bluuebunny/crossref_metadata_2025 huggingface dataset:
Whose Costs and Benefits? Why Economic Evaluations Should Simulate Both Prevalent and All Future Incident Patient Cohorts
Authors: Hoyle Martin , Anderson Rob
Published: March 2010

Background. Most health technology economic evaluations simulate only the prevalent cohort or the next incident cohort of patients. They therefore do not capture all future patient-related benefits and costs. Objective. We show how to estimate and aggregate the incremental cost-effectiveness ratios (ICERs) for both currently eligible (prevalent) and future (incident) patient cohorts within the same model-based analysis. We show why, and in what circumstances, the prevalent and incident cohort ICERs are likely to differ. Methods. Algebraic expressions were developed to capture all components of the ICER in hypothetical cohorts of all prevalent patients and future incident patients. Numerical examples are used to illustrate the approach. Results. The ICER for the first (i.e., next) incident cohort is equivalent to the ICER for all future incident cohorts only when the discount rates for costs and benefits are the same; otherwise, when the discount rate for benefits is lower than for costs, the ICER for all future incident cohorts is lower than the ICER for the first incident cohort. Separate simulation of prevalent and incident patients treated for a hypothetical progressive chronic disease shows widely different ICERs according to which patient cohorts were included when the discount rates were equal. Conclusions. In many circumstances, both the prevalent cohort and all future incident cohorts should be modeled. The need for this approach will depend on the likely difference in the ICERs for prevalent and incident patients, the relative size of the 2 types of cohort, and whether costs and benefits are discounted at equal rates.
A Bibliometric Review of Cost-Effectiveness Analyses in the Economic and Medical Literature: 1976-2006
Authors: Greenberg Dan , Rosen Allison B. , Wacht Oren , Palmer Jennifer , Neumann Peter J.
Published: March 2010

Background. Cost-effectiveness analysis (CEA) presenting a cost per quality-adjusted life year (QALY) ratio is frequently used to determine ‘‘value for money’’ in health care. Despite the proliferation of CEA research, there has been no detailed study focusing on the bibliometric properties of this literature. Objectives. To describe and analyze trends in publications and coauthorship in the CEA literature from 1976 to 2006 and to identify the most prolific authors and research groups conducting CEAs. Methods. The authors used the Tufts Medical Center Registry of original CEAs published through 2006 (www.cearegistry.org). For each article, they recorded the year of publication, the journal title, and the number of contributing authors and their names. Authors were assigned credit based on their weighted contribution to the study (1 credit point for the first and last authors, ½ point for the second author, and 1=n credit points for all other authors, where n reflects the number of coauthors). Results. Approximately 1400 CEAs presenting a cost/QALY ratio were published in 420 journals through 2006. The mean number of contributing authors was 4.7 ± 2.4. Medical journals were characterized by a higher number of coauthors, as compared with the economic and health policy journals: 4.8 ± 2.4 v. 4.2 ± 2.0, P < 0.001. The lowest average number of coauthors was in Medical Decision Making (3.6) and the highest in the Journal of the American College of Cardiology (8.2). The most prolific authors were affiliated with Harvard and Tufts Universities and their affiliated hospitals. The authors identified 4 major research groups that contributed substantially to the field of cost-effectiveness analysis but did not find any substantial academic relationships across these groups. Conclusions. The CEA literature continues to proliferate. Coauthorship trends appear to follow the rapid increase in the mean number of authors found in other publication types.
Cost-Effectiveness Analysis: Discount the Placebo at Your Peril
Authors: Hawkins Neil , Scott David A.
Published: March 2010

Introduction: The authors consider alternative mechanisms that might explain placebo responses and their implications for cost-effectiveness modeling. Three alternative placebo mechanisms are examined: a ‘‘regression to the mean’’ effect arising from natural variation and the preferential selection of patients with acutely severe disease into clinical trials, a patient expectancy effect specific to the clinical trial setting (Hawthorne effect), and a patient expectancy effect generalizable to routine clinical practice (true placebo effect). Methods: To estimate cost-effectiveness, the authors needed to generalize from trial data to estimate responses to treatment that they would see in routine clinical practice. They use an example analysis of the cost-effectiveness of adjunct epilepsy treatments to illustrate the potential effects of these different placebo mechanisms on this generalization and subsequent cost-effectiveness estimates and adoption decisions. Results: If an acceptable willingness-to-pay threshold of 30,000 per quality-adjusted life year (QALY) is assumed, then each of the placebo effect scenarios identifies a different treatment alternative as being optimum. Discussion: Estimated cost-effectiveness ratios and associated policy decisions may be sensitive to assumptions regarding the mechanism underlying placebo responses. These assumptions should, if possible, be investigated through analysis of trial or observational data and, in the absence of other evidence, sensitivity analysis.
Calbindin D28k Expression and the Absence of Apoptosis in the Cerebellum of Solanum bonariense L–Intoxicated Bovines
Authors: Verdes J. M. , Moraña J. A. , Battes D. , Gutiérrez F. , Guerrero F. , Goicoa A. , Fidalgo L. E. , Barbeito C. G. , Zanuzzi C. N. , Portiansky E. L. , Gimeno E. J.
Published: March 2010

