen K. , Lamberg-Allardt C.
Published: February 2010

Context: Vitamin D regulates 3% of the human genome, including effects on bone health throughout life. Maternal vitamin D status may program neonatal skeletal development. The objective here was to determine the association of mothers’ vitamin D status with bone variables of their newborns.

Subjects and Methods: In a birth hospital, pregnant women (n = 125) participated in a cross-sectional study with a longitudinal follow-up of the pregnancy. The mean (sd) values for age, body mass index before pregnancy, pregnancy weight gain, and total vitamin D intake in mothers were 31 (4) yr, 23.5 (3.7) kg/m2, 13.1 (4.3) kg, and 14.3 (5.8) μg, respectively. All newborns were full-term, 99% were appropriate for gestational age, and 53% were boys. Blood samples were collected from mothers during the first trimester and 2 d postpartum and from umbilical cords at birth for analysis of serum 25-hydroxyvitamin D (S-25-OHD), PTH, and bone remodeling markers. Bone variables were measured by pQCT at the 20% site of the newborn tibia on an average of 10 (11) d postpartum. Bone contour was analyzed with a single threshold of 180 mg/mm3 for the detection of total bone mineral density (BMD), bone mineral content (BMC), and cross-sectional area (CSA).

Results: Mean S-25-OHD was 41.0 (13.6), 45.1 (11.9), and 50.7 (14.9) nmol/liter during the first trimester, postpartum, and in the umbilical cord, respectively. The median value of the individual means for first trimester and the 2-d postpartum S-25-OHD was 42.6 nmol/liter, which was used as cutoff to define two equal-sized groups. Groups are called below median and above median in the text. Newborns below median were heavier (P = 0.05), and 60% were boys. Tibia bone mineral content was 0.047 (95% confidence interval, 0.011–0.082) g/cm higher (P = 0.01), and cross-sectional area was 12.3 (95% confidence interval, 2.0–22.6) mm2 larger (P = 0.02), but no difference in bone mineral density was observed, above median compared with below median group. These results were adjusted for newborn Z-score birth weight, maternal height, and newborn age at the measurement. A positive, significant correlation was observed between remodeling markers in mothers at different time points and above median group in the cord.

Conclusions: Although the mean total intake of vitamin D among mothers met current Nordic recommendations, 71% of women and 15% of newborns were vitamin D deficient during the pregnancy. Our results suggest that maternal vitamin D status affects bone mineral accrual during the intrauterine period and influences bone size. More efforts should be made to revise current nutrition recommendations for pregnant women that may have permanent effects on the well-being of children.
Muscle Fiber Conduction Slowing and Decreased Levels of Circulating Muscle Proteins after Short-Term Dexamethasone Administration in Healthy Subjects
Authors: Minetto Marco A. , Botter Alberto , Lanfranco Fabio , Baldi Matteo , Ghigo Ezio , Arvat Emanuela
Published: February 2010

Context: Glucocorticoids are known to decrease protein synthesis and impair membrane excitability of muscle fibers. However, their short-term effects on muscle structure and function of healthy subjects remain poorly understood.

Objective: Our objective was to investigate whether steroid administration could decrease the circulating levels of muscle proteins and modify myoelectric indexes of sarcolemmal excitability and fatigability.

Design: We conducted a single-blind, placebo-controlled study in 20 men randomized to receive dexamethasone (8 mg/d) or placebo for 1 wk. Blood sampling, force measurements for knee extensors and elbow flexors, and electrophysiological tests for biceps brachii, vastus lateralis and medialis, and tibialis anterior muscles were performed before and after the intervention.

Results: Dexamethasone administration improved force by 6.0 ± 6.0% (P = 0.01) for elbow flexors and by 8.5 ± 5.5% (P < 0.01) for knee extensors, decreased levels of creatine kinase by 50.5 ± 30.0% (P < 0.01) and myoglobin by 41.8 ± 17.5% (P < 0.01), and impaired sarcolemmal excitability, as shown by the decline of muscle fiber conduction velocity for the four muscles (range from −6 to −10.5%, P < 0.05). Moreover, significant reductions of the myoelectric manifestations of fatigue were observed for the four muscles; the decrease in the rate of change of the mean frequency of the electromyographic power spectrum ranged from −22.6 to −43.9% (P < 0.05). In contrast, no significant changes were observed in muscle excitability and fatigability in subjects who received the placebo.

