Morphology of Breast Implant Fold Flaw Failure

Journal of Long-term Effects of Medical Implants. 2006  |  Pubmed ID: 17956211

The percent of modern silicone gel breast implants that fail due to shell rupture is quite low, amounting to less than 1% per year. Nonetheless, extensive retrieval and analysis studies are being conducted on failed devices returned to Allergan Medical (formerly Inamed Corporation) in order to determine the modes and causes of failure. With the modes and causes known, solutions can be implemented to eliminate the failure mechanisms. Analyses conducted thus far have demonstrated that there are several causes of breast implant failure. The focus of this paper is on one type of silicone gel breast implant failure, i.e., a failure associated with a fold or wrinkle, which is termed "fold flaw failure." Although fold flaw failure is not a dominant mode of failure for silicone gel breast implants, its failure characteristics must be understood in order for this type of shell rupture to be detected and eventually eliminated. In this study, optical microscopy and scanning electron microscopy are used to describe the morphology of fold flaw failure for explanted silicone gel breast implants with smooth shells. The microscopy analysis demonstrates that there are several different types of shell failure patterns that can be produced by a fold or wrinkle in a silicone gel breast implant.

Conformational Instability of the Cholera Toxin A1 Polypeptide

Journal of Molecular Biology. Dec, 2007  |  Pubmed ID: 17976649

Cholera toxin (CT) moves from the cell surface to the endoplasmic reticulum (ER) by vesicular transport. In the ER, the catalytic CTA1 subunit dissociates from the holotoxin and enters the cytosol by exploiting the quality control system of ER-associated degradation (ERAD). It is hypothesized that CTA1 triggers its ERAD-mediated translocation into the cytosol by masquerading as a misfolded protein, but the process by which CTA1 activates the ERAD system remains unknown. Here, we directly assess the thermal stability of the isolated CTA1 polypeptide by biophysical and biochemical methods and correlate its temperature-dependent conformational state with susceptibility to degradation by the 20S proteasome. Measurements with circular dichroism and fluorescence spectroscopy demonstrated that CTA1 is a thermally unstable protein with a disordered tertiary structure and a disturbed secondary structure at 37 degrees C. A protease sensitivity assay likewise detected the temperature-induced loss of native CTA1 structure. This protease-sensitive conformation was not apparent when CTA1 remained covalently associated with the CTA2 subunit. Thermal instability in the dissociated CTA1 polypeptide could thus allow it to appear as a misfolded protein for ERAD-mediated export to the cytosol. In vitro, the disturbed conformation of CTA1 at 37 degrees C rendered it susceptible to ubiquitin-independent degradation by the core 20S proteasome. In vivo, CTA1 was also susceptible to degradation by a ubiquitin-independent proteasomal mechanism. ADP-ribosylation factor 6, a cytosolic eukaryotic protein that enhances the enzymatic activity of CTA1, stabilized the heat-labile conformation of CTA1 and protected it from in vitro degradation by the 20S proteasome. Thermal instability in the reduced CTA1 polypeptide has not been reported before, yet both the translocation and degradation of CTA1 may depend upon this physical property.

Are Different Groups of Patients with Stroke More Likely to Be Excluded from the New UK General Medical Services Contract? A Cross-sectional Retrospective Analysis of a Large Primary Care Population

BMC Family Practice. 2007  |  Pubmed ID: 17900351

In April 2004, an incentive based contract was introduced to UK primary care. An important element of the new contract is the ability to exclude individuals from quality indicators for a variety of reasons (known as 'exception reporting'). Exception of patients with stroke or TIA from the recording and achievement of quality indicators may have important consequences in terms of stroke recurrence and mortality.

Family-member Presence During Interventions in the Intensive Care Unit: Perceptions of Pediatric Cardiac Intensive Care Providers

Pediatrics. Oct, 2007  |  Pubmed ID: 17908745

Should family members be present during interventions in an ICU? This question is a source of debate among health care providers. We propose to define perceptions and practice regarding family-member presence during ICU interventions from a multidisciplinary group of pediatric cardiac intensive care providers.

Myocardial Fas Ligand Expression Increases Susceptibility to AZT-induced Cardiomyopathy

Cardiovascular Toxicology. 2007  |  Pubmed ID: 17943461

Dilated cardiomyopathy (DCM) and myocarditis occur in many HIV-infected individuals, resulting in symptomatic heart failure in up to 5% of patients. Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality of acquired immunodeficiency syndrome (AIDS), but has resulted in an increase in cardiac and skeletal myopathies.

Soaking It Up: the Complex Lives of Marine Sponges and Their Microbial Associates

The ISME Journal. Jul, 2007  |  Pubmed ID: 18043629

Long-term Botulinum Toxin Dose Consistency for Treatment of Adductor Spasmodic Dysphonia

The Annals of Otology, Rhinology, and Laryngology. Dec, 2007  |  Pubmed ID: 18217507

Botulinum toxin (BTX) injection is currently the primary and most common treatment for adductor spasmodic dysphonia (ADSD). A variety of injection strategies and dosage regimens have been described. This study reports on our experience with the dosage schedule and dosing consistency of BTX for the treatment of ADSD.

Incorporation of C-1 Lateral Mass Screws in Occipitocervical and Atlantoaxial Fusions for Children 8 Years of Age or Younger. Technical Note

Journal of Neurosurgery. Aug, 2007  |  Pubmed ID: 18459894

The authors describe the novel use of C-1 lateral mass screws in four children 8 years of age or younger, in whom occipitocervical or atlantoaxial fusion was performed for trauma or os odontoideum. The authors retrospectively reviewed the demographics and procedural data of four children, ranging in age from 2 to 8 years, who required and underwent surgical fixation. Although C1-2 screw/rod constructs involving individual C-1 lateral mass screws and C-2 pars interarticularis or pedicle screws have been widely applied in adults, only C1-2 transarticular screw fixation has been reported in children less than 8 years of age. This report demonstrates the successful results of rigid occipitocervical and atlantoaxial fusion in four children in whom C-1 lateral mass screws were placed as part of a screw/rod construct. There was one instance of a vertebral artery injury, and the lessons learned from this complication are discussed.

Issues for DSM-V: the Medical Diagnostic Model

The American Journal of Psychiatry. Jul, 2008  |  Pubmed ID: 18593783

The Utility of Ultra-performance Liquid Chromatography/electrospray Ionisation Time-of-flight Mass Spectrometry for Multi-residue Determination of Pesticides in Strawberry

Rapid Communications in Mass Spectrometry : RCM. Sep, 2008  |  Pubmed ID: 18677705

The utility of ultra-performance liquid chromatography/orthogonal-acceleration time-of flight mass spectrometry (UPLC/TOFMS) for the rapid qualitative and quantitative analysis of 100 pesticides targeted in strawberry was assessed by comparing results with those obtained using a validated in-house UPLC tandem mass spectrometry (MS/MS) multi-residue method. Crude extracts from retail strawberry samples received as part of the 2007 annual UK pesticide residues in food surveillance programme were screened for the presence of pesticide residues using UPLC/TOFMS. Accurate mass measurement of positive and negative ions allowed their extraction following 'full mass range data acquisition' with negligible interference from background or co-eluting species observed during UPLC gradient separation (in a cycle time of just 6.5 min per run). Extracted ion data was used to construct calibration curves and to detect and identify any incurred residues (i.e. pesticides incorporated in or on the test material following application during cultivation, harvest and storage). Calibration using matrix-matched standards was performed over a narrow concentration range of 0.005-0.04 mg kg(-1) with determination coefficients (r2) > or =0.99 for all analytes with the exception of malathion/fenarimol/fludioxanil (r2 = 0.98), quassia/pymetrazine (r2 = 0.97) and fenthion sulfone (r2 = 0.95). Residues found in selected samples ranged from 0.025-0.28 mg kg(-1) and were in excellent agreement with results obtained using UPLC/MS/MS. Mass measurement accuracies of < or =5 ppm were achieved consistently throughout the separation, mass range and concentration range of interest thus providing the opportunity to obtain discrete elemental compositions of target ions.

Ensuring Job Site Awareness

Occupational Health & Safety (Waco, Tex.). Jul, 2008  |  Pubmed ID: 18686450

Applying a Reverse Auction to Reduce Stormwater Runoff

Ambio. Jun, 2008  |  Pubmed ID: 18686516

Preliminary Studies on the Relationship Among Peel Force, Quantitative Measures of Skin Damage and Subjective Discomfort

Skin Research and Technology : Official Journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI). Nov, 2008  |  Pubmed ID: 18937785

The ability to anticipate skin damage and subject/patient discomfort due to the removal of adhesive materials without human testing is currently limited. While standardized laboratory methods have been developed, their ability to model and predict the interaction with relevant living substrate is imperfect. The aim of this study was to assess the adhesion of various materials as a function of time using the abdomen as the body site, and determine if a relationship existed with skin damage and subject discomfort.

Allied Mental Health Referral. Trends in the Adelaide Hills Division of General Practice

Australian Family Physician. Oct, 2008  |  Pubmed ID: 19002315

Referrals to allied health professionals as part of Access To Allied Psychological Services (ATAPS) and More Allied Health Services (MAHS) at the Adelaide Hills Division of General Practice were examined to gain insight into the characteristics of referred patients and the characteristics of referring general practitioners.

The Effect of the UK Incentive-based Contract on the Management of Patients with Coronary Heart Disease in Primary Care

Family Practice. Feb, 2008  |  Pubmed ID: 18222938

The new General Medical Services (nGMS) contract was introduced in April 2004 to improve care of chronic diseases such as coronary heart disease (CHD) and reduce differences in treatment between patient subgroups.

Reforming Funding for Chronic Illness: Medicare-CDM

Australian Health Review : a Publication of the Australian Hospital Association. Feb, 2008  |  Pubmed ID: 18241151

Chronic diseases are a major challenge for the Australian health care system in terms of both the provision of quality care and expenditure, and these challenges will only increase in the future. Various programs have been instituted under the Medicare system to provide increased funding for chronic care, but essentially these programs still follow the traditional fee-for-service model. This paper proposes a realignment and extension of current Medicare chronic disease management programs into a framework that provides general practitioners and other health professionals with the necessary "tools" for high quality care planning and ongoing management, and incorporating international models of outcome-linked funding. The integration of social support services with the Medicare system is also a necessary step in providing high quality care for patients with complex needs requiring additional support.

Neurosurgical Implications of Osteogenesis Imperfecta in Children. Report of 4 Cases

Journal of Neurosurgery. Pediatrics. Mar, 2008  |  Pubmed ID: 18352768

Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by disruption of normal collagen formation resulting in varying degrees of skeletal vulnerability, ligamentous laxity, and scleral discoloration. Children with OI may suffer from complex neurosurgical problems affecting the brain and spine. The authors sought to determine the neurosurgical implications of OI in a cohort of patients treated at a quaternary care center for pediatrics. The authors reviewed the case histories of 10 children with OI treated by the neurosurgical service at the Hospital for Sick Children in Toronto between January 1988 and March 2007. The cases of 4 of these children are highlighted in the article. The most common neurosurgical conditions encountered in this cohort included macrocephaly in 5 patients, subdural hematoma in 3 patients, epidural hematoma in 2 patients, and hydrocephalus in 3 patients. Basilar invagination and spinal fractures were observed in 20% of the cohort. Although some patients could be treated nonoperatively, several required craniotomy for clot evacuation, decompression, and spinal fixation for fracture or basilar invagination, and cerebrospinal fluid shunt insertion. Neurosurgical conditions affecting patients with OI include macrocephaly, the development of an acute intracranial hematoma after often minimal trauma, the development of chronic subdural fluid collections that may require drainage, hydrocephalus (both communicating and noncommunicating), basilar invagination, and subaxial spinal fractures. Surgery may be complicated in some children because of the underlying bone fragility and bleeding diathesis commonly observed in patients with OI.

Glycemic Profile in Infants Who Have Undergone the Arterial Switch Operation: Hyperglycemia is Not Associated with Adverse Events

The Journal of Thoracic and Cardiovascular Surgery. Apr, 2008  |  Pubmed ID: 18374750

Tight glycemic control improves outcomes in critically ill adults. There are limited data regarding the effect of glycemic profiles in infants after cardiac operations. The aim of this study was to evaluate the association of hyperglycemia and hypoglycemia on adverse events in infants undergoing the arterial switch operation.

Expression of MAGE and GAGE Genes in Medulloblastoma and Modulation of Resistance to Chemotherapy. Laboratory Investigation

Journal of Neurosurgery. Pediatrics. Apr, 2008  |  Pubmed ID: 18377306

Cancer testis antigens (CTAs) were initially identified by their ability to elicit autologous T-cell-mediated immune responses in patients with melanoma. The CTA genes are widely expressed in a variety of human cancers, such as melanoma, breast cancer, lung cancer, esophageal cancer, and hepatocellular carcinoma; however, their expression in pediatric brain tumors, such as medulloblastoma (MB), has not been the subject of in-depth analysis. The MAGE proteins are members of the CTA family and have been shown to correlate with tumor development, aggressive clinical course, or resistance to chemotherapeutic agents. The authors undertook this study to examine the expression and role of MAGE proteins in human MB cell lines and specimens.

Assessing the Impact of Streaming in a Regional Emergency Department

Emergency Medicine Australasia : EMA. Jun, 2008  |  Pubmed ID: 18400003

To evaluate the impact of a streaming model, previously validated in metropolitan EDs, on selected performance indicators in a regional ED.