Solanum bonariense intoxication is characterized by cerebellar neuronal vacuolation, degeneration, and necrosis. Cerebellar Purkinje cells seem especially susceptible, but more research is needed to determine the pathogenesis of neuronal necrosis and the mechanism of Purkinje cell susceptibility. Calbindin D28k (CbD28k) is highly expressed in Purkinje cells and has been used as a marker for normal and degenerative Purkinje cells. The goal of this study was to describe S bonariense–induced disease by ascertaining Purkinje cell–specific degenerative changes using CbD28k expression and to correlate this with apoptosis in Purkinje cells, as determined using TUNEL (transferase-mediated dUTP-biotin nick end-labeling) and ultrastructural changes. In all cases, an increase in both dose and duration of S bonariense intoxication resulted in a decrease in the number of Purkinje cells. CbD28k immunohistochemistry was an excellent marker for Purkinje cells because immunoreactivity did not change in normal or degenerative tissues. This finding suggests that excessive calcium excitatory stimulation does not induce rapid neuronal degeneration and death. As found in previous studies, TUNEL tests and electron microscopy suggest that Purkinje cell degeneration and death are not occurring via an apoptotic process. These findings suggest that S bonariense poisoning induces progressive Purkinje cell death that is not mediated by excitotoxicity or apoptotic activation.
Gender Differences in the Validity of the Substance Abuse Subtle Screening Inventory—3 (SASSI-3) With a Criminal Justice Population
Authors: Pérez Deanna M. , Wish Eric D.
Published: March 2010

The Substance Abuse Subtle Screening Inventory—3 is a brief, self-administered screening tool designed to measure the probability of having a substance dependence disorder. The present study assessed the validity of this instrument with an inmate population using a DSM-IV diagnosis of substance dependence as the criterion measure. The study also examined instrument validity by gender. Findings revealed differences in the prediction of dependence between male and female inmates. The advantages and shortcomings of the instrument are discussed in light of these findings, and suggestions for future research are advanced.
Reversible cerebral vasoconstriction, internal carotid artery dissection and renal artery stenosis
Authors: Field DK , Kleinig TJ , Thompson PD , Kimber TE
Published: March 2010

Reversible cerebral vasoconstriction is a rare and poorly understood syndrome, without clear diagnostic criteria. It has been described in association with multiple disorders, but has only been reported rarely in the setting of carotid artery dissection and, to our knowledge, never before in association with renal artery stenosis.
High frequency of migraine-only patients negative for the 3243 A>G tRNALeu mtDNA mutation in two MELAS families
Authors: Cevoli Sabina , Pallotti Francesco , Morgia Chiara La , Valentino Maria L , Pierangeli Giulia , Cortelli Pietro , Baruzzi Agostino , Montagna Pasquale , Carelli Valerio
Published: March 2010

Migraine is associated with stroke-like episodes in mitochondrial encephalomyopathy, lactic acidosis, stroke-like syndrome (MELAS). Moreover, abnormalities of oxidative phosphorylation are also reported in migraine. We studied two maternal lineages with MELAS and chronic progressive external ophthalmoplegia (CPEO) affected probands carrying the 3243 A>G tRNALeu (MELAS) mutation, remarkable for a high frequency of subjects suffering only migraine. Thus, migraine could be a monosymptomatic expression of the MELAS mutation. We assessed the 3243 A>G tRNALeu mutational load in skeletal muscle and other somatic tissues from the migraine-only subjects, as well as lactic acid levels after exercise. All migraine-only subjects did not carry the MELAS mutation. Muscle biopsy showed mild mitochondrial abnormalities in the non-mutant, migraine-only subjects and, occasionally, abnormal lactic acid. Clear features of mitochondrial myopathy and pathological lactic acid characterised the subjects carrying the MELAS mutation. Our study demonstrates that migraine-only subjects lacked the MELAS mutation, but still had a possible mtDNA-associated genetic predisposition, being maternally related and having some evidence of impaired mitochondrial oxidative phosphorylation.
Migraine prevalence by age and sex in the United States: A life-span study
Authors: Victor TW , Hu X , Campbell JC , Buse DC , Lipton RB
Published: March 2010

The present study assessed age- and sex-specific patterns of migraine prevalence in a US population of 40,892 men, women, and children who participated in the 2003 National Health Interview Survey. Gaussian mixture models characterised the relationship between migraine, age, and sex. Migraine prevalence was 8.6% (males), 17.5% (females), and 13.2% (overall) and showed a bimodal distribution in both sexes (peaking in the late teens and 20s and around 50 years of age). Rate of change in migraine prevalence for both sexes increased the fastest from age 3 years to the mid-20s. Beyond the age of 10 years, females had a higher prevalence of migraine than males. The prevalence ratio for females versus males was highest during the female reproductive/child-bearing years, consistent with a relationship between menstruation and migraine. After age 42 years, the prevalence ratio was approximately 2-fold higher in women.
Shear Behavior and Performance of RC Beams with Polymer Mortar Systems Under Cyclic Loading
Authors: Ha S.K. , Lee H.K. , Kang I.S.
Published: March 2010