Conclusions: The demonstration that glucocorticoid-induced muscle impairments can be unraveled by means of blood sampling and noninvasive electrophysiological tests has clinical implications for the early identification of subclinical or preclinical forms of myopathy in treated patients.
Long-Run Equilibrium Modeling of Emissions Allowance Allocation Systems in Electric Power Markets
Authors: Zhao Jinye , Hobbs Benjamin F. , Pang Jong-Shi
Published: February 2010

Carbon dioxide allowance trading systems for electricity generators are in place in the European Union and in several U.S. states. An important question in the design of such systems is how allowances are to be initially allocated: by auction, by giving away fixed amounts (grandfathering), or by allocating based on present or recent output, investment, or other decisions. The latter system can bias investment, operations, and product pricing decisions and increase costs relative to the other systems. A nonlinear complementarity model is proposed for investigating the long-run equilibria that would result under alternative systems for power markets characterized by time-varying demand and multiple technology types. Existence of equilibria is shown under mild conditions. Solutions for simple systems show that allocating allowances to new capacity based on fuel use or generator type can yield large distortions in capacity investment, invert the operating order of power plants, and inflate consumer costs. The distortions can be smaller for tighter CO2 restrictions and are somewhat mitigated if there is also a market for electricity capacity or minimum-run restrictions on coal plants. Distortions are also less if allowances are allocated to plants in proportion to sales rather than capacity.
Technical Note—Stochastic Sequential Decision-Making with a Random Number of Jobs
Authors: Nikolaev Alexander G. , Jacobson Sheldon H.
Published: February 2010

This paper addresses a class of problems in which available resources need to be optimally allocated to a random number of jobs with stochastic parameters. Optimal policies are presented for variations of the sequential stochastic assignment problem and the dynamic stochastic knapsack problem, in which the number of arriving jobs is unknown until after the final arrival, and the job parameters are assumed to be independent but not identically distributed random variables.
Cholecalciferol loading dose guideline for vitamin D-deficient adults
Authors: van Groningen Lenneke , Opdenoordt Susanne , van Sorge Adriaan , Telting Darryl , Giesen Astrid , de Boer Hans
Published: February 2010

Introduction

Severe vitamin D deficiency is very common. Evidence-based guidelines for rapid correction with high-dose oral cholecalciferol are not yet available.

Objective

To develop a practical cholecalciferol loading dose regimen.

Materials and methods

A total of 208 vitamin D-deficient subjects (serum 25-hydroxyvitamin D3(25-OHD3) level <50 nmol/l), aged 18–88 years, were treated with solubilized cholecalciferol, 50 000 IU/ml. They received either 25 000 IU every fortnight for 8 weeks (total dose 100 000 IU), 25 000 IU every week for 6 weeks (total dose 150 000 IU), or 25 000 IU every week for 8 weeks (total dose 200 000 IU). Blood samples were collected at baseline and 10 days after the final dose of cholecalciferol.

Results

Most patients were severely vitamin D deficient: 76% had a serum 25-OHD3level <30 nmol/l at baseline. Cholecalciferol in a cumulative dose of 100 000, 150 000, and 200 000 IU increased mean serum 25-OHD3level by 29 nmol/l (95% confidence interval (CI): 23–35 nmol/l), 43 nmol/l (95% CI: 36–50 nmol/l), and 69 nmol/l (95% CI: 64–75 nmol/l) respectively. The change in 25-OHD3(Δ25-OHD3) was related to the dose per kilogram body weight (R2=0.38,P<0.0001), and is described by the equation: Δ25-OHD3=0.025×(dose per kg body weight).