TOF-SIMS Analysis of a 576 Micropatterned Copolymer Array to Reveal Surface Moieties That Control Wettability

Analytical Chemistry. Jan, 2008  |  Pubmed ID: 18044847

Time-of-flight secondary ion mass spectrometry (TOF-SIMS) was used in a high-throughput fashion to obtain mass spectra from the surfaces of 576 novel acrylate-based polymers, synthesized using a combinatorial approach and in a micropatterned format. To identify variations in surface chemistry within the library, principal component analysis (PCA) was used. PCA clearly identified surface chemical commonality and differences within the library. The TOF-SIMS spectra were also used to determine the relationship between water contact angle (WCA) and the surface chemistry of the polymer library using partial least-squares regression (PLS). A good correlation between the TOF-SIMS data from the novel polymers and water contact angle was obtained. Examination of the PLS regression vector allowed surface moieties that correlate with high and low WCA to be identified. This in turn provided an insight into molecular structures that significantly influence wettability. This study demonstrates that multivariate analysis can be successfully applied to TOF-SIMS data from a large library of samples and highlights the potential of these techniques for building complex surface property/chemistry models.

Update on Neuroendocrine Regulation and Medical Intervention of Reproduction in Birds

The Veterinary Clinics of North America. Exotic Animal Practice. Jan, 2008  |  Pubmed ID: 18165139

In avian species, reproductive disorders and undesirable behaviors commonly reflect abnormalities in the neuroendocrine regulation of the reproductive system. Current treatment options are often disappointing, show no long-lasting effect, or have significant side effects. A possible reason for our lack of success is a dearth of knowledge of the underlying neuroendocrine, behavioral, and autonomous physiology of the reproductive processes. Tremendous progress has been made in the last few years in our understanding of the neuroendocrine control of reproduction in birds. Advantage should be taken of these experimentally derived data to develop appropriate and safe treatment protocols for avian patients suffering from reproductive disorders.

Diversity and Mode of Transmission of Ammonia-oxidizing Archaea in Marine Sponges

Environmental Microbiology. Apr, 2008  |  Pubmed ID: 18177367

The model marine crenarchaeote 'Cenarchaeum symbiosum' is until now the only ammonia-oxidizing archaeon known from a marine sponge. Here, phylogenetic analyses based on the 16S rRNA and ammonia monooxygenase subunit A (amoA) genes revealed the presence of putative ammonia-oxidizing archaea (AOA) in a diverse range of sponges from the western Pacific, Caribbean and Mediterranean. amoA diversity was limited even between different oceans, with many of the obtained sequences (75.9%; n(total) = 83) forming a monophyletic, apparently sponge- (and coral-) specific lineage, analogous to those previously inferred from comparative 16S rRNA gene studies of sponge-associated microbes. The presence of AOA in sponge larvae, as detected by 16S rRNA and amoA PCR assays as well as by fluorescence in situ hybridization, suggests they are vertically transmitted and thus might be of importance for ammonia detoxification within the sponge.

Mef2 Activity Levels Differentially Affect Gene Expression During Drosophila Muscle Development

Proceedings of the National Academy of Sciences of the United States of America. Jan, 2008  |  Pubmed ID: 18198273

Cell differentiation is controlled by key transcription factors, and a major question is how they orchestrate cell-type-specific genetic programs. Muscle differentiation is a well studied paradigm in which the conserved Mef2 transcription factor plays a pivotal role. Recent genomic studies have identified a large number of mef2-regulated target genes with distinct temporal expression profiles during Drosophila myogenesis. However, the question remains as to how a single transcription factor can control such diverse patterns of gene expression. In this study we used a strategy combining genomics and developmental genetics to address this issue in vivo during Drosophila muscle development. We found that groups of mef2-regulated genes respond differently to changes in mef2 activity levels: some require higher levels for their expression than others. Furthermore, this differential requirement correlates with when the gene is first expressed during the muscle differentiation program. Genes that require higher levels are activated later. These results implicate mef2 in the temporal regulation of muscle gene expression, and, consistent with this, we show that changes in mef2 activity levels can alter the start of gene expression in a predictable manner. Together these results indicate that Mef2 is not an all-or-none regulator; rather, its action is more subtle, and levels of its activity are important in the differential expression of muscle genes. This suggests a route by which mef2 can orchestrate the muscle differentiation program and contribute to the stringent regulation of gene expression during myogenesis.

Experimental Simulation of Non-ballistic Wounding by Sharp and Blunt Punches

Forensic Science, Medicine, and Pathology. 2008  |  Pubmed ID: 19291441

Despite a long history of gross and microscopic descriptions of blunt and sharp force injury to the dermal tissues, few have addressed the mechanisms underlying such trauma. The need to develop an understanding of how non-ballistic injury occurs calls for an ability to biomechanically model the process. We recently introduced a basic skin and subcutaneous model, which we used to investigate wounding from a spherical object. Here we employ the same model to examine wounding caused by a sharp wedge shaped object and a blunt rectangular object. Macroscopic examination and SEM views of the surface and cross sections of blunt and sharp force tears show that while in the former there is a clean cut through the skin into the underlying sponge, in the latter there is a tissue plug confined to the skin that is smaller than the impacting rectangle. Fracture initiation in the subdermal tissue occurs at the angles of the impacting object. In sharp force trauma, there is localized breaching of the skin layer coupled with the wedging action of the impacting object. Because the subdermal tissue, in this case the underlying hydrated foam, is attached to the base of the skin, it will contribute to further tearing of the foam beneath the line of contact.

The Biomechanical Modelling of Non-ballistic Skin Wounding: Blunt-force Injury

Forensic Science, Medicine, and Pathology. 2008  |  Pubmed ID: 19291467

Knowledge of the biomechanical dynamics of blunt force trauma is indispensable for forensic reconstruction of a wounding event. In this study, we describe and interpret wound features on a synthetic skin model under defined laboratory conditions. To simulate skin and the sub-dermal tissues we used open-celled polyurethane sponge (foam), covered by a silicone layer. A drop tube device with three tube lengths (300, 400, and 500 mm), each secured to a weighted steel scaffold and into which a round, 5-kg Federal dumbbell of length 180 mm and diameter 8 cm was placed delivered blows of known impact. To calculate energy and velocity at impact the experimental set-up was replicated using rigid-body dynamics and motion simulation software. We soaked each foam square in 500 mL water, until fully saturated, immediately before placing it beneath the drop tube. We then recorded and classified both external and internal lacerations. The association between external wounding rates and the explanatory variables sponge type, sponge thickness, and height were investigated using Poisson regression. Tears (lacerations) of the silicone skin layer resembled linear lacerations seen in the clinical literature and resulted from only 48.6% of impacts. Poisson regression showed there was no significant difference between the rate of external wounding for different sponge types (P = 0.294) or different drop heights (P = 0.276). Most impacts produced "internal wounds" or subsurface cavitation (96%). There were four internal "wound" types; Y-shape (53%), linear (25%), stellate (16%), and double crescent (6%). The two-way interaction height by sponge type was statistically significant in the analysis of variance model (P = 0.035). The other two-way interactions; height by thickness and sponge type by thickness, were also bordering on statistical significance (P = 0.061 and P = 0.071, respectively). The observation that external wounds were present for less than half of impacts only, but that nearly all impacts resulted in internal wounds, might explain the observed haematoma formation and contusions so often associated with blunt-force injuries. Our study also confirms the key role of hydrodynamic pressure changes in the actual tearing of subcutaneous tissue. At the moment and site of impact, transferred kinetic energy creates a region of high pressure on the fluid inside the tissue. As a result of the incompressibility of the fluid, this will be displaced away from the impact at a rate that depends on the velocity (or kinetic energy) of impact and the permeability and stiffness of the polymeric foam and skin layer.

An Epigenetic Genome-wide Screen Identifies SPINT2 As a Novel Tumor Suppressor Gene in Pediatric Medulloblastoma

Cancer Research. Dec, 2008  |  Pubmed ID: 19047176

Medulloblastoma (MB) is a malignant cerebellar tumor that occurs primarily in children. The hepatocyte growth factor (HGF)/MET pathway has an established role in both normal cerebellar development as well as the development and progression of human brain tumors, including MB. To identify novel tumor suppressor genes involved in MB pathogenesis, we performed an epigenome-wide screen in MB cell lines, using 5-aza-2'deoxycytidine to identify genes aberrantly silenced by promoter hypermethylation. Using this technique, we identified an inhibitor of HGF/MET signaling, serine protease inhibitor kunitz-type 2 (SPINT2/HAI-2), as a putative tumor suppressor silenced by promoter methylation in MB. In addition, based on single nucleotide polymorphism array analysis in primary MB samples, we identified hemizygous deletions targeting the SPINT2 locus in addition to gains on chromosome 7 encompassing the HGF and MET loci. SPINT2 gene expression was down-regulated and MET expression was up-regulated in 73.2% and 45.5% of tumors, respectively, by quantitative real-time PCR. SPINT2 promoter methylation was detected in 34.3% of primary MBs examined by methylation-specific PCR. SPINT2 reexpression in MB cell lines reduced proliferative capacity, anchorage independent growth, cell motility in vitro, and increased overall survival times in vivo in a xenograft model (P<0.0001). Taken together, these data support the role of SPINT2 as a putative tumor suppressor gene in MB, and further implicate dysregulation of the HGF/MET signaling pathway in the pathogenesis of MB.

Hardwiring of Fine Synaptic Layers in the Zebrafish Visual Pathway

Neural Development. 2008  |  Pubmed ID: 19087349

Neuronal connections are often arranged in layers, which are divided into sublaminae harboring synapses with similar response properties. It is still debated how fine-grained synaptic layering is established during development. Here we investigated two stratified areas of the zebrafish visual pathway, the inner plexiform layer (IPL) of the retina and the neuropil of the optic tectum, and determined if activity is required for their organization.

A Legionnaires' Disease Outbreak: a Water Blaster and Roof-collected Rainwater Systems

Water Research. Mar, 2008  |  Pubmed ID: 17991506

In February 2006, an outbreak of Legionnaires' disease (LD) was identified in Beachlands, a small, isolated east Auckland suburb. It was investigated through case finding, a case-control study, sampling potential sources of infection and by molecular typing (using sequence-based typing (SBT) of all Legionella pneumophila serogroup 1 (Lp1) isolates). Lp1 was isolated from the respiratory tract of one case, the roof-collected rainwater systems of five households (three associated with cases) and from a water blaster at a nearby marina. All isolates were indistinguishable, exhibiting the same SBT allele pattern. Three LD cases lived within 500m of the water blaster (the fourth case within 1250m) and downwind in prevailing conditions. Another domestic roof-collected rainwater supply contaminated by Lp1 (identical SBT pattern) was incidentally identified in another suburb 4km east of Beachlands. This is the first outbreak of LD linked to roof-collected rainwater supplies and the first isolation of Legionella from these systems in New Zealand. Aerosols containing Legionella discharged to air by the marina water blaster may have infected some cases directly or may have seeded roof-collected rainwater systems. Some cases may have been exposed by contaminated bathroom showers. Roof-collected rainwater systems need appropriate design, careful cleaning and the maintenance of hot water temperatures at a minimum of 60 degrees C to reduce the chances of Legionella multiplying. Further research into the ecology of Legionella in roof-collected rain water systems is indicated.

The Medical Evidence-based Model for Psychiatric Syndromes: Return to a Classical Paradigm

Acta Psychiatrica Scandinavica. Feb, 2008  |  Pubmed ID: 18199152

Sharing: Public Databases Combat Mistrust and Secrecy

Nature. Oct, 2009  |  Pubmed ID: 19847240

Manganese Tissue Dosimetry in Rats and Monkeys: Accounting for Dietary and Inhaled Mn with Physiologically Based Pharmacokinetic Modeling

Toxicological Sciences : an Official Journal of the Society of Toxicology. Mar, 2009  |  Pubmed ID: 19098275

Manganese (Mn) is an essential nutrient required for normal tissue growth and function. Following exposures to high concentrations of inhaled Mn, there is preferential accumulation of Mn in certain brain regions such as the striatum and globus pallidus. The goal of this research was to complete a physiologically based pharmacokinetic (PBPK) model for Mn in rats and scale the model to describe Mn tissue accumulation in nonhuman primates exposed to Mn by inhalation and diet. The model structure includes saturable tissue binding with association and dissociation rate constants, asymmetric tissue permeation flux rate constants to specific tissues, and inducible biliary excretion. The rat PBPK model described tissue time-course studies for various dietary Mn intakes and accounted for inhalation studies of both 14-day and 90-day duration. In monkeys, model parameters were first calibrated using steady-state tissue Mn concentrations from rhesus monkeys fed a diet containing 133 ppm Mn. The model was then applied to simulate 65 exposure days of weekly (6 h/day; 5 days/week) inhalation exposures to soluble MnSO(4) at 0.03 to 1.5 mg Mn/m(3). Sensitivity analysis showed that Mn tissue concentrations in the models have dose-dependencies in (1) biliary excretion of free Mn from liver, (2) saturable tissue binding in all tissues, and (3) differential influx/efflux rates for tissues that preferentially accumulate Mn. This multispecies PBPK model is consistent with the available experimental kinetic data, indicating preferential increases in some brain regions with exposures above 0.2 mg/m(3) and fairly rapid return to steady-state levels (within several weeks rather than months) after cessation of exposure. PBPK models that account for preferential Mn tissue accumulation from both oral and inhalation exposures will be essential to support tissue dosimetry-based human risk assessments for Mn.