A series of static cyclic loading tests were carried out to investigate the shear behavior and performance of RC beams with three different polymer mortar systems: (1) a (typical) polymer mortar without fibers, (2) a short-fiber reinforced polymer mortar, and (3) a hybrid polymer mortar incorporating honeycomb steel mesh (HPM). The effectiveness of the three different systems under static cyclic loading was investigated through the crack patterns, failure modes, and load-deflection curves of the RC beams. Stiffness degradation and energy dissipation of the RC beams with the three different systems were identified, and the level of damage of structures caused by occurrence, growth, and increase in number of cracks was also analyzed. A hybrid polymer mortar system incorporating a honeycomb steel mesh (HPM system) appears to be a feasible strengthening system for shear-deficient concrete structures. In addition, a comparison between the present experimental result and theoretical result in accordance with the ACI 318 (Building Code Requirements for Reinforced Concrete (ACI 318-89) and Commentary-ACI 318R-89, American Concrete Institute, Farmington Hills) was made to evaluate the shear strength of a control beam as a deep beam.
Improving Student Comprehension of Social Studies Text: A Self-Questioning Strategy for Inclusive Middle School Classes
Authors: Berkeley Sheri , Marshak Lisa , Mastropieri Margo A. , Scruggs Thomas E.
Published: March 2010

This study employed a randomized experimental design to investigate the effectiveness of a self-questioning strategy for improving student reading comprehension of grade-level social studies text material. Fifty-seven seventh grade students with a range of abilities, including English as second language learners and students with learning and other disabilities, from three inclusive middle school classes participated. Results indicated that students in the self-questioning strategy group outperformed students in a typical practice group on both multiple-choice and open-ended comprehension tests of the social studies content read. Implications for practice and future research are discussed.
The Utility of Conflict Resolution and Study Skills Interventions With Middle School Students at Risk for Antisocial Behavior
Authors: Kalberg Jemma Robertson , Lane Kathleen , Lambert Warren
Published: March 2010

This article provides a methodological illustration of how to conduct randomized controls trials (RCT) for secondary levels of prevention within the context of three-tiered models of support. First, the authors demonstrate one method of using school-wide data to identify middle school students ( N = 45) who were struggling in academic and behavioral domains. Second, the authors describe the procedures for conducting an RCT to compare two interventions (study skills [ n = 34] and conflict resolution [ n = 31]) relative to a business-as-usual condition (study skills [ n = 34]). Third, the authors conclude by offering recommendations for conducting scientifically rigorous—yet feasible—investigations within three-tiered models of prevention that adhere to the core quality indicators recommended by Gersten, Fuchs, Compton, Coyne, Greenwood, and Innocenti.
Reading Instruction in Secondary Day Treatment and Residential Schools for Youth With Emotional or Behavioral Disorders
Authors: Wilkerson Kimber L. , Gagnon Joseph Calvin , Melekoglu Macid Ayhan , Cakiroglu Orhan
Published: March 2010

This study was designed to obtain the first national picture of the characteristics of special educators who provide reading or English instruction in secondary day treatment and residential schools for youth with emotional or behavioral disorders (EBD) as well as their approach to reading instruction.Also, information was collected concerning the characteristics of the students in their classes.A national random sample of 123 (35%) reading or English teachers responded to a mail and online survey. No statistically significant differences existed between respondent and nonrespondent schools. Results indicated that teachers commonly hold master’s degrees and have an average of 9 years of teaching experience.Teachers reported using research-based instructional approaches but rarely integrate technology or peer tutoring into instruction. In many cases, teachers reported that students could not read well enough to gain basic information from text.Additional results and implications are discussed.
Evaluation in Urban Planning: Advances and Prospects
Authors: Oliveira Vitor , Pinho Paulo
Published: March 2010

This article provides an overview on the current debate on evaluation in urban planning. An initial evaluation state of the art is presented in three parts: the evolution of evaluation theory and methods, the contemporary planning debate around different perspectives and paradigms, and the nature and extent of evaluation practice in planning. The second part of the article focuses on the growing emphasis on urban form issues in different planning systems. This comprehensive literature review provides the background to support the authors’ proposal for a set of general principles to evaluate the implementation of urban plans.
Small-Angle X-ray Scattering Study on Covalently Cross-linked Polyvinyl Alcohol/Epoxy Resin Membrane in Polyphosphoric Acid
Authors: Cuihua Li  , Jianhong Liu  , Caizheng Zhu  , Qianling Zhang  , Zhongkuan Luo  , Rong Guan
Published: March 2010

Covalently cross-linked polyvinyl alcohol/epoxy resin membranes were prepared with different ratios of epoxy resin and cross-linking time in polyphosphoric acid (PPA). The structure and the membrane swelling behavior were investigated by small angle X-ray scattering (SAXS). It was found that fewer hydrophilic segments resulted in fewer and smaller hydrophilic domains during structural reorganization upon water swelling. The analogous swelling behavior of the membranes in the mixture of water and methanol has also been found. With higher content of epoxy resin, fewer hydrophilic segments aggregated into smaller hydrophilic domains and the distance between the two incompatible microdomains decreased.
Synthesis and Characterization of Processable Aromatic Polyimides
Authors: Thiruvasagam P. , Venkatesan D.
Published: March 2010