Conclusion

The cholecalciferol loading dose required to reach the serum 25-OHD3target level of 75 nmol/l can be calculated as follows: dose (IU)=40×(75−serum 25-OHD3)×body weight.
The Role of Advantageous Mutations in Enhancing the Evolution of a Recombination Modifier
Authors: Hartfield Matthew , Otto Sarah P , Keightley Peter D
Published: February 2010

Although the evolution of recombination is still a major problem in evolutionary genetics, recent theoretical studies have shown that recombination can evolve by breaking down interference (“Hill–Robertson effects”) among multiple loci. This leads to selection on a recombination modifier in a population subject to recurrent deleterious mutation. Here, we use computer simulations to investigate the evolution of a recombination modifier under three different scenarios of recurrent mutation in a finite population: (1) mutations are deleterious only, (2) mutations are advantageous only, and (3) there is a mixture of deleterious and advantageous mutations. We also investigate how linkage disequilibrium, the strength of selection acting on a modifier, and effective population size change under the different scenarios. We observe that adding even a small number of advantageous mutations increases the fixation rate of modifiers that increase recombination, especially if the effects of deleterious mutations are weak. However, the strength of selection on a modifier is less than the summed strengths had there been deleterious mutations only and advantageous mutations only.
Alterations in DNA Replication and Histone Levels Promote Histone Gene Amplification in Saccharomyces cerevisiae
Authors: Libuda Diana E , Winston Fred
Published: February 2010

Gene amplification, a process that increases the copy number of a gene or a genomic region to two or more, is utilized by many organisms in response to environmental stress or decreased levels of a gene product. Our previous studies in Saccharomyces cerevisiae identified the amplification of a histone H2A-H2B gene pair, HTA2-HTB2, in response to the deletion of the other H2A-H2B gene pair, HTA1-HTB1. This amplification arises from a recombination event between two flanking Ty1 elements to form a new, stable circular chromosome and occurs at a frequency higher than has been observed for other Ty1-Ty1 recombination events. To understand the regulation of this amplification event, we screened the S. cerevisiae nonessential deletion set for mutations that alter the amplification frequency. Among the deletions that increase HTA2-HTB2 amplification frequency, we identified those that either decrease DNA replication fork progression (rrm3Δ, dpb3Δ, dpb4Δ, and clb5Δ) or that reduce histone H3-H4 levels (hht2-hhf2Δ). These two classes are related because reduced histone H3-H4 levels increase replication fork pauses, and impaired replication forks cause a reduction in histone levels. Consistent with our mutant screen, we found that the introduction of DNA replication stress by hydroxyurea induces the HTA2-HTB2 amplification event. Taken together, our results suggest that either reduced histone levels or slowed replication forks stimulate the HTA2-HTB2 amplification event, contributing to the restoration of normal chromatin structure.
Ume6 Is Required for the MATa/MATα Cellular Identity and Transcriptional Silencing in Kluyveromyces lactis
Authors: Barsoum E , Sjöstrand J O O , Åström S U
Published: February 2010

To explore the similarities and differences of regulatory circuits among budding yeasts, we characterized the role of the unscheduled meiotic gene expression 6 (UME6) gene in Kluyveromyces lactis. We found that Ume6 was required for transcriptional silencing of the cryptic mating-type loci HMLα and HMRa. Chromatin immunoprecipitation (ChIP) suggested that Ume6 acted directly by binding the cis-regulatory silencers of these loci. Unexpectedly, a MATa  ume6 strain was mating proficient, whereas a MATα ume6 strain was sterile. This observation was explained by the fact that ume6 derepressed HMLα2 only weakly, but derepressed HMRa1 strongly. Consistently, two a/α-repressed genes (MTS1 and STE4) were repressed in the MATα ume6 strain, but were expressed in the MATa  ume6 strain. Surprisingly, ume6 partially suppressed the mating defect of a MATa  sir2 strain. MTS1 and STE4 were repressed in the MATa  sir2 ume6 double-mutant strain, indicating that the suppression acted downstream of the a1/α2-repressor. We show that both STE12 and the MATa2/HMRa2 genes were overexpressed in the MATa  sir2 ume6 strain. Consistent with the idea that this deregulation suppressed the mating defect, ectopic overexpression of Ste12 and a2 in a MATa  sir2 strain resulted in efficient mating. In addition, Ume6 served as a block to polyploidy, since ume6/ume6 diploids mated as pseudo a-strains. Finally, Ume6 was required for repression of three meiotic genes, independently of the Rpd3 and Sin3 corepressors.
Interns Overestimate the Effectiveness of Their Hand-off Communication
Authors: Chang Vivian Y. , Arora Vineet M. , Lev-Ari Shiri , D'Arcy Michael , Keysar Boaz
Published: February 2010

OBJECTIVE:

Theories from the psychology of communication may be applicable in understanding why hand-off communication is inherently problematic. The purpose of this study was to assess whether postcall pediatric interns can correctly estimate the patient care information and rationale received by on-call interns during hand-off communication.