Unusually Reactive and Selective Carbonyl Ylides for Three-component Cycloaddition Reactions

Journal of the American Chemical Society. Jan, 2009  |  Pubmed ID: 19128053

Conditions are described for the Rh-catalyzed formation of highly functionalized dihydro- and tetrahydrofuran products via three-component reactions of aldehydes, alpha-alkyl-alpha-diazoesters, and dipolarophiles. The alkyl-substituted carbonyl ylides that are generated in this fashion are highly reactive in cycloaddition reactions and display a scope of reactivity that is much broader than the three-component reactions of carbonyl ylides derived from ethyl diazoacetate or alpha-aryl-alpha-diazoesters. The reactions of alkyl-substituted carbonyl ylides proceed with high regioselectivity and diastereoselectivity that are rationalized in terms of an asynchronous, endo-selective transition state.

Follicular Lymphoma in the United States: First Report of the National LymphoCare Study

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Mar, 2009  |  Pubmed ID: 19204203

Optimal therapy of follicular lymphoma (FL) is not defined. We analyzed a large prospective cohort study to identify current demographics and patterns of care of FL in the United States.

An SIR Epidemic Model with Partial Temporary Immunity Modeled with Delay

Journal of Mathematical Biology. Dec, 2009  |  Pubmed ID: 19266170

The SIR epidemic model for disease dynamics considers recovered individuals to be permanently immune, while the SIS epidemic model considers recovered individuals to be immediately resusceptible. We study the case of temporary immunity in an SIR-based model with delayed coupling between the susceptible and removed classes, which results in a coupled set of delay differential equations. We find conditions for which the endemic steady state becomes unstable to periodic outbreaks. We then use analytical and numerical bifurcation analysis to describe how the severity and period of the outbreaks depend on the model parameters.

Multiple Recurrent Genetic Events Converge on Control of Histone Lysine Methylation in Medulloblastoma

Nature Genetics. Apr, 2009  |  Pubmed ID: 19270706

We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.

WFSBP Task Force Report on Biological Markers in Depression is Unduly Pessimistic in Failing to Find Diagnostically Helpful Measures

The World Journal of Biological Psychiatry : the Official Journal of the World Federation of Societies of Biological Psychiatry. 2009  |  Pubmed ID: 19629859

Lactational Transfer of Manganese in Rats: Predicting Manganese Tissue Concentration in the Dam and Pups from Inhalation Exposure with a Pharmacokinetic Model

Toxicological Sciences : an Official Journal of the Society of Toxicology. Nov, 2009  |  Pubmed ID: 19726576

Manganese (Mn) is an essential element. However, excess Mn causes neurotoxicity. Fetuses and neonates have been discussed as potentially sensitive subpopulations for Mn. In the present study, a previously published physiologically based pharmacokinetic model for Mn in adult rats was extended to examine exposure conditions that could lead to increased central nervous system Mn in developing rats. The basic structure had saturable tissue binding, homeostatic control of uptake and excretion, and tissue-specific increases in Mn from inhalation. Modifications made for lactating dam and pups included differential tissue-binding capacities in developing pups, increased absorption of dietary Mn in lactating dam, and more efficient gastrointestinal absorption and lower basal biliary excretion in pups. Enhancement of biliary excretion in pups was also required to accurately simulate tissue Mn during early postnatal inhalation. Overall, these changes were concordant with the biology of Mn and other essential metals during development. The resulting model simulations match a variety of published studies on maternal Mn homeostasis during lactation, milk Mn levels, and changing patterns of neonatal tissue Mn for normal dietary intake and with Mn inhalation. Our successful description of Mn kinetics across these life stages suggests that the present model can help describe the relationship between dose of exposure and target tissue Mn concentrations across different developmental stages and its potential risks and assess whether infants and children should be regarded as susceptible populations for Mn inhalation.

Evaluating Placental Transfer and Tissue Concentrations of Manganese in the Pregnant Rat and Fetuses After Inhalation Exposures with a PBPK Model

Toxicological Sciences : an Official Journal of the Society of Toxicology. Nov, 2009  |  Pubmed ID: 19726578

A Physiologically Based Pharmaco Kinetic (PBPK) model, based on a published description of manganese (Mn) kinetics in adult rats, has been developed to describe Mn uptake and tissue distribution in the pregnant dam and fetus during dietary and inhalation exposures. This extension incorporated key physiological processes controlling Mn pharmacokinetics during pregnancy and fetal development. After calibration against tissue Mn concentrations observed during late gestation, the model accurately simulated Mn tissue distribution in the dam and fetus following both diet and inhalation exposures to the pregnant rat. Maternal to fetal transfer of Mn through placenta was described using two pathways: a saturable active transport with high affinity and a simple diffusion. The active transport dominates at basal and lower Mn exposure, whereas at higher Mn exposure, the relative contribution of the diffusion pathway increases. To simulate fetal tissue Mn, tissue-binding parameters and preferential influx/efflux rates in fetal brain were adjusted from the adult model based on differential developmental processes and varying tissue demands for Mn in early life. Model simulations were consistent with observed tissue Mn concentrations in fetal tissues, including brain for diet alone and for combined diet and inhalation. Simulations of Mn in placenta and other maternal tissues in late gestation correlated well with measured tissue concentrations. This model, together with our published models for Mn kinetics during lactation and postnatal development, will help to address concerns about Mn neurotoxicity in potentially sensitive human subpopulation, such as infants and children by providing an estimate of Mn exposure in the population of interest.

Tuberous Sclerosis Complex Suppression in Cerebellar Development and Medulloblastoma: Separate Regulation of Mammalian Target of Rapamycin Activity and P27 Kip1 Localization

Cancer Research. Sep, 2009  |  Pubmed ID: 19738049

During development, proliferation of cerebellar granule neuron precursors (CGNP), candidate cells-of-origin for the pediatric brain tumor medulloblastoma, requires signaling by Sonic hedgehog (Shh) and insulin-like growth factor (IGF), the pathways of which are also implicated in medulloblastoma. One of the consequences of IGF signaling is inactivation of the mammalian target of rapamycin (mTOR)-suppressing tuberous sclerosis complex (TSC), comprised of TSC1 and TSC2, leading to increased mRNA translation. We show that mice, in which TSC function is impaired, display increased mTOR pathway activation, enhanced CGNP proliferation, glycogen synthase kinase-3 alpha/beta (GSK-3 alpha/beta) inactivation, and cytoplasmic localization of the cyclin-dependent kinase inhibitor p27(Kip1), which has been proposed to cause its inactivation or gain of oncogenic functions. We observed the same characteristics in wild-type primary cultures of CGNPs in which TSC1 and/or TSC2 were knocked down, and in mouse medulloblastomas induced by ectopic Shh pathway activation. Moreover, Shh-induced mouse medulloblastomas manifested Akt-mediated TSC2 inactivation, and the mutant TSC2 allele synergized with aberrant Shh signaling to increase medulloblastoma incidence in mice. Driving exogenous TSC2 expression in Shh-induced medulloblastoma cells corrected p27(Kip1) localization and reduced proliferation. GSK-3 alpha/beta inactivation in the tumors in vivo and in primary CGNP cultures was mTOR-dependent, whereas p27(Kip1) cytoplasmic localization was regulated upstream of mTOR by TSC2. These results indicate that a balance between Shh mitogenic signaling and TSC function regulating new protein synthesis and cyclin-dependent kinase inhibition is essential for the normal development and prevention of tumor formation or expansion.

Stabilization of the Tertiary Structure of the Cholera Toxin A1 Subunit Inhibits Toxin Dislocation and Cellular Intoxication

Journal of Molecular Biology. Nov, 2009  |  Pubmed ID: 19748510

Cholera toxin (CT) moves from the cell surface to the endoplasmic reticulum (ER) by retrograde vesicular transport. The catalytic subunit of CT (CTA1) then crosses the ER membrane and enters the cytosol in a process that involves the quality control mechanism of ER-associated degradation. The molecular details of this dislocation event have not been fully characterized. Here, we report that thermal instability in the CTA1 subunit-specifically, the loss of CTA1 tertiary structure at 37 degrees C-triggers toxin dislocation. Biophysical studies found that glycerol preferentially stabilized the tertiary structure of CTA1 without having any noticeable effect on the thermal stability of its secondary structure. The thermal disordering of CTA1 tertiary structure normally preceded the perturbation of its secondary structure, but in the presence of 10% glycerol the temperature-induced loss of CTA1 tertiary structure occurred at higher temperatures in tandem with the loss of CTA1 secondary structure. The glycerol-induced stabilization of CTA1 tertiary structure blocked CTA1 dislocation from the ER and instead promoted CTA1 secretion into the extracellular medium. This, in turn, inhibited CT intoxication. Glycerol treatment also inhibited the in vitro degradation of CTA1 by the core 20S proteasome. Collectively, these findings indicate that toxin thermal instability plays a key role in the intoxication process. They also suggest the stabilization of CTA1 tertiary structure is a potential goal for novel antitoxin therapeutic agents.

White Matter Tract Injury and Cognitive Impairment in Human Immunodeficiency Virus-infected Individuals

Journal of Neurovirology. Apr, 2009  |  Pubmed ID: 19306228

Approximately half of those infected with the human immunodeficiency virus (HIV) exhibit cognitive impairment, which has been related to cerebral white matter damage. Despite the effectiveness of antiretroviral treatment, cognitive impairment remains common even in individuals with undetectable viral loads. One explanation for this may be subtherapeutic concentrations of some antiretrovirals in the central nervous system (CNS). We utilized diffusion tensor imaging and a comprehensive neuropsychological evaluation to investigate the relationship of white matter integrity to cognitive impairment and antiretroviral treatment variables. Participants included 39 HIV-infected individuals (49% with acquired immunodeficiency syndrome [AIDS]; mean CD4 = 529) and 25 seronegative subjects. Diffusion tensor imaging indices were mapped onto a common whole-brain white matter tract skeleton, allowing between-subject voxelwise comparisons. The total HIV-infected group exhibited abnormal white matter in the internal capsule, inferior longitudinal fasciculus, and optic radiation; whereas those with AIDS exhibited more widespread damage, including in the internal capsule and the corpus callosum. Cognitive impairment in the HIV-infected group was related to white matter injury in the internal capsule, corpus callosum, and superior longitudinal fasciculus. White matter injury was not found to be associated with HIV viral load or estimated CNS penetration of antiretrovirals. Diffusion tensor imaging was useful in identifying changes in white matter tracts associated with more advanced HIV infection. Relationships between diffusion alterations in specific white matter tracts and cognitive impairment support the potential utility of diffusion tensor imaging in examining the anatomical underpinnings of HIV-related cognitive impairment. The study also confirms that CNS injury is evident in persons infected with HIV despite effective antiretroviral treatment.

MicroRNA-199b-5p Impairs Cancer Stem Cells Through Negative Regulation of HES1 in Medulloblastoma

PloS One. 2009  |  Pubmed ID: 19308264

Through negative regulation of gene expression, microRNAs (miRNAs) can function in cancers as oncosuppressors, and they can show altered expression in various tumor types. Here we have investigated medulloblastoma tumors (MBs), which arise from an early impairment of developmental processes in the cerebellum, where Notch signaling is involved in many cell-fate-determining stages. MBs occur bimodally, with the peak incidence seen between 3-4 years and 8-9 years of age, although it can also occur in adults. Notch regulates a subset of the MB cells that have stem-cell-like properties and can promote tumor growth. On the basis of this evidence, we hypothesized that miRNAs targeting the Notch pathway can regulated these phenomena, and can be used in anti-cancer therapies.

The Him Gene Inhibits the Development of Drosophila Flight Muscles During Metamorphosis

Mechanisms of Development. Jul, 2009  |  Pubmed ID: 19324085

During Drosophila metamorphosis some larval tissues escape the general histolysis and are remodelled to form adult tissues. One example is the dorso-longitudinal muscles (DLMs) of the indirect flight musculature. They are formed by an intriguing process in which residual larval oblique muscles (LOMs) split and fuse with imaginal myoblasts associated with the wing disc. These myoblasts arise in the embryo, but remain undifferentiated throughout embryogenesis and larval life, and thus share characteristics with mammalian satellite cells. However, the mechanisms that maintain the Drosophila myoblasts in an undifferentiated state until needed for LOM remodelling are not understood. Here we show that the Him gene is expressed in these myoblasts, but is undetectable in developing DLM fibres. Consistent with this, we found that Him could inhibit DLM development: it inhibited LOM splitting and resulted in fibre degeneration. We then uncovered a balance between mef2, a positive factor required for proper DLM development, and the inhibitory action of Him. Mef2 suppressed the inhibitory effect of Him on DLM development, while Him could suppress the premature myosin expression induced by mef2 in myoblasts. Furthermore, either decreased Him function or increased mef2 function disrupted DLM development. These findings, together with the co-expression of Him and Mef2 in myoblasts, indicate that Him may antagonise mef2 function during normal DLM development and that Him participates in a balance of signals that controls adult myoblast differentiation and remodelling of these muscle fibres. Lastly, we provide evidence for a link between Notch function and Him and mef2 in this balance.