Two novel aromatic diamine monomers, Bis-4,4′[(4-aminophenyl-2,2′-isopropylidene phenyloxy)] diphenylsulfone and Bis-4,4′[(4-aminophenyl-2,2′-isopropylidene phenyloxy)] benzophenone were synthesized and characterized by IR and 1H-NMR. A series of processable polyimides were prepared by polycondensation of diamines with aromatic dianhydrides. The polyimides were characterized by infrared, 1H-NMR, X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, gel-permeation chromatography, solution viscosity and solubility. Polyimides were soluble in polar approtic solvents and increases in solubility in common organic solvents were observed due to the presence of flexible groups and methyl groups in the chain backbone. The polyimides exhibited good thermal stability, and the temperature at which 10% weight loss occurred ranged from 378 to 465 °C in nitrogen. X-ray diffraction measurements revealed that the polyimides were amorphous.
Conducting Outcomes Research in Pediatric Palliative Care
Authors: Knapp Caprice , Madden Vanessa
Published: March 2010

Around the globe, health care costs continue to rise resulting in the emphasis on allocating scarce resources toward interventions that have been found to be cost- and clinically effective. Palliative care is no exception, yet the science of outcomes measurement in palliative care, and especially in pediatric palliative care, lags behind other disciplines. National and international experts and organizations have recognized the importance of outcomes measurement and have included this as a research priority. This article outlines some of the complexities of measuring outcomes in pediatric palliative care. It is recommended that national and international collaborations include representatives of the pediatric palliative care community.
Ethical Imperatives for Intervention with Elder Families
Authors: Bradley Loretta J. , Whiting Peggy P. , Hendricks Bret , Wheat Laura S.
Published: March 2010

This article discusses the ethical dilemmas common to counseling practice with elder families and describes virtue ethics, rule ethics, and principle ethics in their application to the unique challenges of the life stage of diverse adults 60 years and older. The Five P Model of Ethical Decision Making of Gamino and Ritter is examined as a process for conceptualizing the ethics of care in complex situations like those of elder families. The authors challenge family counselors to expand their gerontological knowledge, including that of end-of-life care and bereavement, and to use a developmental lens when taking perspective on issues of aging clients and their families.
Homeostatic Regulation of Neuronal Excitability by K+ Channels in Normal and Diseased Brains
Authors: Misonou Hiroaki
Published: March 2010

K+-selective ion channels are critical determinants of membrane excitability in neuronal cells. Like many other cells in our body, neuronal cells have a propensity to maintain their homeostasis. Action potential firing is the most important function to maintain in brain neurons, as they are the elements of neural networks. If one element fires action potentials at an abnormally high rate, the entire network could become epileptic. Therefore, brain neurons adjust their intrinsic membrane excitability to maintain the firing rate within their own optimal operational range. When a neuron receives an enormous input, it will reduce the membrane excitability to prevent overshooting. When it is deprived of stimulus, the membrane becomes more excitable to avoid total quiescence. The homeostatic regulation of intrinsic excitability provides stability to the neural network in the face of dynamic and plastic synaptic inputs. In the past decade, we have learned that neurons achieve this type of homeostatic regulation through a variety of ion channels, including K+ channels. It has also become clear that under certain pathological conditions, these homeostatic mechanisms provide neuroprotection. In this article, I will review recent advances in our understanding of K+ channel—mediated homeostatic regulation of neuronal excitability and discuss involvement of these channels in hyperexcitable diseases where they provide neuroprotection.
A Compound Herbal Preparation (CHP) in the Treatment of Children With ADHD: A Randomized Controlled Trial
Authors: Katz M. , Adar Levine A. , Kol-Degani H. , Kav-Venaki L.
Published: March 2010

Objective: Evaluation of the efficacy of a patented, compound herbal preparation (CHP) in improving attention, cognition, and impulse control in children with ADHD. Method: Design: A randomized, double-blind, placebo-controlled trial. Setting: University-affiliated tertiary medical center. Participants: 120 children newly diagnosed with ADHD, meeting DSM-IV criteria. Intervention: Random assignment to the herbal treatment group ( n = 80) or control group (placebo; n = 40); 73 patients in the treatment group (91%) and 19 in the control group (48%) completed the 4-month trial. Outcome measure: Test of Variables of Attention (TOVA) administered before and after the treatment period; overall score and 4 subscales. Results: The treatment group showed substantial, statistically significant improvement in the 4 subscales and overall TOVA scores, compared with no improvement in the control group, which persisted in an intention-to-treat analysis. Conclusions: The well-tolerated CHP demonstrated improved attention, cognition, and impulse control in the intervention group, indicating promise for ADHD treatment in children.
Changing patterns of secondary preventive medication among newly diagnosed coronary heart disease patients with diabetes in Finland: A register-based study
Authors: Vehko Tuulikki , Manderbacka Kristna , Arffman Martti , Sund Reijo , Reunanen Antti , Keskimäki Ilmo
Published: March 2010