METHODS:

Pediatric interns at the University of Chicago were interviewed about the hand-off. Postcall interns were asked to predict what on-call interns would report as the important pieces of information communicated during the hand-off about each patient, with accompanying rationale. Postcall interns also guessed on-call interns' rating of how well the hand-offs went. Then, on-call interns were asked to list the most important pieces of information for each patient that postcall interns communicated during the hand-off, with accompanying rationale. On-call interns also rated how well the hand-offs went. Interns had access to written hand-offs during the interviews.

RESULTS:

We conducted 52 interviews, which constituted 59% of eligible interviews. Seventy-two patients were discussed. The most important piece of information about a patient was not successfully communicated 60% of the time, despite the postcall intern's believing that it was communicated. Postcall and on-call interns did not agree on the rationales provided for 60% of items. In addition, an item was more likely to be effectively communicated when it was a to-do item (65%) or an item related to anticipatory guidance (69%) compared with a knowledge item (38%). Despite the lack of agreement on content and rationale of information communicated during hand-offs, peer ratings of hand-off quality were high.

CONCLUSIONS:

Pediatric interns overestimated the effectiveness of their hand-off communication. Theories from communication psychology suggest that miscommunication is caused by egocentric thought processes and a tendency for the speaker to overestimate the receiver's understanding. This study demonstrates that systematic causes of miscommunication may play a role in hand-off quality.
Anti-Vascular Endothelial Growth Factor Therapies and Cardiovascular Toxicity: What Are the Important Clinical Markers to Target?
Authors: Vaklavas Christos , Lenihan Daniel , Kurzrock Razelle , Tsimberidou Apostolia Maria
Published: February 2010

Learning Objectives

After completing this course, the reader will be able to: Promptly recognize cardiovascular adverse events associated with anti-VEGF therapy in order to formulate treatment plans to counteract them.Explain possible mechanisms by which bevacizumab, sunitinib, and sorafenib lead to cardiovascular complications and develop strategies for managing these complications.Describe the role of RAAS in vasoconstriction and capillary rarefaction and strategize the use of RAAS inhibition to manage these toxicities.

This article is available for continuing medical education credit at CME.TheOncologist.com

Background.

Therapies targeting vascular endothelial growth factor (VEGF) are associated with hypertension, cardiotoxicity, and thromboembolic events.

Methods.

All prospective phase I–III clinical trials published up to December 2008 of approved anti-VEGF therapies (bevacizumab, sunitinib, sorafenib) and relevant literature were reviewed.

Results.

The rates of Common Toxicity Criteria (version 3) grade 3–4 hypertension with bevacizumab, sunitinib, and sorafenib were 9.2%, 6.9%, and 7.2%, respectively. Grade 3–4 left ventricular systolic dysfunction was noted in 0.3%, 1.4%, and 0.05% of patients, respectively, whereas the rates of grade 3–4 thromboembolism were 9.6%, 1.2%, and 3.8%, respectively. The renin–angiotensin–aldosterone system (RAAS) may play a key role in vasoconstriction and capillary rarefaction, which are unleashed when VEGF signaling is targeted. Inhibiting RAAS may be the optimal approach for managing these toxicities.

Conclusions.