The MiR-17/92 Polycistron is Up-regulated in Sonic Hedgehog-driven Medulloblastomas and Induced by N-myc in Sonic Hedgehog-treated Cerebellar Neural Precursors

Cancer Research. Apr, 2009  |  Pubmed ID: 19351822

Medulloblastoma is the most common malignant pediatric brain tumor, and mechanisms underlying its development are poorly understood. We identified recurrent amplification of the miR-17/92 polycistron proto-oncogene in 6% of pediatric medulloblastomas by high-resolution single-nucleotide polymorphism genotyping arrays and subsequent interphase fluorescence in situ hybridization on a human medulloblastoma tissue microarray. Profiling the expression of 427 mature microRNAs (miRNA) in a series of 90 primary human medulloblastomas revealed that components of the miR-17/92 polycistron are the most highly up-regulated miRNAs in medulloblastoma. Expression of miR-17/92 was highest in the subgroup of medulloblastomas associated with activation of the sonic hedgehog (Shh) signaling pathway compared with other subgroups of medulloblastoma. Medulloblastomas in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. Consistent with its regulation by Shh, we observed that Shh treatment of primary cerebellar granule neuron precursors (CGNP), proposed cells of origin for the Shh-associated medulloblastomas, resulted in increased miR-17/92 expression. In CGNPs, the Shh effector N-myc, but not Gli1, induced miR-17/92 expression. Ectopic miR-17/92 expression in CGNPs synergized with exogenous Shh to increase proliferation and also enabled them to proliferate in the absence of Shh. We conclude that miR-17/92 is a positive effector of Shh-mediated proliferation and that aberrant expression/amplification of this miR confers a growth advantage to medulloblastomas.

Legionella, Protozoa, and Biofilms: Interactions Within Complex Microbial Systems

Microbial Ecology. Oct, 2009  |  Pubmed ID: 19365668

Currently, the investigation of Legionella ecology falls into two distinct areas of research activity: (1) that Legionella multiply within water sources by parasitizing amoebic or ciliate hosts or (2) that Legionella grows extracellularly within biofilms. Less focus has been given to the overlaps that may occur between these two areas or the likelihood that Legionella employs multiple survival strategies to persist in water sources. It is likely that Legionella interacts with protozoa, bacteria, algae, fungi, etc., and biofilm components in a more complex fashion than multiplication or death due to the presence or absence of single components of these complex microbial systems. This paper addresses gaps that exist in the understanding of Legionella ecology and serves to pinpoint areas of future research. To assume that only one other class of organism is important to Legionella ecology may limit our understanding of how this bacterium proliferates in heated water sources and also limit our strategies for its control in the built environment.

Sagnac-interferometer-based Characterization of Spatial Light Modulators

Applied Optics. Apr, 2009  |  Pubmed ID: 19381172

A method for characterizing the phase response of spatial light modulators (SLMs) by using a Sagnac interferometer is proposed and demonstrated. The method represents an improvement over conventional diffraction-based or interferometric techniques by providing a simple and accurate phase measurement while taking advantage of the inherent phase stability of a Sagnac interferometer. As a demonstration, the phase response of a commercial liquid crystal on a silicon SLM is characterized and then linearized by using a programmable lookup table. The transverse phase profile over the SLM surface is also measured.

Differential Effects of Chronic Unpredictable Stress on Hippocampal CB1 Receptors in Male and Female Rats

Behavioural Brain Research. Nov, 2009  |  Pubmed ID: 19460405

Chronic unpredictable mild stress (CMS), an animal model of depression, downregulates hippocampal CB1 receptors in adult male rats. Given that endocannabinoids are implicated in modulating stress and anxiety and that women are vulnerable to stress-related disorders, we tested the effects of CMS on both female and male rats. Gonadectomized (gndx) and gonadally intact male and female rats were exposed to a three-week chronic stress protocol. Following CMS, CB1 receptor and fatty-acid-amide-hydrolase (FAAH) expression levels in the hippocampus were assessed by western blot analysis. CMS reliably produced a downregulation of CB1 receptors ( approximately 50%) in the hippocampus of both gndx and intact males. This effect was more robust in the dorsal than in the ventral hippocampus. Conversely, CMS produced an upregulation of CB1 receptors ( approximately 150%) in the hippocampus of both gndx and intact females. This upregulation was only observed in the dorsal hippocampus of female animals. CMS produced an upregulation of FAAH levels in both male and female animals. In non-stress control animals, males were observed to have higher CB1 levels than females, but no differences in FAAH were found. These findings suggest that the endocannabinoid (eCB) system is preferentially organized in male and female animals to respond differentially to chronic stress. These sex differences in the eCB system may help development of novel treatments for stress and depression that are designed specifically for women and men.

How Well Are General Practice Trainees Prepared for Paediatric Prescribing?

British Journal of Clinical Pharmacology. Mar, 2009  |  Pubmed ID: 19523018

We invited 232 General Practice Trainees to complete an on-line questionnaire to assess how they rated their training for the task of paediatric prescribing and therapeutics in the community.

The Genetic and Epigenetic Basis of Ependymoma

Child's Nervous System : ChNS : Official Journal of the International Society for Pediatric Neurosurgery. Oct, 2009  |  Pubmed ID: 19536551

Although ependymoma is the third most common pediatric brain tumor, we know little about the genetic/epigenetic basis of its initiation, maintenance, or progression. This is due in part to the heterogeneity of the disease, as well as the small sample size of the cohorts analyzed in most studies.

Co-activation of Hedgehog and AKT Pathways Promote Tumorigenesis in Zebrafish

Molecular Cancer. 2009  |  Pubmed ID: 19555497

The zebrafish has become an important model for cancer research. Several cancer models have been established by transgenic expression of human or mouse oncogenes in zebrafish. Since it is amenable to efficient transgenesis, zebrafish have immense potential to be used for studying interaction of oncogenes and pathways at the organismal level. Using the Gal4VP16-UAS binary transgenic expression approach, we established stable transgenic lines expressing an EGFP fusion protein of an activated zebrafish Smoothened (Smoa1-EGFP). Expression of the zebrafish Smoa1-EGFP itself did not lead to tumor formation either in founder fish or subsequent generations, however, co-expressing a constitutively active human AKT1 resulted in several tumor types, including spindle cell sarcoma, rhabdomyoma, ocular melanoma, astrocytoma, and myxoma. All tumor types showed GFP expression and increased Patched 1 levels, suggesting involvement of zebrafish Smoa1 in tumorigenesis. Immunofluorescence studies showed that tumors also expressed elevated levels of phosphorylated AKT, indicating activation of the PI3K-AKT pathway. These results suggest that co-activation of the hedgehog and AKT pathways promote tumorigenesis, and that the binary transgenic approach is a useful tool for studying interaction of oncogenes and oncogenic pathways in zebrafish.

Breathing Frequency Bias in Fractal Analysis of Heart Rate Variability

Biological Psychology. Sep, 2009  |  Pubmed ID: 19559748

Detrended Fluctuation Analysis (DFA) is an algorithm widely used to determine fractal long-range correlations in physiological signals. Its application to heart rate variability (HRV) has proven useful in distinguishing healthy subjects from patients with cardiovascular disease. In this study we examined the effect of respiratory sinus arrhythmia (RSA) on the performance of DFA applied to HRV. Predictions based on a mathematical model were compared with those obtained from a sample of 14 normal subjects at three breathing frequencies: 0.1Hz, 0.2Hz and 0.25Hz. Results revealed that: (1) the periodical properties of RSA produce a change of the correlation exponent in HRV at a scale corresponding to the respiratory period, (2) the short-term DFA exponent is significantly reduced when breathing frequency rises from 0.1Hz to 0.2Hz. These findings raise important methodological questions regarding the application of fractal measures to short-term HRV.

Comparative Study of in Vivo Lymphatic Sealing Capability of the Porcine Thoracic Duct Using Laparoscopic Dissection Devices

The Journal of Urology. Jan, 2009  |  Pubmed ID: 19010491

Sealing the lymphatic vessels during abdominal and pelvic surgery is important to prevent the leakage of lymphatic fluid and its resultant sequelae. To our knowledge we compared for the first time the quality of lymphatic sealing by each of 4 commonly used laparoscopic dissection devices.

Deep Sequencing Reveals Exceptional Diversity and Modes of Transmission for Bacterial Sponge Symbionts

Environmental Microbiology. Sep, 2009  |  Pubmed ID: 19788652

Summary Marine sponges contain complex bacterial communities of considerable ecological and biotechnological importance, with many of these organisms postulated to be specific to sponge hosts. Testing this hypothesis in light of the recent discovery of the rare microbial biosphere, we investigated three Australian sponges by massively parallel 16S rRNA gene tag pyrosequencing. Here we show bacterial diversity that is unparalleled in an invertebrate host, with more than 250 000 sponge-derived sequence tags being assigned to 23 bacterial phyla and revealing up to 2996 operational taxonomic units (95% sequence similarity) per sponge species. Of the 33 previously described 'sponge-specific' clusters that were detected in this study, 48% were found exclusively in adults and larvae - implying vertical transmission of these groups. The remaining taxa, including 'Poribacteria', were also found at very low abundance among the 135 000 tags retrieved from surrounding seawater. Thus, members of the rare seawater biosphere may serve as seed organisms for widely occurring symbiont populations in sponges and their host association might have evolved much more recently than previously thought.

Small Vessel Ischemic Disease of the Brain and Brain Metastases in Lung Cancer Patients

PloS One. 2009  |  Pubmed ID: 19789633

Brain metastases occur commonly in patients with lung cancer. Small vessel ischemic disease is frequently found when imaging the brain to detect metastases. We aimed to determine if the presence of small vessel ischemic disease (SVID) of the brain is protective against the development of brain metastases in lung cancer patients.

Comparative Genomic and Phylogeographic Analysis of Mycobacterium Leprae

Nature Genetics. Dec, 2009  |  Pubmed ID: 19881526

Reductive evolution and massive pseudogene formation have shaped the 3.31-Mb genome of Mycobacterium leprae, an unculturable obligate pathogen that causes leprosy in humans. The complete genome sequence of M. leprae strain Br4923 from Brazil was obtained by conventional methods (6x coverage), and Illumina resequencing technology was used to obtain the sequences of strains Thai53 (38x coverage) and NHDP63 (46x coverage) from Thailand and the United States, respectively. Whole-genome comparisons with the previously sequenced TN strain from India revealed that the four strains share 99.995% sequence identity and differ only in 215 polymorphic sites, mainly SNPs, and by 5 pseudogenes. Sixteen interrelated SNP subtypes were defined by genotyping both extant and extinct strains of M. leprae from around the world. The 16 SNP subtypes showed a strong geographical association that reflects the migration patterns of early humans and trade routes, with the Silk Road linking Europe to China having contributed to the spread of leprosy.

The Catatonia Syndrome: Forgotten but Not Gone

Archives of General Psychiatry. Nov, 2009  |  Pubmed ID: 19884605

A Refrigeration Temperature of 4 Degrees C Does Not Prevent Static Growth of Yersinia Pestis in Heart Infusion Broth

Canadian Journal of Microbiology. Sep, 2009  |  Pubmed ID: 19898555

Multiple barriers such as inspections, testing, and proper storage conditions are used to minimize the risk of contaminated food. Knowledge of which barriers, such as refrigeration, are effective in preventing pathogen growth and persistence, can help direct the focus of efforts during food sampling. In this study, the doubling times were evaluated for 10 strains of Yersinia pestis of different genetic background cultured in heart infusion broth (HIB) kept at 4 degrees C +/- 1 degrees C under static conditions. Nine out of the 10 strains were able to grow at 4 degrees C +/- 1 degrees C. Apparent doubling times for 7 of the strains ranged from 41 to 50 h. Strain Harbin and strain D1 had apparent doubling times of 65 and 35 h, respectively, and strain O19 Ca-6 did not grow at all. Analysis of variance showed that the averaged growth data (colony forming units per mL) between strains that grew were not significantly different. The data presented here demonstrate that refrigeration alone is not an effective barrier to prevent static growth of Y. pestis in HIB. These findings provide the preliminary impetus to investigate Y. pestis growth in a variety of food matrices that may provide a similar environment as HIB.

Detection of Yersinia Pestis over Time in Seeded Bottled Water Samples by Cultivation on Heart Infusion Agar

Canadian Journal of Microbiology. Sep, 2009  |  Pubmed ID: 19898556

The viable persistence of Yersinia pestis seeded in bottled spring water was evaluated by performing 2 studies that involved inoculating a total of 21 different test strains into individual 500 mL reservoirs. Approximately 2 x 104 CFU/mL of Y. pestis was inoculated into each reservoir and held for sampling at 26 degrees C +/- 1 degrees C. In study No. 2, 9 strains (Harbin, Nepal, UNH 1A, UNH 1B, ZE94, CO92, PB6, PB6 DP, and Pexu) could no longer be recovered using a plate count assay between 79 and 138 days post-seeding; other strains (K25 lcr, O19 Ca-6, and K25 pst) could no longer be recovered between 112 and 160 days post seeding. The data generated in this study demonstrate that certain strains of Y. pestis can remain viable in bottled water for extended periods of time.

Normal and Oncogenic Roles for MicroRNAs in the Developing Brain

Cell Cycle (Georgetown, Tex.). Dec, 2009  |  Pubmed ID: 19901543

MicroRNAS (miRNAs) are small endogenous non-coding RNAs that play important roles in many different biological processes including proliferation, differentiation and apoptosis through silencing of target genes. Emerging evidence indicates that miRNAs are key players in mammalian development that, when altered, contribute to tumorigenesis. However, only a few studies to date have focused on the role of miRNAs in medulloblastoma, the most common malignant pediatric brain tumor. These tumors arise in the cerebellum and may attribute their origins to deregulated proliferation of neural progenitor cells during development. Understanding the interplay between normal brain development and medulloblastoma pathogenesis is necessary in order for more efficient, less toxic targeted therapies to be developed and implemented. MiRNA expression profiling of both mouse and human medulloblastomas has led to the identification of signatures correlating with the molecular subgroups of medulloblastoma, tumor diagnosis and response to treatment, as well as novel targets of potential clinical relevance. This review summarizes the recent miRNA literature in both medulloblastoma and normal brain development.