Aims: Information on medicine use among coronary heart disease (CHD) patients with diabetes in unselected patient populations is scarce. This study examines the use of medication to prevent new cardiac events among newly diagnosed CHD patients with diabetes comparing them to patients without diabetes and examines socioeconomic differences in medicine use in these patient groups. Methods: Data on CHD patients (43,501 men and 31,125 women) with or without diabetes were individually linked from nationwide registers (covering both patients treated in ambulatory and in hospital inpatient care). Age-standardised rates for medication use were calculated and differences between patient groups examined using Poisson regression. Results: β-blocker use was high in all patient groups in 1997—2002, angiotensin-converting enzyme (ACE) inhibitor and angiotensin II antagonist use increased and remained higher among patients with diabetes. More than half of men and women with diabetes used ACE inhibitors and one out of five used angiotensin II antagonists in 2002. Lipid-lowering medication use increased, especially among women. In 1997—98 it was lower in lower socioeconomic groups; among men with diabetes the use remained lower than among others. Conclusions: β-blocker use was constant and ACE inhibitor and angiotensin II antagonist use increased. Lipid-lowering medication use increased considerably after a health insurance reform in 2000, in which elevated reimbursement of drug costs (75%) was extended to include all CHD patients with hyperlipidaemia.Socioeconomic differences in medication use disappeared after the reform. However, lipid-lowering medication use remained at a lower level among men with diabetes, suggesting that their treatment did not follow guidelines.
Lower Limb Coordination in Hemiparetic Subjects: Impact of Botulinum Toxin Injections Into Rectus Femoris
Authors: Hutin Emilie , Pradon Didier , Barbier Franck , Gracies Jean-Michel , Bussel Bernard , Roche Nicolas
Published: March 2010

Background. Botulinum toxin (BTX) injection into rectus femoris (RF) is a therapeutic modality used to improve knee flexion during the swing phase of gait in hemiparesis. The impact of this treatment on lower limb coordination is unknown. The authors evaluated whether BTX injection into RF is associated with modifications of intersegmental coordination in hemiparesis. Methods. The authors evaluated gait in 10 control and 14 hemiparetic subjects with low peak knee flexion associated with inappropriate RF activity in mid-swing, using 3-dimensional analysis before and 1 month after BTX injection into RF (Botox, 200 units). Thigh—shank coordination was measured in the sagittal plane by averaging the continuous relative phase (CRPThigh— Shank) during each phase of the gait cycle in both lower limbs. The CRP is a validated metric that integrates angle positions and velocities of 2 limb segments to quantify their temporal—spatial coordination. Results. Before treatment, the low peak knee flexion in hemiparetic subjects (paretic limb 29 ± 9°) was associated with a decreased CRP Thigh—Shank in the paretic limb in swing (paretic limb 26.0 ± 16.6° vs controls 73.5 ± 7.4°, P < .001) and with a trend of an increased CRPThigh —Shank in the nonparetic limb over the full gait cycle (nonparetic limb 77.9 ± 14.1° vs controls 66.2 ± 19.8°, P = .083). After treatment, the CRPThigh— Shank increased by 11.9° in the swing phase of the paretic limb ( P = .002) and decreased by 8.0° over the full gait cycle ( P = .002) in the nonparetic limb. Conclusions. BTX injection into RF was associated with improved thigh—shank coordination in parts of the gait cycle, in both injected paretic and noninjected nonparetic limbs.
Review: Procedure- and Device-Related Complications of Intrathecal Baclofen Administration for Management of Adult Muscle Hypertonia: A Review
Authors: Stetkarova Ivana , Yablon Stuart A. , Kofler Markus , Stokic Dobrivoje S.
Published: March 2010

Background. Intrathecal baclofen (ITB) effectively reduces muscle hypertonia; however, associated complications influence its utility and acceptance. Objective. To systematically review the literature on procedure- and device-related complications associated with ITB infusion therapy for adult muscle hypertonia of spinal or cerebral origin. Methods. The authors searched the PubMed database for full-length articles published in English that reported ITB-associated complications in adults. Of 147 articles retrieved, 32 full-length manuscripts and 10 case reports were reviewed in detail. Results. Overall, 558 complications were reported after 1362 pump implants (0.41 per implant). Methods for characterizing complications varied greatly between studies, as did complication rates, ranging from 0 to 2.24 per implant. Of the 558 complications, 148 (27%) were related to surgical procedures, 39 (7%) to pump problems, and 369 (66%) to catheter malfunctions. The overall complication rate was higher for studies that followed patients for more than 18 months on average (mean 0.56/implant) versus studies with shorter follow-up (0.23/implant, P < .05). Although correlation between the number of implants and the number of complications was significant ( r = .58), the goodness of linear fit was poor because of clusters with varied complication rates. Conclusions. Catheter problems are relatively common and more frequent than pump or surgical procedure complications after ITB pump implantation. Higher complication rates should be expected in centers that follow patients for a longer period of time. Standardized data collection and complication-reporting procedures along with appropriate training should be implemented in centers offering ITB treatment for management of muscle hypertonia.
Generation of iPSCs from cultured human malignant cells
Authors: Carette Jan E. , Pruszak Jan , Varadarajan Malini , Blomen Vincent A. , Gokhale Sumita , Camargo Fernando D. , Wernig Marius , Jaenisch Rudolf , Brummelkamp Thijn R.
Published: March 2010