In anticipation of cardiovascular complications with anti-VEGF therapies, early detection and personalized management may improve clinical outcomes and tolerance.
Gonadotropin-induced ovarian cancer cell migration and proliferation require extracellular signal-regulated kinase 1/2 activation regulated by calcium and protein kinase Cδ
Authors: Mertens-Walker Inga , Bolitho Christine , Baxter Robert C , Marsh Deborah J
Published: February 2010

The gonadotropin hypothesis proposes that elevated serum gonadotropin levels may increase the risk of epithelial ovarian cancer (EOC). We have studied the effect of treating EOC cell lines (OV207 and OVCAR-3) with FSH or LH. Both gonadotropins activated the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and increased cell migration that was inhibited by the MAPK 1 inhibitor PD98059. Both extra- and intracellular calcium ion signalling were implicated in gonadotropin-induced ERK1/2 activation as treatment with either the calcium chelator EGTA or an inhibitor of intracellular calcium release, dantrolene, inhibited gonadotropin-induced ERK1/2 activation. Verapamil was also inhibitory, indicating that gonadotropins activate calcium influx via L-type voltage-dependent calcium channels. The cAMP/protein kinase A (PKA) pathway was not involved in the mediation of gonadotropin action in these cells as gonadotropins did not increase intracellular cAMP formation and inhibition of PKA did not affect gonadotropin-induced phosphorylation of ERK1/2. Activation of ERK1/2 was inhibited by the protein kinase C (PKC) inhibitor GF 109203X as well as by the PKCδ inhibitor rottlerin, and downregulation of PKCδ was inhibited by small interfering RNA (siRNA), highlighting the importance of PKCδ in the gonadotropin signalling cascade. Furthermore, in addition to inhibition by PD98059, gonadotropin-induced ovarian cancer cell migration was also inhibited by verapamil, GF 109203X and rottlerin. Similarly, gonadotropin-induced proliferation was inhibited by PD98059, verapamil, GF 109203X and PKCδ siRNA. Taken together, these results demonstrate that gonadotropins induce both ovarian cancer cell migration and proliferation by activation of ERK1/2 signalling in a calcium- and PKCδ-dependent manner.
Use of a prolactin-Cre/ROSA-YFP transgenic mouse provides no evidence for lactotroph transdifferentiation after weaning, or increase in lactotroph/somatotroph proportion in lactation
Authors: Castrique Emma , Fernandez-Fuente Marta , Le Tissier Paul , Herman Andy , Levy Andy
Published: February 2010

In rats, a shift from somatotroph dominance to lactotroph dominance during pregnancy and lactation is well reported. Somatotroph to lactotroph transdifferentiation and increased lactotroph mitotic activity are believed to account for this and associated pituitary hypertrophy. A combination of cell death and transdifferentiation away from the lactotroph phenotype has been reported to restore non-pregnant pituitary proportions after weaning. To attempt to confirm that a similar process occurs in mice, we generated and used a transgenic reporter mouse model (prolactin (PRL)-Cre/ROSA26-expression of yellow fluorescent protein (EYFP)) in which PRL promoter activity at any time resulted in permanent, stable, and highly specific EYFP. Triple immunochemistry for GH, PRL, and EYFP was used to quantify EYFP+ve, PRL−ve, and GH+ve cell populations during pregnancy and lactation, and for up to 3 weeks after weaning, and concurrent changes in cell size were estimated. At all stages, the EYFP reporter was expressed in 80% of the lactotrophs, but in fewer than 1% of other pituitary cell types, indicating that transdifferentiation from those lactotrophs where reporter expression was activated is extremely rare. Contrary to expectations, no increase in the lactotroph/somatotroph ratio was seen during pregnancy and lactation, whether assessed by immunochemistry for the reporter or PRL: findings confirmed by PRL immunochemistry in non-transgenic mice. Mammosomatotrophs were rarely encountered at the age group studied. Individual EYFP+ve cell volumes increased significantly by mid-lactation compared with virgin animals. This, in combination with a modest and non-cell type-specific estrogen-induced increase in mitotic activity, could account for pregnancy-induced changes in overall pituitary size.
OCD and Intolerance of Uncertainty: Treatment Issues
Authors: Grayson Jonathan B.
Published: February 2010