YAP1 is Amplified and Up-regulated in Hedgehog-associated Medulloblastomas and Mediates Sonic Hedgehog-driven Neural Precursor Proliferation

Genes & Development. Dec, 2009  |  Pubmed ID: 19952108

Medulloblastoma is the most common solid malignancy of childhood, with treatment side effects reducing survivors' quality of life and lethality being associated with tumor recurrence. Activation of the Sonic hedgehog (Shh) signaling pathway is implicated in human medulloblastomas. Cerebellar granule neuron precursors (CGNPs) depend on signaling by the morphogen Shh for expansion during development, and have been suggested as a cell of origin for certain medulloblastomas. Mechanisms contributing to Shh pathway-mediated proliferation and transformation remain poorly understood. We investigated interactions between Shh signaling and the recently described tumor-suppressive Hippo pathway in the developing brain and medulloblastomas. We report up-regulation of the oncogenic transcriptional coactivator yes-associated protein 1 (YAP1), which is negatively regulated by the Hippo pathway, in human medulloblastomas with aberrant Shh signaling. Consistent with conserved mechanisms between brain tumorigenesis and development, Shh induces YAP1 expression in CGNPs. Shh also promotes YAP1 nuclear localization in CGNPs, and YAP1 can drive CGNP proliferation. Furthermore, YAP1 is found in cells of the perivascular niche, where proposed tumor-repopulating cells reside. Post-irradiation, YAP1 was found in newly growing tumor cells. These findings implicate YAP1 as a new Shh effector that may be targeted by medulloblastoma therapies aimed at eliminating medulloblastoma recurrence.

Frequent Amplification of a Chr19q13.41 MicroRNA Polycistron in Aggressive Primitive Neuroectodermal Brain Tumors

Cancer Cell. Dec, 2009  |  Pubmed ID: 19962671

We discovered a high-level amplicon involving the chr19q13.41 microRNA (miRNA) cluster (C19MC) in 11/45 ( approximately 25%) primary CNS-PNET, which results in striking overexpression of miR-517c and 520g. Constitutive expression of miR-517c or 520g promotes in vitro and in vivo oncogenicity, modulates cell survival, and robustly enhances growth of untransformed human neural stem cells (hNSCs) in part by upregulating WNT pathway signaling and restricting differentiation of hNSCs. Remarkably, the C19MC amplicon, which is very rare in other brain tumors (1/263), identifies an aggressive subgroup of CNS-PNET with distinct gene-expression profiles, characteristic histology, and dismal survival. Our data implicate miR-517c and 520g as oncogenes and promising biological markers for CNS-PNET and provide important insights into oncogenic properties of the C19MC locus.

Review of Vitreous Islet Cryopreservation: Some Practical Issues and Their Resolution

Organogenesis. Jul, 2009  |  Pubmed ID: 20046679

Transplantation of pancreatic islets for the treatment of diabetes mellitus is widely anticipated to eventually provide a cure once a means for preventing rejection is found without reliance upon global immunosuppression. Long-term storage of islets is crucial for the organization of transplantation, islet banking, tissue matching, organ sharing, immuno-manipulation and multiple donor transplantation. Existing methods of cryopreservation involving freezing are known to be suboptimal providing only about 50% survival. The development of techniques for ice-free cryopreservation of mammalian tissues using both natural and synthetic ice blocking molecules, and the process of vitrification (formation of a glass as opposed to crystalline ice) has been a focus of research during recent years. These approaches have established in other tissues that vitrification can markedly improve survival by circumventing ice-induced injury. Here we review some of the underlying issues that impact the vitrification approach to islet cryopreservation and describe some initial studies to apply these new technologies to the long-term storage of pancreatic islets. These studies were designed to optimize both the pre-vitrification hypothermic exposure conditions using newly developed media and to compare new techniques for ice-free cryopreservation with conventional freezing protocols. Some practical constraints and feasible resolutions are discussed. Eventually the optimized techniques will be applied to clinical allografts and xenografts or genetically-modified islets designed to overcome immune responses in the diabetic host.

Activity Profiles for Marine Sponge-associated Bacteria Obtained by 16S RRNA Vs 16S RRNA Gene Comparisons

The ISME Journal. Apr, 2010  |  Pubmed ID: 20054355

The phylogenetic diversity of microorganisms in marine sponges is becoming increasingly well described, yet relatively little is known about the activities of these symbionts. Given the seemingly favourable environment provided to microbes by their sponge hosts, as indicated by the extraordinarily high abundance of sponge symbionts, we hypothesized that the majority of sponge-associated bacteria are active in situ. To test this hypothesis we compared, for the first time in sponges, 16S rRNA gene- vs 16S rRNA-derived bacterial community profiles to gain insights into symbiont composition and activity, respectively. Clone libraries revealed a highly diverse bacterial community in Ancorina alata, and a much lower diversity in Polymastia sp., which were identified by electron microscopy as a high- and a low-microbial abundance sponge, respectively. Substantial overlap between DNA and RNA libraries was evident at both phylum and phylotype levels, indicating in situ activity for a large fraction of sponge-associated bacteria. This active fraction included uncultivated, sponge-specific lineages within, for example, Actinobacteria, Chloroflexi and Gemmatimonadetes. This study shows the potential of RNA vs DNA comparisons based on the 16S rRNA gene to provide insights into the activity of sponge-associated microorganisms.

Genetic and Epigenetic Inactivation of Kruppel-like Factor 4 in Medulloblastoma

Neoplasia (New York, N.Y.). Jan, 2010  |  Pubmed ID: 20072650

Although medulloblastoma is the most common pediatric malignant brain tumor, its molecular underpinnings are largely unknown. We have identified rare, recurrent homozygous deletions of Kruppel-like Factor 4 (KLF4) in medulloblastoma using high-resolution single nucleotide polymorphism arrays, digital karyotyping, and genomic real-time polymerase chain reaction (PCR). Furthermore, we show that there is loss of physiological KLF4 expression in more than 40% of primary medulloblastomas both at the RNA and protein levels. Medulloblastoma cell lines drastically increase the expression of KLF4 in response to the demethylating agent 5-azacytidine and demonstrate dense methylation of the promoter CpG island by bisulfite sequencing. Methylation-specific PCR targeting the KLF4 promoter demonstrates CpG methylation in approximately 16% of primary medulloblastomas. Reexpression of KLF4 in the D283 medulloblastoma cell line results in significant growth suppression both in vitro and in vivo. We conclude that KLF4 is inactivated by either genetic or epigenetic mechanisms in a large subset of medulloblastomas and that it likely functions as a tumor suppressor gene in the pathogenesis of medulloblastoma.

Multi-dose-route, Multi-species Pharmacokinetic Models for Manganese and Their Use in Risk Assessment

Journal of Toxicology and Environmental Health. Part A. 2010  |  Pubmed ID: 20077292

Manganese (Mn) is an essential element that may be toxic in conditions of overexposure. Nearly 10 years ago, some of the authors of this article published a proposed methodology to perform a tissue-dose-based risk assessment and a detailed list of data needs necessary to perform the assessment. Since that time, a substantial body of Mn pharmacokinetic (PK) data has been generated in rats and nonhuman primates, allowing for the construction of physiologically based pharmacokinetic (PBPK) models for Mn. This study reviews the development of the Mn PBPK models, reassesses the previously identified data needs, and details potential uses of these models in risk assessment of Mn. Based upon numerous animal experiments, pharmacokinetic (PK) models have effectively simulated tissue kinetics of Mn from both inhaled and oral Mn intake. PK models achieve this by incorporating homeostatic control processes, saturable tissue binding capacities, and preferential fluxes in various tissue regions. While minor data gaps still exist, the models captured the main dose-dependent characteristics of Mn disposition in rodents and monkeys and provide a structure to parameterize an equivalent PK description in humans. These models are organized to contribute to a tissue-dose based risk assessment of Mn that simultaneously considers ingestion and inhalation kinetics of Mn along with homeostatic control of Mn.

Effects of Nadir CD4 Count and Duration of Human Immunodeficiency Virus Infection on Brain Volumes in the Highly Active Antiretroviral Therapy Era

Journal of Neurovirology. Feb, 2010  |  Pubmed ID: 20113183

Cerebral atrophy is a well-described, but poorly understood complication of human immunodeficiency virus (HIV) infection. Despite reduced prevalence of HIV-associated dementia in the highly active antiretroviral therapy (HAART) era, HIV continues to affect the brains of patients with chronic infection. In this study we examine patterns of brain volume loss in HIV-infected patients on HAART, and demographic and clinical factors contributing to brain volume loss. We hypothesized that nadir CD4+ lymphocyte count, duration of HIV infection, and age would be associated with reduced cortical volumes. Volumes of cortical and subcortical regions in 69 HIV-infected neuroasymptomatic (NA) individuals and 13 with at least mild acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) were measured using voxel-based morphometry. Demographic and clinical factors (age, plasma HIV RNA level, current and nadir CD4 counts, duration of infection, central nervous system [CNS] penetration of antiretroviral regimen) along with their interactions were entered into a regression model selection algorithm to determine the final models that best described regional brain volumes. Relative to NA, individuals with ADC exhibited decreased total gray matter and parietal cortex volumes and increased total ventricular volumes. Final regression models showed overall cerebral volume, including gray and white matter volume and volumes of the parietal, temporal, and frontal lobes and the hippocampus, were most strongly associated with disease history factors (nadir CD4 and duration of infection). In contrast, basal ganglia volumes were related most strongly to current disease factors, most notably plasma HIV RNA. These findings indicate that individuals with a history of chronic HIV infection with previous episodes of severely impaired immune function, as reflected by reduced nadir CD4+ lymphocyte count, may be at greatest risk for cerebral atrophy. The pattern of HIV-associated brain loss may be changing from a subcortical to a cortical disease among patients who are largely asymptomatic on HAART.

Universal Poor Survival in Children with Medulloblastoma Harboring Somatic TP53 Mutations

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Mar, 2010  |  Pubmed ID: 20142599

Medulloblastoma is the prototype of treatment success in modern pediatric neuro-oncology. Unfortunately, 20% to 30% of tumors recur despite maximal resection and multimodal therapy. Multiple biologic prognostic markers have been investigated to predict recurrences, but controversy remains regarding their clinical utility. Because p53 immunopositivity is an adverse prognostic marker in pediatric medulloblastoma and TP53 mutations are associated with chemotherapy and radiation therapy resistance, we aimed to determine the extent and role of TP53 mutations in pediatric medulloblastoma treatment failure.

Islet Isolation from Juvenile Porcine Pancreas After 24-h Hypothermic Machine Perfusion Preservation

Cell Transplantation. 2010  |  Pubmed ID: 20149300

Pancreas procurement for islet isolation and transplantation is limited by concerns for the detrimental effects of postmortem ischemia. Hypothermic machine perfusion (HMP) preservation technology has had a major impact in circumventing ischemic injury in clinical kidney transplantation and is applied here to the preservation and procurement of viable islets after hypothermic perfusion preservation of porcine pancreata because pigs are now considered the donor species of choice for xenogeneic islet transplantation. Pancreases were surgically removed from young (<6 months) domestic Yorkshire pigs (25-32 kg), either before or after 30 min of warm ischemia time (WIT), and cannulated for perfusion. Each pancreas was assigned to one of six preservation treatment groups: fresh controls-processed immediately (cold ischemia <1 h) (G1, n = 7); static cold storage-flushed with cold UW-Viaspan and stored in UW-Viaspan at 2-4 degrees C for 24 h with no prior WIT (G2, n = 9); HMP perfused on a LifePort(R) machine at 4-6 degrees C and low pressure (10 mmHg) for 24 h with either KPS1 solution (G3, n = 7) or Unisol-UHK (G4, n = 7). Additional treatment groups to evaluate the effects of prior warm ischemia examined islet isolation after 30 min WIT in situ without (G5, n = 6) or with subsequent 24-h HMP with KPS1 (G6, n = 7). The pancreas was intraductally distended with Liberase PI enzyme and normothermically digested. The isolated islets were purified by a continuous density-gradient centrifugation. Perfusion-induced glandular edema was G3 = 138 +/- 19%, G4 = 160 +/- 16%, and G6 = 127 +/- 22%. Islet yield (IEQ/g of pancreas) varied between the groups: G1 = 1,425 +/- 610, G2 = 1,002 +/- 262, G3 = 2,242 +/- 449 (p < 0.05 vs. G2), G4 = 1,901 +/- 420 (p < 0.05 vs. G2), G5 = 1,756 +/- 329, and G6 = 1,396 +/- 243. Islet stimulation indices were equivalent between the groups and similar to controls (G1). Insulin content (ng/IE) was different between the treatment groups with the highest insulin content in islets harvested from HMP pancreata. Dithizone staining for islets consistently showed more uniform digestion of the perfused organs, with greater separation of the tissue, less entrapped islets, and higher islet yield and purity. The salutary effects of HMP for 24 h were also manifest after 30-min prior warm ischemia. We conclude that 24 h of HMP is well tolerated, leading to moderate edema but no loss of function of the harvested islets. The edema appears to aid in enzymatic digestion, producing a greater yield and purity of islets compared with pancreas subjected to 24 h of static cold storage.