Induced pluripotent stem cells (iPSCs) can be generated from various differentiated cell types by the expression of a set of defined transcription factors. So far, iPSCs have been generated from primary cells, but it is unclear whether human cancer cell lines can be reprogrammed. Here we describe the generation and characterization of iPSCs derived from human chronic myeloid leukemia cells. We show that, despite the presence of oncogenic mutations, these cells acquired pluripotency by the expression of 4 transcription factors and underwent differentiation into cell types derived of all 3 germ layers during teratoma formation. Interestingly, although the parental cell line was strictly dependent on continuous signaling of the BCR-ABL oncogene, also termed oncogene addiction, reprogrammed cells lost this dependency and became resistant to the BCR-ABL inhibitor imatinib. This finding indicates that the therapeutic agent imatinib targets cells in a specific epigenetic differentiated cell state, and this may contribute to its inability to fully eradicate disease in chronic myeloid leukemia patients.
Mast cells and the neurofibroma microenvironment
Authors: Staser Karl , Yang Feng-Chun , Clapp D. Wade
Published: March 2010

Neurofibromatosis type 1 (NF1) is the most common genetic disorder with a predisposition to malignancy and affects 1 in 3500 persons worldwide. NF1 is caused by a mutation in the NF1 tumor suppressor gene that encodes the protein neurofibromin. Patients with NF1 have cutaneous, diffuse, and plexiform neurofibromas, tumors comprised primarily of Schwann cells, blood vessels, fibroblasts, and mast cells. Studies from human and murine models that closely recapitulate human plexiform neurofibroma formation indicate that tumorigenesis necessitates NF1 loss of heterozygosity in the Schwann cell. In addition, our most recent studies with bone marrow transplantation and pharmacologic experiments implicate haploinsufficiency of Nf1 (Nf1+/−) and c-kit signaling in the hematopoietic system as required and sufficient for tumor progression. Here, we review recent studies implicating the hematopoietic system in plexiform neurofibroma genesis, delineate the physiology of stem cell factor–dependent hematopoietic cells and their contribution to the neurofibroma microenvironment, and highlight the application of this research toward the first successful, targeted medical treatment of a patient with a nonresectable and debilitating neurofibroma. Finally, we emphasize the importance of the tumor microenvironment hypothesis, asserting that tumorigenic cells in the neurofibroma do not arise and grow in isolation.
Contrasting effects of Sox17- and Sox18-sustained expression at the onset of blood specification
Authors: Serrano Alicia G. , Gandillet Arnaud , Pearson Stella , Lacaud Georges , Kouskoff Valerie
Published: March 2010

We have previously shown that Sox7 was transiently expressed at the onset of blood specification and was implicated in the regulation of cell survival, proliferation, and maturation of hematopoietic precursors. Here, we assessed, using embryonic stem cell differentiation as a model system, whether Sox17 and Sox18, 2 close homologs of Sox7, may act similarly to Sox7 at the onset of hematopoietic development. Sox18-enforced expression led to the enhanced proliferation of early hematopoietic precursors while blocking their maturation, phenotype highly reminiscent of Sox7-enforced expression. In striking contrast, Sox17-enforced expression dramatically increased the apoptosis of these early precursors. Similarly to Sox7, Sox18 was transiently expressed during early hematopoiesis, but its expression was predominantly observed in CD41+ cells, contrasting with Sox7, mostly expressed in Flk1+ cells. Conversely, Sox17 remained marginally expressed during blood specification. Overall, our data uncover contrasting effect and expression pattern for Sox18 and Sox17 at the onset of hematopoiesis specification.
End-of-life experience of children undergoing stem cell transplantation for malignancy: parent and provider perspectives and patterns of care
Authors: Ullrich Christina K. , Dussel Veronica , Hilden Joanne M. , Sheaffer Jan W. , Lehmann Leslie , Wolfe Joanne
Published: March 2010

The end-of-life (EOL) experience of children who undergo stem cell transplantation (SCT) may differ from that of other children with cancer. To evaluate perspectives and patterns of EOL care after SCT, we surveyed 141 parents of children who died of cancer (response rate, 64%) and their physicians. Chart review provided additional information. Children for whom SCT was the last cancer therapy (n = 31) were compared with those for whom it was not (n = 110). SCT parents and physicians recognized no realistic chance for cure later than non-SCT peers (both P < .001) and were more likely to have a primary goal of cure at death (parents, P < .001; physicians, P = .02). SCT children were more likely to suffer highly from their last cancer therapy and die in the intensive care unit (both P < .001), with less opportunity for EOL preparation. SCT parents who recognized no realistic chance for cure more than 7 days before death along with the physician were more likely to prepare for EOL, and if their primary goal was to reduce suffering, to achieve this (P < .001). SCT is associated with significant suffering and less opportunity to prepare for EOL. Children and families undergoing SCT may benefit from ongoing discussions regarding prognosis, goals, and opportunities to maximize quality of life.
Complementary transcriptomic, lipidomic, and targeted functional genetic analyses in cultured Drosophila cells highlight the role of glycerophospholipid metabolism in Flock House virus RNA replication
Authors: Castorena Kathryn M , Stapleford Kenneth A , Miller David J
Published: March 2010

Background

Cellular membranes are crucial host components utilized by positive-strand RNA viruses for replication of their genomes. Published studies have suggested that the synthesis and distribution of membrane lipids are particularly important for the assembly and function of positive-strand RNA virus replication complexes. However, the impact of specific lipid metabolism pathways in this process have not been well defined, nor have potential changes in lipid expression associated with positive-strand RNA virus replication been examined in detail.