Recognition of the importance of intolerance of uncertainty (IU) as a critical cognitive distortion in anxiety disorders has been growing. The clinical challenge for researchers and clinicians is to understand the nature of IU and what it means to help clients to cope with it. Obsessive compulsive disorder (OCD) is the ideal diagnosis to examine the challenges IU can present, since, in the author’s opinion, it is the core of almost all manifestations of OCD. The article then focuses upon three factors in which IU factors play a role in successful/unsuccessful treatment: (a) the role of the therapist in helping the sufferer to understand IU and the goals of treatment; (b) techniques for helping the sufferer to accept and carry out the goals of treatment; and (c) patient factors/problems leading to “resistance” in coping with IU.
The CTSA Mandate: Are We There Yet?
Authors: Sampselle Carolyn M. , Pienta Kenneth J. , Markel Dorene S.
Published: February 2010

The ultimate aim of the National Institutes of Health Clinical and Translational Science Award (CTSA) initiative is to accelerate the movement of discoveries that can benefit human health into widespread public use. To accomplish this translational mandate, the contributions of multiple disciplines, such as dentistry, nursing, pharmacy, public health, biostatistics, epidemiology, and bioengineering, are required in addition to medicine. The research community is also mandated to establish new partnerships with organized patient communities and front line health care providers to assure the bidirectional flow of information in order that health priorities experienced by the community inform the research agenda. This article summarizes current clinical research directives, the experience of the University of Michigan faculty during the first 2 years of CTSA support, and recommendations to enhance the effectiveness of future CTSA as well as other interdisciplinary initiatives. While the manuscript focuses most closely on the CTSA Community Engagement mission, the challenges to interdisciplinarity and bidirectionality extend beyond the focus of community engagement.
Depression in Nursing Homes: Prevalence, Recognition, and Treatment
Authors: Kramer Dietmar , Allgaier Antje-Kathrin , Fejtkova Sabina , Mergl Roland , Hegerl Ulrich
Published: February 2010

Objective:

Depression is very common in people above 65 years living in long-term care. However, little is known about how well depression is recognized and how adequately it is treated. Therefore, the present study aimed at assessing accuracy of the unaided clinical diagnosis of the attending physicians, and the medical treatment situation in nursing home residents.

Methods:

A random sample of 97 residents of 10 nursing homes in Munich was examined with the Section A “Affective Syndrome” of the Structured Clinical Interview (SCID) for DSM-IV to detect depression. Information concerning clinical diagnosis and medication was obtained from the subjects' medical records.

Results:

14.4% suffered acutely from major depression, 14.4% suffered from minor depression, and 18.6% were diagnosed as depressive according to the physician and nursing records. In total, 27.8% received antidepressants. Merely 42.9% of the subjects with acute major depression were diagnosed by their attending physicians as depressive, and only half of them received an antidepressant; 17.5% received antidepressants without a diagnosis of depression in their physician and nursing records. In accordance with the guidelines, 73.3% of the antidepressants prescribed were SSRIs or newer antidepressants. Only 20.0% were tricyclic antidepressants.

Conclusions:

Findings show that depression is relatively frequent in residents of nursing homes. Moreover, it is insufficiently recognized by physicians and is even more seldom adequately treated. Also, a significant proportion of residents receive antidepressants without a documented associated indication. Therefore, the recognition and guideline-based treatment of depression should be improved in this high-risk group.
Trajectory of Posttraumatic Stress Disorder Caused by Myocardial Infarction: A Two-Year Follow-up Study
Authors: Abbas Chiara C. , Schmid Jean-Paul , Guler Erika , Wiedemar Lina , Begré Stefan , Saner Hugo , Schnyder Ulrich , Von Känel Roland
Published: February 2010

Objective:

A substantial proportion of patients develop posttraumatic stress disorder (PTSD) following myocardial infarction (MI). Previous research on the trajectory over time of PTSD in post-MI patients is scant and refers to self-rated posttraumatic symptoms. The aim of this study was to investigate the longitudinal course of an interviewer-rated diagnosis of PTSD and PTSD symptom severity following MI.

Methods:

Study participants were 40 patients (78% men, mean age 54 α 8 years) who were diagnosed with PTSD using the Clinician-administered PTSD Scale (CAPS) after an average of 5 α 4 months (range 2–16 months) following an index MI. After a mean follow-up of 26 α 6 months (range 12–36 months), 24 patients underwent a second diagnostic interview.