An Overview of Second Generation Biofuel Technologies

Bioresource Technology. Mar, 2010  |  Pubmed ID: 19963372

The recently identified limitations of 1st-generation biofuels produced from food crops (with perhaps the exception of sugarcane ethanol) have caused greater emphasis to be placed on 2nd-generation biofuels produced from ligno-cellulosic feedstocks. Although significant progress continues to be made to overcome the technical and economic challenges, 2nd-generation biofuels production will continue to face major constraints to full commercial deployment. The logistics of providing a competitive, all-year-round, supply of biomass feedstock to a commercial-scale plant is challenging, as is improving the performance of the conversion process to reduce costs. The biochemical route, being less mature, probably has a greater cost reduction potential than the thermo-chemical route, but here a wider range of synthetic fuels can be produced to better suit heavy truck, aviation and marine applications. Continued investment in research and demonstration by both public and private sectors, coupled with appropriate policy support mechanisms, are essential if full commercialisation is to be achieved within the next decade. After that, the biofuel industry will grow only at a steady rate and encompass both 1st- and 2nd-generation technologies that meet agreed environmental, sustainability and economic policy goals.

Novel Cardiac Findings in Periventricular Nodular Heterotopia

American Journal of Medical Genetics. Part A. Jan, 2010  |  Pubmed ID: 20014127

Periventricular nodular heterotopia (PNH) is a set of neuronal migration disorders that occur during fetal development. Neurons in the brain fail to migrate from the lining of the lateral ventricles to the cortex of the brain. When the neurons fail to migrate, ectopic neuronal nodules form. Epilepsy is a common symptom of PNH. The majority of PNH cases appear to be due to mutations in filamin A, an X-linked gene. Most of the affected individuals are female because affected males typically die in utero. Filamin A anchors integral membrane proteins to the cytoskeleton by binding actin filaments in the cytoplasm. Both animal and human studies indicate that filamin A also plays a role in blood vessel development. In this report, we describe novel cardiac findings in an 18-month-old girl with PNH associated with a nonsense mutation in FLNA, including a dysplastic pulmonary valve and clefting of the mitral valve. These findings broaden the range of cardiac anomalies associated with filamin A mutations to include abnormality of the pulmonary valve and clefting of the mitral valve, consistent with a role for filamin A in valve leaflet development.

OTX2 is Critical for the Maintenance and Progression of Shh-independent Medulloblastomas

Cancer Research. Jan, 2010  |  Pubmed ID: 20028867

OTX2 is a developmentally regulated transcription factor involved in early morphogenesis of the central nervous system. This gene is amplified and overexpressed in medulloblastoma cell lines, but the nature and extent of its genetic alterations in primary tumors have not been evaluated. Analysis of a large cohort of primary medulloblastomas revealed frequent focal copy number gain of a region minimally containing OTX2 as a single gene. OTX2 copy number gain was restricted to tumor subtypes that did not express a molecular signature of Wnt or Shh pathway activation. FISH analysis revealed copy number gain in a subset of cells within medulloblastoma samples, suggesting a late event in tumor progression. Gain of OTX2 copy number was associated with the presence of anaplastic histologic features and shorter survival in medulloblastoma patients. In support of a functional role, ectopic OTX2 expression enhanced proliferation and tumorigenicity of immortalized primary cells, whereas OTX2 knockdown in medulloblastoma cells prolonged the survival of animals bearing xenograft tumors. Mechanistic investigations revealed upregulation of MYC as a potential mechanism whereby OTX2 promotes tumor progression. Our findings define OTX2 as an important oncogenic driver in medulloblastoma.

Genomics of Medulloblastoma: from Giemsa-banding to Next-generation Sequencing in 20 Years

Neurosurgical Focus. Jan, 2010  |  Pubmed ID: 20043721

Advances in the field of genomics have recently enabled the unprecedented characterization of the cancer genome, providing novel insight into the molecular mechanisms underlying malignancies in humans. The application of high-resolution microarray platforms to the study of medulloblastoma has revealed new oncogenes and tumor suppressors and has implicated changes in DNA copy number, gene expression, and methylation state in its etiology. Additionally, the integration of medulloblastoma genomics with patient clinical data has confirmed molecular markers of prognostic significance and highlighted the potential utility of molecular disease stratification. The advent of next-generation sequencing technologies promises to greatly transform our understanding of medulloblastoma pathogenesis in the next few years, permitting comprehensive analyses of all aspects of the genome and increasing the likelihood that genomic medicine will become part of the routine diagnosis and treatment of medulloblastoma.

KARDIA: a Matlab Software for the Analysis of Cardiac Interbeat Intervals

Computer Methods and Programs in Biomedicine. Apr, 2010  |  Pubmed ID: 19896748

This article presents KARDIA, a Matlab (MathWorks Inc., MA) software developed for the analysis of cardiac interbeat interval (IBI) data. Available functions are called through a graphical user interface and permit the study of phasic cardiac responses (PCRs) and the estimation of time and frequency domain heart rate variability (HRV) parameters. Scaling exponents of heartbeat fluctuations are calculated with the detrended fluctuation analysis (DFA) algorithm. Grand average and individual subject results can be exported to spreadsheets for further statistical analysis. KARDIA is distributed free of charge under the terms of GNU public license so that other users can modify the code and adjust the program's performance according to their own scientific requirements.

ALCAPA: the Role of Myocardial Viability Studies in Determining Prognosis

Pediatric Radiology. Feb, 2010  |  Pubmed ID: 19795113

ALCAPA is optimally treated by coronary artery reimplantation early in neonatal life. Delayed diagnosis, however, is not infrequent, because symptoms often do not manifest until about 3 months of age, coinciding with the physiological nadir in pulmonary vascular resistance. With delayed diagnosis, there is potential for coronary steal and irreversible myocardial injury, which worsens outcome.

Rapamycin (sirolimus) in Tuberous Sclerosis Associated Pediatric Central Nervous System Tumors

Pediatric Blood & Cancer. Mar, 2010  |  Pubmed ID: 19856393

Tuberous sclerosis complex (TSC) is associated with hamartomatous growths including subependymal giant cell astrocytomas (SEGAs). Since chemo-radiation therapies offer scant benefit, oncologists had traditionally been little involved in managing SEGAs. Recent evidence demonstrating rapamycin efficacy in adults and children with TSC-associated tumors foresee a practice change. We summarize our institutional experience and literature review that highlight potential benefits and hazards of rapamycin therapy, for TSC patients with SEGA, and other syndromal brain tumors.

Current State of Hypothermic Machine Perfusion Preservation of Organs: The Clinical Perspective

Cryobiology. Jul, 2010  |  Pubmed ID: 19857479

This review focuses on the application of hypothermic perfusion technology as a topic of current interest with the potential to have a salutary impact on the mounting clinical challenges to improve the quantity and quality of donor organs and the outcome of transplantation. The ex vivo perfusion of donor organs on a machine prior to transplant, as opposed to static cold storage on ice, is not a new idea but is being re-visited because of the prospects of making available more and better organs for transplantation. The rationale for pursuing perfusion technology will be discussed in relation to emerging data on clinical outcomes and economic benefits for kidney transplantation. Reference will also be made to on-going research using other organs with special emphasis on the pancreas for both segmental pancreas and isolated islet transplantation. Anticipated and emerging benefits of hypothermic machine perfusion of organs are: (i) maintaining the patency of the vascular bed, (ii) providing nutrients and low demand oxygen to support reduced energy demands, (iii) removal of metabolic by-products and toxins, (iv) provision of access for administration of cytoprotective agents and/or immunomodulatory drugs, (v) increase of available assays for organ viability assessment and tissue matching, (vi) facilitation of a change from emergency to elective scheduled surgery with reduced costs and improved outcomes, (vii) improved clinical outcomes as demonstrated by reduced PNF and DGF parameters, (viii) improved stabilization or rescue of ECD kidneys or organs from NHBD that increase the size of the donor pool, (ix) significant economic benefit for the transplant centers and reduced health care costs, and (x) provision of a technology for ex vivo use of non-transplanted human organs for pharmaceutical development research.

Catatonia is Not Schizophrenia: Kraepelin's Error and the Need to Recognize Catatonia As an Independent Syndrome in Medical Nomenclature

Schizophrenia Bulletin. Mar, 2010  |  Pubmed ID: 19586994

Catatonia is a motor dysregulation syndrome described by Karl Kahlbaum in 1874. He understood catatonia as a disease of its own. Others quickly recognized it among diverse disorders, but Emil Kraepelin made it a linchpin of his concept of dementia praecox. Eugen Bleuler endorsed this singular association. During the 20th century, catatonia has been considered a type of schizophrenia. In the 1970s, American authors identified catatonia in patients with mania and depression, as a toxic response, and in general medical and neurologic illnesses. It was only occasionally found in patients with schizophrenia. When looked for, catatonia is found in 10% or more of acute psychiatric admissions. It is readily diagnosable, verifiable by a lorazepam challenge test, and rapidly treatable. Even in its most lethal forms, it responds to high doses of lorazepam or to electroconvulsive therapy. These treatments are not accepted for patients with schizophrenia. Prompt recognition and treatment saves lives. It is time to place catatonia into its own home in the psychiatric classification.

Integrated Approaches for the Public Health Prioritization of Foodborne and Zoonotic Pathogens

Risk Analysis : an Official Publication of the Society for Risk Analysis. May, 2010  |  Pubmed ID: 19765248

To address the persistent problems of foodborne and zoonotic disease, public health officials worldwide face difficult choices about how to best allocate limited resources and target interventions to reduce morbidity and mortality. Data-driven approaches to informing these decisions have been developed in a number of countries. Integrated comparative frameworks generally share three methodological components: estimating incidence of acute illnesses, chronic sequelae, and mortality; attributing pathogen-specific illnesses to foods; and calculating integrated measures of disease burden such as cost of illness, willingness to pay, and health-adjusted life years (HALYs). To discuss the similarities and differences in these approaches, to seek consensus on principles, and to improve international collaboration, the E.U. MED-VET-NET and the U.S.-based Food Safety Research Consortium organized an international conference convened in Berlin, Germany, on July 19-21, 2006. This article draws in part on the deliberations of the conference and discusses general principles, data needs, methodological issues and challenges, and future research needs pertinent to objective data-driven analyses and their potential use for priority setting of foodborne and zoonotic pathogens in public health policy.

Using Oral Microbial DNA Analysis to Identify Expirated Bloodspatter

International Journal of Legal Medicine. Nov, 2010  |  Pubmed ID: 20162292

Distinguishing expirated bloodstains (blood forced by airflow out of the nose, mouth or a chest wound) from impact spatter (blood from gunshots, explosives, blunt force trauma and/or machinery accidents) is an important challenge in forensic science. Streptococcal bacteria are only found in the human mouth and saliva. This study developed a polymerase chain reaction (PCR) method that detects DNA from these bacteria as a sensitive tool to detect the presence of saliva. The PCR method was very specific to human oral streptococci, with no PCR product being made from human DNA or DNA from other microbes that were tested. It was also very sensitive, detecting as little as 60 fg of target DNA. The PCR amplification gave product with 99 out of 100 saliva samples tested. PCR was not inhibited by the presence of blood and could detect target DNA in expirated bloodstains in a range of materials and for up to 92 days after deposit on cardboard or cotton fabric. In a blind trial, the PCR method was able to distinguish three mock forensic samples that contained expirated blood from four that did not. Our data show that bacteria present in the oral cavity can be detected in bloodstains that contain saliva and therefore can potentially be used as a marker in forensic work to distinguish mouth-expirated bloodstains from other types of bloodstains.

Subcuticular Bacteria Associated with Two Common New Zealand Echinoderms: Characterization Using 16S RRNA Sequence Analysis and Fluorescence in Situ Hybridization

The Biological Bulletin. Feb, 2010  |  Pubmed ID: 20203257

Many echinoderms contain subcuticular bacteria (SCB), symbionts which reside in the lumen between the host's epidermal cells and outer cuticle. This relationship is common, existing in about 60% of echinoderms studied so far, yet the function of SCB remains largely unknown. In this study, phylogenetic analysis was carried out on 16S rRNA sequences obtained from echinoderm-associated bacteria, resulting in the identification of four species of putative SCB. All four bacteria were identified from the holothurian Stichopus mollis, and two of the four were also found in the asteroid Patiriella sp. Two of these bacteria belong to the Alphaproteobacteria, and two to the Gammaproteobacteria. In addition to phylogenetic analysis, fluorescence in situ hybridization (FISH) assays were carried out on Patiriella sp., S. mollis, and the asteroid Astrostole scabra. Results showed that Patiriella sp. and S. mollis contain SCB, in agreement with the phylogenetic analysis, while SCB were not detected in A. scabra. Of the bacteria detected using FISH, more than 80% were recognized as belonging to the Alphaproteobacteria in both host species. However, in S. mollis about 20% of the detected SCB successfully hybridized with the Gammaproteobacteria-specific probe, whereas bacteria belonging to this class were never observed in Patiriella sp. This is only the second study to characterize SCB by molecular means, and is the first to identify SCB in situ using FISH.

International Network of Cancer Genome Projects

Nature. Apr, 2010  |  Pubmed ID: 20393554

The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

HDAC5 and HDAC9 in Medulloblastoma: Novel Markers for Risk Stratification and Role in Tumor Cell Growth

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Jun, 2010  |  Pubmed ID: 20413433

Medulloblastomas are the most common malignant brain tumors in childhood. Survivors suffer from high morbidity because of therapy-related side effects. Thus, therapies targeting tumors in a specific manner with small molecules such as histone deacetylase (HDAC) inhibitors are urgently warranted. This study investigated the expression levels of individual human HDAC family members in primary medulloblastoma samples, their potential as risk stratification markers, and their roles in tumor cell growth.