Results

In this study we used parallel and complementary global and targeted approaches to examine the impact of lipid metabolism on the replication of the well-studied model alphanodavirus Flock House virus (FHV). We found that FHV RNA replication in cultured Drosophila S2 cells stimulated the transcriptional upregulation of several lipid metabolism genes, and was also associated with increased phosphatidylcholine accumulation with preferential increases in lipid molecules with longer and unsaturated acyl chains. Furthermore, targeted RNA interference-mediated downregulation of candidate glycerophospholipid metabolism genes revealed a functional role of several genes in virus replication. In particular, we found that downregulation of Cct1 or Cct2, which encode essential enzymes for phosphatidylcholine biosynthesis, suppressed FHV RNA replication.

Conclusion

These results indicate that glycerophospholipid metabolism, and in particular phosphatidylcholine biosynthesis, plays an important role in FHV RNA replication. Furthermore, they provide a framework in which to further explore the impact of specific steps in lipid metabolism on FHV replication, and potentially identify novel cellular targets for the development of drugs to inhibit positive-strand RNA viruses.
Functional analysis of B and C class floral organ genes in spinach demonstrates their role in sexual dimorphism
Authors: Sather D Noah , Jovanovic Maja , Golenberg Edward M
Published: March 2010

Background

Evolution of unisexual flowers entails one of the most extreme changes in plant development. Cultivated spinach, Spinacia oleracea L., is uniquely suited for the study of unisexual flower development as it is dioecious and it achieves unisexually by the absence of organ development, rather than by organ abortion or suppression. Male staminate flowers lack fourth whorl primordia and female pistillate flowers lack third whorl primordia. Based on theoretical considerations, early inflorescence or floral organ identity genes would likely be directly involved in sex-determination in those species in which organ initiation rather than organ maturation is regulated. In this study, we tested the hypothesis that sexual dimorphism occurs through the regulation of B class floral organ gene expression by experimentally knocking down gene expression by viral induced gene silencing.

Results

Suppression of B class genes in spinach resulted in the expected homeotic transformation of stamens into carpels but also affected the number of perianth parts and the presence of fourth whorl. Phenotypically normal female flowers developed on SpPI-silenced male plants. Suppression of the spinach C class floral organ identity gene, SpAG, resulted in loss of reproductive organ identity, and indeterminate flowers, but did not result in additional sex-specific characteristics or structures. Analysis of the genomic sequences of both SpAP3 and SpPI did not reveal any allelic differences between males and females.

Conclusion

Sexual dimorphism in spinach is not the result of homeotic transformation of established organs, but rather is the result of differential initiation and development of the third and fourth whorl primordia. SpAG is inferred to have organ identity and meristem termination functions similar to other angiosperm C class genes. In contrast, while SpPI and SpAP3 resemble other angiosperms in their essential functions in establishing stamen identity, they also appear to have an additional function in regulating organ number and identity outside of the third whorl. We present a model for the evolution of dioecy in spinach based on the regulation of B class expression.
The prevalence of common skin infections in four districts in Timor-Leste: a cross sectional survey
Authors: dos Santos Milena ML , Amaral Salvador , Harmen Sonia P , Joseph Hayley M , Fernandes Jose L , Counahan Megan L
Published: March 2010

Background

Skin infections are a common public health problem in developing countries; however, they are rarely managed using a population based approach. Recent data on the burden of skin infections in Timor-Leste are limited. Our survey appears to be the only widespread survey conducted in more than 30 years and was designed to determine the baseline prevalence of some common skin infections in Timor-Leste.

Methods

We conducted a cross sectional survey in 14 sites including community health clinics, schools and hospitals within four different geographical regions. Participants were examined for five conditions (scabies, pyoderma, fungal infections, leprosy and yaws) by a multidisciplinary team. Analyses were conducted using EpiInfo version 6.04d.

Results

We examined the skin of 1535 participants aged between four months and 97 years. The majority of participants were male, aged between 11 and 20 years and had at least one condition of interest (56.0%, 56.0%, and 63.1%, respectively). Fungal infections were the most common presentation (39.0%) and males were more commonly affected than females (42.3% vs 34.0%, respectively, pvalue < 0.0001).

Among those people with more than one condition the two most common co-infections were scabies with either pyoderma or a fungal infection (38.0% and 32.0%, respectively). The survey identified 29 previously undiagnosed cases of leprosy and six cases of yaws.

Conclusions

Our findings indicate the need for a comprehensive programme to address these conditions. There are successful disease control programmes in place within the country and it is hoped a healthy skin programme could be integrated into an established disease control programme in order to maximise health benefits and resources.
Diet and lifestyle interventions in postpartum women in China: study design and rationale of a multicenter randomized controlled trial
Authors: Bao Wei , Ma Aiguo , Mao Limei , Lai Jianqiang , Xiao Mei , Sun Guoqiang , Ouyang Yingying , Wu Shuang , Yang Wei , Wang Nanping , Zhao Yanting , Fu Juan , Liu Liegang
Published: March 2010

Background

"Doing the month", or "sitting month", is a traditional practice for postpartum women in China and other Asian countries, which includes some taboos against well-accepted healthy diet and lifestyles in general population. Previous studies have shown this practice may be associated with higher prevalence of postpartum problems. The current multicenter randomized controlled trial (RCT) aims to evaluate outcomes of diet and lifestyle interventions in Chinese postpartum women.