Results:

Two-thirds of patients ( n = 16) still qualified for a diagnosis of PTSD at follow-up. In all 24 patients, total PTSD symptoms ( p = 0.001), re-experiencing symptoms ( p < 0.001), avoidance symptoms ( p = 0.015), and, with borderline significance, hyperarousal symptoms ( p < 0.06) had all decreased over time. However, in the subgroup of the 16 patients who had retained PTSD diagnostic status at follow-up, symptoms of avoidance ( p = 0.23) and of hyperarousal ( p = 0.48) showed no longitudinal decline. Longer duration of follow-up was associated with a greater decrease in avoidance symptoms ( p = 0.029) and, with borderline significance, in re-experiencing symptoms ( p < 0.07) across all patients.

Conclusion:

Although PTSD symptomatology waned over time and in relation to longer follow-up, two-thirds of patients still qualified for a diagnosis of PTSD 2 years after the initial diagnosis. In post-MI patients, clinical PTSD is a considerably persistent condition.
A Randomized Trial of the Effect of Prayer on Depression and Anxiety
Authors: Boelens Peter A. , Reeves Roy R. , Replogle William H. , Koenig Harold G.
Published: February 2010

Objective:

To investigate the effect of direct contact person-to-person prayer on depression, anxiety, positive emotions, and salivary cortisol levels.

Design, Setting, and Participants:

Cross-over clinical trial with depression or anxiety conducted in an office setting. Following randomization to the prayer intervention or control groups, subjects (95% women) completed Hamilton Rating Scales for Depression and Anxiety, Life Orientation Test, Daily Spiritual Experiences Scale, and underwent measurement of cortisol levels. Individuals in the direct person-to-person prayer contact intervention group received six weekly 1–hour prayer sessions while those in the control group received none. Rating scales and cortisol levels were repeated for both groups after completion of the prayer sessions, and a month later. ANOVAs were used to compare pre- and post-prayer measures for each group.

Results:

At the completion of the trial, participants receiving the prayer intervention showed significant improvement of depression and anxiety, as well as increases of daily spiritual experiences and optimism compared to controls ( p < 0.01 in all cases). Subjects in the prayer group maintained these significant improvements ( p < 0.01 in all cases) for a duration of at least 1 month after the final prayer session. Participants in the control group did not show significant changes during the study. Cortisol levels did not differ significantly between intervention and control groups, or between pre- and post-prayer conditions.

Conclusions:

Direct contact person-to-person prayer may be useful as an adjunct to standard medical care for patients with depression and anxiety. Further research in this area is indicated.
Exploring the Link between Religious Attitudes and Subjective Well-Being in Chronic Pain Patients
Authors: Dezutter Jessie , Luyckx Koen , Büssing Arndt , Hutsebaut Dirk
Published: February 2010

Objective:

The aim of the present study was to explore the relations between religious attitudes and subjective well-being in a sample of chronic pain (CP) patients and to investigate whether these associations would differ from those obtained with healthy controls.

Method:

A total of 155 CP patients (72% women) and 166 healthy controls (72% women) completed questionnaires on pain, religious attitudes, and subjective well-being. The religious attitudes focused both on religiosity as such (Inclusion vs Exclusion of Transcendence) as on the cognitive approach of religious contents (Symbolic vs Literal).

Results:

Mean-level analyses showed significant differences between the CP and control samples on subjective well-being and Literal Exclusion. Mediation analyses found a direct influence of sample (CP vs control) on subjective well-being as well as an indirect effect via Literal Exclusion. Correlation analyses revealed that Literal Exclusion correlated negatively with well-being in both samples, whereas Literal Inclusion did not. The differential variable between the two samples was the symbolic approach of religion (Symbolic Inclusion and Exclusion), which was significantly associated with higher levels of well-being only in the CP sample.