The Genetics of Pediatric Brain Tumors

Current Neurology and Neuroscience Reports. May, 2010  |  Pubmed ID: 20425037

Brain tumors are the most common childhood solid malignancy and the leading cause of cancer-related death in children. Medulloblastoma, ependymoma, supratentorial primitive neuroectodermal tumors, and pilocytic astrocytoma are the most prevalent types, all of which are clinically, histologically, and genetically heterogeneous. Despite an incomplete molecular understanding of these tumors, we have made significant headway in the past 5 years in identifying and classifying important genetic alterations and pathways central to the disease process. This review summarizes our current state of knowledge, emphasizes recent seminal findings in the field, and proposes future research efforts needed to further characterize the genetic basis of pediatric brain tumors.

Clinical and Pathologic Features of an Adenomatous Polyp of the Colon in a Domestic Ferret (Mustela Putorius Furo)

The Canadian Veterinary Journal. La Revue Vétérinaire Canadienne. Nov, 2010  |  Pubmed ID: 21286327

A 6-year-old castrated male domestic ferret (Mustela putorius furo) with a 4-week history of intermittent diarrhea and straining during defecation had an intraluminal mass in the descending colon identified by abdominal ultrasound. The histopathological diagnosis of the resected mass was an adenomatous polyp of the colon. No post-operative complications were identified over a 32-month follow-up period.

Issues for DSM-5: Whither Melancholia? The Case for Its Classification As a Distinct Mood Disorder

The American Journal of Psychiatry. Jul, 2010  |  Pubmed ID: 20595426

The Failure of the Schizophrenia Concept and the Argument for Its Replacement by Hebephrenia: Applying the Medical Model for Disease Recognition

Acta Psychiatrica Scandinavica. Sep, 2010  |  Pubmed ID: 20649527

Hsp90 is Required for Transfer of the Cholera Toxin A1 Subunit from the Endoplasmic Reticulum to the Cytosol

The Journal of Biological Chemistry. Oct, 2010  |  Pubmed ID: 20667832

Cholera toxin (CT) is an AB(5) toxin that moves from the cell surface to the endoplasmic reticulum (ER) by retrograde vesicular transport. In the ER, the catalytic A1 subunit dissociates from the rest of the toxin and enters the cytosol by exploiting the quality control system of ER-associated degradation (ERAD). The driving force for CTA1 dislocation into the cytosol is unknown. Here, we demonstrate that the cytosolic chaperone Hsp90 is required for CTA1 passage into the cytosol. Hsp90 bound to CTA1 in an ATP-dependent manner that was blocked by geldanamycin (GA), an established Hsp90 inhibitor. CT activity against cultured cells and ileal loops was also blocked by GA, as was the ER-to-cytosol export of CTA1. Experiments using RNA interference or N-ethylcarboxamidoadenosine, a drug that inhibits ER-localized GRP94 but not cytosolic Hsp90, confirmed that the inhibitory effects of GA resulted specifically from the loss of Hsp90 activity. This work establishes a functional role for Hsp90 in the ERAD-mediated dislocation of CTA1.

Use of Ifosfamide, Carboplatin, and Etoposide Chemotherapy in Choroid Plexus Carcinoma

Journal of Neurosurgery. Pediatrics. Jun, 2010  |  Pubmed ID: 20515336

Choroid plexus carcinomas (CPCs) are rare pediatric tumors with a generally poor prognosis. Although the role of surgery is well recognized, the role of adjuvant chemotherapy and radiation therapy remains unclear. In this paper, the authors' goal was to assess the role of second-look surgery and neoadjuvant ifosfamide, carboplatin, etoposide (ICE) chemotherapy in the management of CPC and to study neurocognitive outcome.

Deep Sequencing Reveals Exceptional Diversity and Modes of Transmission for Bacterial Sponge Symbionts

Environmental Microbiology. Aug, 2010  |  Pubmed ID: 21966903

Marine sponges contain complex bacterial communities of considerable ecological and biotechnological importance, with many of these organisms postulated to be specific to sponge hosts. Testing this hypothesis in light of the recent discovery of the rare microbial biosphere, we investigated three Australian sponges by massively parallel 16S rRNA gene tag pyrosequencing. Here we show bacterial diversity that is unparalleled in an invertebrate host, with more than 250,000 sponge-derived sequence tags being assigned to 23 bacterial phyla and revealing up to 2996 operational taxonomic units (95% sequence similarity) per sponge species. Of the 33 previously described 'sponge-specific' clusters that were detected in this study, 48% were found exclusively in adults and larvae - implying vertical transmission of these groups. The remaining taxa, including 'Poribacteria', were also found at very low abundance among the 135,000 tags retrieved from surrounding seawater. Thus, members of the rare seawater biosphere may serve as seed organisms for widely occurring symbiont populations in sponges and their host association might have evolved much more recently than previously thought.

TP53 Mutation is Frequently Associated with CTNNB1 Mutation or MYCN Amplification and is Compatible with Long-term Survival in Medulloblastoma

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Dec, 2010  |  Pubmed ID: 21060032

The role of TP53 mutations in the tumorigenesis of sporadic medulloblastoma (MB) and the value of TP53 mutation status as a prognostic marker are not yet definitely elucidated. A recent report identified TP53 mutations in MB as an adverse prognostic marker. Hence, the current study was conducted to validate the prognostic role of TP53 mutation in MB and to understand its contribution to tumorigenesis.

Use of Flatbed Transparency Scanners in Zebrafish Research: Versatile and Economical Adjuncts to Traditional Imaging Tools for the Danio Rerio Laboratory

Methods in Cell Biology. 2010  |  Pubmed ID: 21111223

Flatbed transparency scanners are typically relegated to routine office tasks, yet they do offer a variety of potentially useful imaging tools for the zebrafish laboratory. These include motility screens, oocyte maturation and egg activation assays as well as counting and measuring tasks. When coupled with Macroscheduler (http://www.mjtnet.com) and ImageJ (http://rsbweb.nih.gov/ij), the scanner becomes a stable platform for imaging large arrays of zebrafish oocytes, embryos, larvae, and adults. Such large arrays are a prerequisite to the development of high-throughput screens for small molecules as potential therapeutic drugs in the treatment of many diseases including cancer and epilepsy. Thus the scanner may have a role in adapting zebrafish to future drug and mutagenesis screening. In this chapter, some of the uses of scanners are outlined to bring attention to the potentials of this simple-to-use, flexible, inexpensive device for the zebrafish research community.

Long-term Outcome of Treatment of Dental Abscesses with a Wound-packing Technique in Pet Rabbits: 13 Cases (1998-2007)

Journal of the American Veterinary Medical Association. Dec, 2010  |  Pubmed ID: 21155684

To evaluate the effectiveness and treatment outcome of a minimal surgical debridement and antimicrobial-impregnated gauze packing technique for treatment of dental abscesses in rabbits.

Posterior Fossa Ependymomas: New Radiological Classification with Surgical Correlation

Child's Nervous System : ChNS : Official Journal of the International Society for Pediatric Neurosurgery. Dec, 2010  |  Pubmed ID: 20680298

The key determinant of long-term outcome in infratentorial ependymomas remains the extent of surgical resection. We describe a new radiological classification system which is validated against surgical findings and correlated with risk of post-operative residual tumour.

Comment on "On the Insensitivity of Single Field Planar Dosimetry to IMRT Inaccuracies" [Med. Phys. 37, 2516-2524 (2010)]

Medical Physics. Jul, 2010  |  Pubmed ID: 20831096

A ZASP Missense Mutation, S196L, Leads to Cytoskeletal and Electrical Abnormalities in a Mouse Model of Cardiomyopathy

Circulation. Arrhythmia and Electrophysiology. Dec, 2010  |  Pubmed ID: 20852297

Dilated cardiomyopathy (DCM) is a primary disease of the heart muscle associated with sudden cardiac death secondary to ventricular tachyarrhythmias and asystole. However, the molecular pathways linking DCM to arrhythmias and sudden cardiac death are unknown. We previously identified a S196L mutation in exon 4 of LBD3-encoded ZASP in a family with DCM and sudden cardiac death. These findings led us to hypothesize that this mutation may precipitate both cytoskeletal and conduction abnormalities in vivo. Therefore, we investigated the role of the ZASP4 mutation S196L in cardiac cytoarchitecture and ion channel biology.

Silencing of Thrombospondin-1 is Critical for Myc-induced Metastatic Phenotypes in Medulloblastoma

Cancer Research. Oct, 2010  |  Pubmed ID: 20876797

Mechanisms by which c-Myc (Myc) amplification confers aggressive medulloblastoma phenotypes are poorly defined. Here, we show using orthotopic models that high Myc expression promotes cell migration/invasion and induces metastatic tumors, which recapitulate aggressive histologic features of Myc-amplified primary human medulloblastoma. Using ChIP-chip analysis, we identified cell migration and adhesion genes, including Tsp-1/THBS1, ING4, PVRL3, and PPAP2B, as Myc-bound loci in medulloblastoma cells. Expression of Tsp-1 was most consistently and robustly diminished in medulloblastoma cell lines and primary human tumors with high Myc expression (n = 101, P = 0.032). Strikingly, stable Tsp-1 expression significantly attenuated in vitro transformation and invasive/migratory properties of high Myc-expressing medulloblastoma cells without altering cell proliferation, whereas RNA interference-mediated Myc knockdown was consistently accompanied by increased Tsp-1 levels and reduced cell migration and invasion in medulloblastoma cells. Chromatin immunoprecipitation (ChIP) assays revealed colocalization of Myc and obligate partner Max and correlated diminished RNA polymerase II occupancy (∼3-fold decrease, P < 0.01) with increased Myc binding at a core Tsp-1 promoter. Reporter gene and/or gel shift assays confirmed direct repression of Tsp-1 transcription by Myc and also identified JPO2, a Myc interactor associated with metastatic medulloblastoma, as a cofactor in Myc-mediated Tsp-1 repression. These findings indicate the Myc-regulatory network targets Tsp-1 via multiple mechanisms in medulloblastoma transformation, and highlight a novel critical role for Tsp-1 in Myc-mediated aggressive medulloblastoma phenotypes.

Molecular Diagnostics of CNS Embryonal Tumors

Acta Neuropathologica. Nov, 2010  |  Pubmed ID: 20882288

Tremendous progress has recently been made in both molecular subgrouping, and the establishment of prognostic biomarkers for embryonal brain tumors, particularly medulloblastoma. Several prognostic biomarkers that were initially identified in retrospective cohorts of medulloblastoma, including MYC and MYCN amplification, nuclear β-catenin accumulation, and chromosome 17 aberrations have now been validated in clinical trials. Moreover, molecular subgroups based on distinct transcriptome profiles have been consistently reported from various groups on different platforms demonstrating that the concept of distinct medulloblastoma subgroups is very robust. Well-described subgroups of medulloblastomas include tumors showing wingless signaling pathway (Wnt) activation, and another characterized by sonic hedgehog pathway activity. Two or more additional subgroups were consistently reported to contain the vast majority of high-risk tumors, including most tumors with metastatic disease at diagnosis and/or large cell/anaplastic histology. Several years ago, atypical teratoid rhabdoid tumor (AT/RT) was recognized as a separate entity based on its distinct biology and particularly aggressive clinical behavior. These tumors may occur supra or infratentorially and are usually found to have genetic alterations of SMARCB1 (INI1/hSNF5), a tumor suppressor gene located on chromosome 22q. Subsequent loss of SMARCB1 protein expression comprises a relatively specific and sensitive diagnostic marker for AT/RT. For CNS primitive neuroectodermal tumors (CNS PNETs), a consistent finding has been that they are molecularly distinct from medulloblastoma. Furthermore, a distinct fraction of CNS PNETs with particularly poor prognosis only occurring in young children was delineated, which was previously labeled ependymoblastoma or embryonal tumor with abundant neuropil and true rosettes (ETANTR) and which is morphologically characterized by the presence of multilayered "ependymoblastic" rosettes. This group of tumors shows a unique cytogenetic abnormality not seen in other brain tumors: focal amplification of a micro-RNA cluster at chromosome 19q13.42, which has never been found to be amplified in other CNS PNETs, medulloblastoma or AT/RT. In summary, these consistent findings have significantly contributed to our ability to sub-classify embryonal brain tumors into clinically and biologically meaningful strata and, for some of the subgroups, have led to the identification of specific targets for future development of molecularly targeted therapies.

Role of LIM and SH3 Protein 1 (LASP1) in the Metastatic Dissemination of Medulloblastoma

Cancer Research. Oct, 2010  |  Pubmed ID: 20924110

Medulloblastoma is the most common malignant pediatric brain tumor and is one of the leading causes of cancer-related mortality in children. Treatment failure mainly occurs in children harboring metastatic tumors, which typically carry an isochromosome 17 or gain of 17q, a common hallmark of intermediate and high-risk medulloblastoma. Through mRNA expression profiling, we identified LIM and SH3 protein 1 (LASP1) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. In an independent validation cohort of 101 medulloblastoma samples, the abundance of LASP1 mRNA was significantly associated with 17q gain, metastatic dissemination, and unfavorable outcome. LASP1 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n = 207), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival. In vitro experiments in medulloblastoma cell lines showed a strong reduction of cell migration, increased adhesion, and decreased proliferation upon LASP1 knockdown by small interfering RNA-mediated silencing, further indicating a functional role for LASP1 in the progression and metastatic dissemination of medulloblastoma.