Methods/Design

The current multicenter RCT will be conducted in three representative areas in China, Shandong province, Hubei province and Guangdong province, which locate in northern, central and southern parts of China, respectively. Women who attend routine pregnancy diagnosis in hospitals or maternal healthcare centers will be invited to take part in this study. At least 800 women who meet our eligibility criteria will be recruited and randomly assigned to the intervention group (n > = 400) and the control group (n > = 400). A three-dimension comprehensive intervention strategy, which incorporates intervention measures simultaneously to individual postpartum woman, their family members and community environment, will be utilized to maximize the effectiveness of intervention. Regular visiting and follow-up will be done in both group; nutrition and health-related measurements will be assessed both before and after the intervention.

Discussion

To our knowledge, this current study is the first and largest multicenter RCT which focus on the effectiveness of diet and lifestyle intervention on reducing the incidence rate of postpartum diseases and improving health status in postpartum women. We hypothesize that the intervention will reduce the incidence rates of postpartum diseases and improve nutrition and health status due to a balanced diet and reasonable lifestyle in comparison with the control condition. If so, the results of our study will provide especially important evidence for changes in both the concept and action of traditional postpartum practice in China.

Trial Registration

ClinicalTrials.gov ID NCT01039051.
Factors influencing implementation of the Ministry of Health-led private medicine retailer programmes on malaria in Kenya
Authors: Rowa Yvonne , Abuya Timothy O , Mutemi Wilfred K , Ochola Sam , Molyneux Sassy , Marsh Vicki
Published: March 2010

Background

Kenya has experienced a number of retail sector initiatives aimed at improving access to antimalarial medicines. This study explored stakeholders' perceptions of the role of private medicine retailers (PMRs), the value and feasibility of programme goals, perceived programme impact, factors influencing implementation and recommendations in three districts of Kenya.

Methods

This study was part of a larger evaluation of PMR programmes, including quantitative and qualitative components. The qualitative research was conducted to assess implementation processes and actors' experiences in the programmes, through focus group discussions with trained PMRs and mothers of children under five years, and in-depth interviews with programme managers, trainers and co-trainers.

Results

PMRs were perceived to provide rapid cheap treatment for non-serious conditions and used as a deliberate and continuously evaluated choice between different treatment sources. All stakeholders supported programme goals and most PMRs described increased customer satisfaction, more rational purchasing of medicine stock and increased medicine sales after participation. Factors undermining programme implementation included a lack of MoH resources to train and monitor large numbers of PMRs, the relative instability of outlets, medicines stocked and retail personnel, the large number of proprietary brands and financial challenges to retailers in stocking antimalarial medicines, and their customers in buying them. Unambiguous national support and a broad range of strategies are important to strengthen the feasibility of change in OTC antimalarial use.

Conclusions

Understanding the context and implementation processes of PMR programmes and the perspectives of key actors are critical to identifying measures to support their effective implementation. Financial barriers underlie many described challenges, with important implications for policies on subsidies in this sector. In spite of barriers to implementation, increased exposure to programme activities promoted trust and improved relationships between PMRs and their clients and trainers, strengthening feasibility of such interventions. Public information can strengthen PMR training programmes by engaging local communities and may facilitate performance monitoring of PMRs by their clients.
LIMD1 is more frequently altered than RB1 in head and neck squamous cell carcinoma: clinical and prognostic implications
Authors: Ghosh Susmita , Ghosh Amlan , Maiti Guru P , Mukherjee Nupur , Dutta Sankhadeep , Roy Anup , Roychoudhury Susanta , Panda Chinmay K
Published: March 2010

Introduction

To understand the role of two interacting proteins LIMD1 and pRB in development of head and neck squamous cell carcinoma (HNSCC), alterations of these genes were analyzed in 25 dysplastic head and neck lesions, 58 primary HNSCC samples and two HNSCC cell lines.

Methods

Deletions of LIMD1 and RB1 were analyzed along with mutation and promoter methylation analysis of LIMD1. The genotyping of LIMD1 linked microsatellite marker, hmlimD1, was done to find out any risk allele. The mRNA expression of LIMD1 and RB1 were analyzed by Q-PCR. Immunohistochemical analysis of RB1 was performed. Alterations of these genes were correlated with different clinicopathological parameters.

Results

High frequency [94% (78/83)] of LIMD1 alterations was observed in the samples studied. Compare to frequent deletion and methylation, mutation of LIMD1 was increased during tumor progression (P = 0.007). Six novel mutations in exon1 and one novel intron4/exon5 splice-junction mutation were detected in LIMD1 along with a susceptible hmlimD1 (CA)20 allele. Some of these mutations [42% (14/33)] produced non-functional proteins. RB1 deletion was infrequent (27%). Highly reduced mRNA expression of LIMD1 (25.1 ± 19.04) was seen than RB1 (3.8 ± 8.09), concordant to their molecular alterations. The pRB expression supported this data. Tumors with LIMD1 alterations in tobacco addicted patients without HPV infection showed poor prognosis. Co-alterations of these genes led the worse patients' outcome.

Conclusions

Our study suggests LIMD1 inactivation as primary event than inactivation of RB1 in HNSCC development.