Conclusion:

A literal approach toward religion in combination with a rejection of religion (Literal Exclusion) was, in general—both for CP patients as for healthy controls—associated with lower levels of well-being. In CP patients (but not in healthy controls), a symbolic approach toward religion (regardless of Inclusion or Exclusion of religion) was significantly associated with higher levels of subjective well-being.
A Prospective Observational Study of Decisional Capacity Determinations in an Academic Medical Center
Authors: Kahn Debra R. , Bourgeois James A. , Klein Sally C. , Iosif Ana-Maria
Published: February 2010

Objective:

The main goals of this observational study were to clarify and categorize decisional capacity assessments performed by a psychosomatic medicine (PSM) consult service at an academic medical center. Areas of investigation included types of decisional capacity requests, the relationship between Folstein Mini-Mental State Exam (MMSE) and PSM decisional capacity determination, psychiatric diagnoses of patients, and the agreement between primary clinician capacity assessment and that of the PSM clinician.

Method:

This was a prospective study of 100 consecutive decisional capacity consultations. Twelve requests were for second consultations for patients previously seen, for a net of 88 patients.

Results:

In 77 cases, patients lacked decisional capacity. Assessments for capacity to leave against medical advice (AMA), capacity to accept medical/surgical procedures, capacity to refuse medical/surgical procedures, and capacity to participate in discharge planning were nearly equally frequent. An MMSE cutoff score of < 21 was found to be 100% specific and 69% sensitive for identifying the patients without capacity, while a cutoff of < 24 was found to be 83% sensitive and 90% specific for identifying patients without capacity. The primary psychiatric diagnosis was a cognitive disorder in 52 cases. In 38 of the 39 cases where the primary team believed the patient lacked capacity, the PSM service agreed. In only two of the seven cases where primary teams believed patients had capacity did the PSM team agree.

Conclusions:

The MMSE was a useful predictor of capacity determination by PSM personnel, but using MMSE alone results in a number of erroneous determinations. Cognitive disorders were the most common primary psychiatric diagnoses in decisional capacity cases. Primary teams tended to be more accurate when they found patients to lack capacity.
Relationship between Child Abuse and Adult Smoking
Authors: Spratt Eve G. , Back Sudie E. , Yeatts Sharon D. , Simpson Annie N. , McRae-Clark Aimee , Maria Megan M. Moran-Santa , Price Kimber L. , Hartwell Karen T. , Brady Kathleen T.
Published: February 2010

Objective:

A strong association between a history of child abuse and subsequent psychiatric disorders including substance use has been demonstrated. However, few studies have examined the relationship between child abuse and cigarette smoking in individuals without co-occurring psychiatric disorders. In this study, the relationship between severe childhood abuse and smoking were examined in a group of adults without significant psychopathology.

Methods:

Participants ( N = 57) represent the control group of a larger study of substance dependence. Participants were without major DSM-IV psychopathology, including substance use disorders, major depression, or posttraumatic stress disorder. The Early Trauma Inventory [20] assessed history of exposure to traumatic events prior to age 18.

Results:

The majority of individuals with, as compared to without, a history of severe child abuse (79% vs. 47%, p = .02) were current cigarette smokers. The odds of smoking was four times as high in participants with versus without a severe childhood abuse history (OR = 4.0, p = 0.04).

Conclusions:

Although preliminary, the findings demonstrate a strong link between early childhood trauma and later adult cigarette smoking among individuals without significant substance use or other psychopathology.
Framing Written Emotional Expression from a Religious Perspective: Effects on Depressive Symptoms
Authors: Chen Yung Y. , Contrada Richard J.
Published: February 2010

Objective:

Previous research has found an inverse association between exposure to emotional trauma and well-being. More recently, studies on written emotional expression found that repeated expression of a traumatic experience is beneficial to physical health. However, possible mechanisms through which written emotional expression may work to influence health are still under investigation. Recent research on psychological stress has also found associations among religion, meaning, and health. This study evaluated the effects of taking a religious perspective while engaged in written emotional expression.

Method:

Participants included 215 college students, who were assigned randomly to one of three experimental groups. One was given conventional written emotional expression instructions for writing about a traumatic experience; another was instructed to write about the trauma from a religious/spiritual perspective; a control group wrote about a trivial topic.

Results:

Compared with control participants, those in the trauma-religion condition experienced significantly greater reductions in depressive symptoms at 1-month follow-up. Conventional trauma writing had no effect on dependent measures.

Conclusion:

These findings encourage further investigation of religion as a factor that may augment the health-promoting effects of written emotional expression.