Calculating a Cure for Cancer: Managing Medulloblastoma MATH1-ematically

Expert Review of Neurotherapeutics. Oct, 2010  |  Pubmed ID: 20925463

High Throughput Surface Characterization: A Review of a New Tool for Screening Prospective Biomedical Material Arrays

Journal of Drug Targeting. Dec, 2010  |  Pubmed ID: 20945971

The application of high throughput surface characterization (HTSC) to the analysis of polymeric biomaterial libraries is an important advancement for the discovery and development of new biomedical materials and is the focus of this review. The potential for HTSC to identify structure/activity relationships for large libraries of materials can be utilized to accelerate materials discovery as well as providing insight into the underlying biological-material interactions. Furthermore, the correlations identified between surface chemical structure and cellular behavior could not have been predicted by a rational design approach based simply on review of bulk structure, which demonstrates the importance of HTSC in the assessment of cell-material and cell-biomolecular interactions that are dependent on surface properties.

Nebulette Mutations Are Associated with Dilated Cardiomyopathy and Endocardial Fibroelastosis

Journal of the American College of Cardiology. Oct, 2010  |  Pubmed ID: 20951326

Four variants (K60N, Q128R, G202R, and A592E) in the nebulette gene were identified in patients with dilated cardiomyopathy (DCM) and endocardial fibroelastosis. We sought to determine if these mutations are cardiomyopathy causing.

Cerebral Metabolite Abnormalities in Human Immunodeficiency Virus Are Associated with Cortical and Subcortical Volumes

Journal of Neurovirology. Nov, 2010  |  Pubmed ID: 20961212

Cerebral metabolite disturbances occur among human immunodeficiency virus (HIV)-infected people, and are thought to reflect neuropathology, including proinflammatory processes, and neuronal loss. HIV-associated cortical atrophy continues to occur, though its basis is not well understood, and the relationship of cerebral metabolic disturbance to structural brain abnormalities in HIV has not been well delineated. We hypothesized that metabolite disturbances would be associated with reduced cortical and subcortical volumes. Cerebral volumes were measured in 67 HIV-infected people, including 10 people with mild dementia (acquired immunodeficiency syndrome [AIDS] dimentia complex [ADC] stage >1) via automated magnetic resonance imaging (MRI) segmentation. Magnetic resonance spectroscopy (MRS) was used to measure levels of cerebral metabolites N-acetylaspartate (NAA), myo-inositol (MI), choline-containing compounds (Cho), glutamate/glutamine (Glx), and creatine (Cr) from three brain regions (frontal gray matter, frontal white matter, basal ganglia). Analyses were conducted to examine the associations between MRS and cerebral volumetric measures using both absolute and relative metabolite concentrations. NAA in the mid-frontal gray matter was most consistently associated with cortical (global, frontal, and parietal), ventricular, and caudate volumes based on analysis of absolute metabolite levels, whereas temporal lobe volume was associated with basal ganglia NAA and Glx, and Cho concentrations in the frontal cortex and basal ganglia. Hippocampal volume was associated with frontal white matter NAA, whereas thalamic volume was associated with both frontal white matter NAA and basal ganglia Glx. Analyses of relative metabolite concentrations (referenced to Cr) yielded weaker effects, although more metabolites were retained as significant predictors in the models than the analysis of absolute concentrations. These findings demonstrate that reduced cortical and subcortical volumes, which have been previously found to be linked to HIV status and history, are also strongly associated with the degree of cerebral metabolite disturbance observed via MRS. Reduced cortical and hippocampal volumes were most strongly associated with decreased NAA, though reduced Glx also tended to be associated with reduced cortical and subcortical volumes (caudate and thalamus) as well, suggesting both neuronal and glial disturbances. Interestingly, metabolite-volumetric relationships were not limited to the cortical region from which MRS was measured, possibly reflecting shared pathophysiological processes. The relationships between Cho and volumetric measures suggest a complicated relationship possibly related to the effects of inflammatory processes on brain volume. The findings demonstrate the relationship between MRI-derived measures of cerebral metabolite disturbances and structural brain integrity, which has implication in understanding HIV-associated neuropathological mechanisms.

The Transcription Factor Mef2 is Required for Normal Circadian Behavior in Drosophila

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Apr, 2010  |  Pubmed ID: 20427646

The transcription factor Mef2 has well established roles in muscle development in Drosophila and in the differentiation of many cell types in mammals, including neurons. Here, we describe a role for Mef2 in the Drosophila pacemaker neurons that regulate circadian behavioral rhythms. We found that Mef2 is normally produced in all adult clock neurons and that Mef2 overexpression in clock neurons leads to long period and complex rhythms of adult locomotor behavior. Knocking down Mef2 expression via RNAi or expressing a repressor form of Mef2 caused flies to lose circadian behavioral rhythms. These behavioral changes are correlated with altered molecular clocks in pacemaker neurons: Mef2 overexpression causes the oscillations in individual pacemaker neurons to become desynchronized, while Mef2 knockdown strongly dampens molecular rhythms. Thus, a normal level of Mef2 activity is required in clock neurons to maintain robust and accurate circadian behavioral rhythms.

Widespread Genomic Divergence During Sympatric Speciation

Proceedings of the National Academy of Sciences of the United States of America. May, 2010  |  Pubmed ID: 20457907

Speciation with gene flow is expected to generate a heterogeneous pattern of genomic differentiation. The few genes under or physically linked to loci experiencing strong disruptive selection can diverge, whereas gene flow will homogenize the remainder of the genome, resulting in isolated "genomic islands of speciation." We conducted an experimental test of this hypothesis in Rhagoletis pomonella, a model for sympatric ecological speciation. Contrary to expectations, we found widespread divergence throughout the Rhagoletis genome, with the majority of loci displaying host differences, latitudinal clines, associations with adult eclosion time, and within-generation responses to selection in a manipulative overwintering experiment. The latter two results, coupled with linkage disequilibrium analyses, provide experimental evidence that divergence was driven by selection on numerous independent genomic regions rather than by genome-wide genetic drift. "Continents" of multiple differentiated loci, rather than isolated islands of divergence, may characterize even the early stages of speciation. Our results also illustrate how these continents can exhibit variable topography, depending on selection strength, availability of preexisting genetic variation, linkage relationships, and genomic features that reduce recombination. For example, the divergence observed throughout the Rhagoletis genome was clearly accentuated in some regions, such as those harboring chromosomal inversions. These results highlight how the individual genes driving speciation can be embedded within an actively diverging genome.

Pleiotropic Role for MYCN in Medulloblastoma

Genes & Development. May, 2010  |  Pubmed ID: 20478998

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Sonic Hedgehog (SHH) signaling drives a minority of MB, correlating with desmoplastic pathology and favorable outcome. The majority, however, arises independently of SHH and displays classic or large cell anaplastic (LCA) pathology and poor prognosis. To identify common signaling abnormalities, we profiled mRNA, demonstrating misexpression of MYCN in the majority of human MB and negligible expression in normal cerebella. We clarified a role in pathogenesis by targeting MYCN (and luciferase) to cerebella of transgenic mice. MYCN-driven MB showed either classic or LCA pathologies, with Shh signaling activated in approximately 5% of tumors, demonstrating that MYCN can drive MB independently of Shh. MB arose at high penetrance, consistent with a role for MYCN in initiation. Tumor burden correlated with bioluminescence, with rare metastatic spread to the leptomeninges, suggesting roles for MYCN in both progression and metastasis. Transient pharmacological down-regulation of MYCN led to both clearance and senescence of tumor cells, and improved survival. Targeted expression of MYCN thus contributes to initiation, progression, and maintenance of MB, suggesting a central role for MYCN in pathogenesis.

Non-invasive Vesicoureteral Reflux Imaging

Journal of Pediatric Urology. Dec, 2010  |  Pubmed ID: 20488755

To evaluate non-invasive and non-ionizing methods of determining the presence of vesicoureteral reflux (VUR) and to preview upcoming ideas that have the potential of finding VUR non-invasively.

Atypical Teratoid or Rhabdoid Tumors: Improved Outcome with High-dose Chemotherapy

Journal of Pediatric Hematology/oncology. Jul, 2010  |  Pubmed ID: 20495479

To retrospectively review an institutional experience in managing atypical teratoid/rhabdoid tumors (AT/RT) of the Central Nervous System with high-dose chemotherapy in infants and children less than 4 years old.

Branchial Cysts in Two Amazon Parrots (Amazona Species)

Journal of Avian Medicine and Surgery. Mar, 2010  |  Pubmed ID: 20496605

A 37-year-old yellow-crowned Amazon parrot (Amazona ochrocephala) and a 20-year-old red-lored Amazon parrot (Amazona autumnalis) each presented with a large mass localized on the lateral neck. With the first bird, there was no evidence of signs of pain or discomfort, and the bird prehended and swallowed food normally. The second bird showed signs of mild upper-gastrointestinal discomfort. Results of an ultrasound examination and aspiration of the mass on each bird revealed a cystic structure. A computed tomography performed on the second bird revealed a large polycystic mass connected to the pharynx by a lateral tract. During surgical resection, both masses were found to originate from the subpharyngeal area. Based on topography and the histopathologic and immunohistochemical results, the masses were determined to be a second branchial cleft cyst for the first case and a second branchial pouch cyst for the second case. In addition, a carcinoma was present in situ within the epithelium of case 1, and the cyst in case 2 was secondarily infected. Branchial cysts are uncommonly diagnosed in veterinary and human medicine. These 2 cases are the first documented in parrots and appear similar to second branchial cysts reported in adult humans.

Medicare and Chronic Disease Management: Integrated Care As an Exceptional Circumstance?

Australian Health Review : a Publication of the Australian Hospital Association. May, 2010  |  Pubmed ID: 20497727

Chronic disease represents a significant challenge to the design and reform of the Australian healthcare system. The Medicare Benefits Schedule (MBS) provides a framework of numerous chronic disease management programs; however, their use at the patient level is complex. This analysis of the MBS chronic disease framework uses a hypothetical case study of a diabetic patient (with disease-related complications and a complex psychosocial background) to illustrate the difficulties in delivering appropriate multidisciplinary chronic disease care under the MBS. The complexities at each step - from care planning, service provision, and monitoring and review - are described, as are the intricacies involved in providing patient care under different MBS programs as well as those in the broader health and community care system. As demonstrated by this case study, under certain circumstances the provision of truly integrated care to this hypothetical patient would constitute an 'exceptional circumstance' under the MBS. Although quality improvement efforts can improve functioning within the limitations of the current system, system-wide reforms are necessary to overcome complexity and fragmentation.

Hypertrophic Cardiomyopathy and Dysregulation of Cardiac Energetics in a Mouse Model of Biliary Fibrosis

Hepatology (Baltimore, Md.). Jun, 2010  |  Pubmed ID: 20512997

Cardiac dysfunction is a major cause of morbidity and mortality in patients with end-stage liver disease; yet the mechanisms remain largely unknown. We hypothesized that the complex interrelated impairments in cardiac structure and function secondary to progression of liver diseases involve alterations in signaling pathways engaged in cardiac energy metabolism and hypertrophy, augmented by direct effects of high circulating levels of bile acids. Biliary fibrosis was induced in male C57BL/6J mice by feeding a 0.1% 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) supplemented diet. After 3 weeks, mice underwent live imaging (dual energy x-ray absorptiometry [DEXA] scanning, two-dimensional echocardiography [2DE], electrocardiography, cardiac magnetic resonance imaging), exercise treadmill testing, and histological and biochemical analyses of livers and hearts. Compared with chow-fed mice, DDC-fed mice fatigued earlier on the treadmill, with reduced VO(2). Marked changes were identified electrophysiologically (bradycardia and prolonged QT interval) and functionally (hyperdynamic left ventricular [LV] contractility along with increased LV thickness). Hearts of DDC-fed mice showed hypertrophic signaling (activation of v-akt murine thymoma viral oncogene/protein kinase B [AKT], inhibition of glycogen synthase kinase-3beta [GSK3beta], a 20-fold up-regulation of beta myosin heavy chain RNA and elevated G(s)alpha/G(i)alpha ratio. Genes regulating cardiac fatty acid oxidation pathways were suppressed, along with a threefold increase in myocardial glycogen content. Treatment of mouse cardiomyocytes (which express the membrane bile acid receptor TGR5) with potent natural TGR5 agonists, taurochenodeoxycholic acid and lithocholic acid, activated AKT and inhibited GSK3beta, similar to the changes seen in DDC-fed mouse hearts. This provides support for a novel mechanism whereby circulating natural bile acids can induce signaling pathways in heart associated with hypertrophy. CONCLUSION: Three weeks of DDC feeding-induced biliary fibrosis leads to multiple functional, metabolic, electrophysiological, and hypertrophic adaptations in the mouse heart, recapitulating some of the features of human cirrhotic cardiomyopathy.

The Effect of Vessel Speed on the Survivorship of Biofouling Organisms at Different Hull Locations

Biofouling. Jul, 2010  |  Pubmed ID: 20526914

This study used a specially designed MAGPLATE system to quantify the en route survivorship and post-voyage recovery of biofouling assemblages subjected to short voyages (< 12 h) across a range of vessel speeds (slow, medium, fast; in the range 4.0-21.5 knots). The effect of hull location (bow, amidships and stern) was also examined. While no significant differences were evident in en route survivorship of biofouling organisms amongst hull locations, biofouling cover and richness were markedly reduced on faster vessels relative to slower craft. Therefore, the potential inoculum size of non-indigenous marine species and richness is likely to be reduced for vessels that travel at faster speeds (> 14 knots), which is likely to also reduce the chances of successful introductions. Despite this, the magnitude of introductions from biofouling on fast vessels can be considered minor, especially for species richness where 90% of source-port species were recorded at destinations.

Avian Bornavirus is Present in Many Tissues of Psittacine Birds with Histopathologic Evidence of Proventricular Dilatation Disease

Journal of Veterinary Diagnostic Investigation : Official Publication of the American Association of Veterinary Laboratory Diagnosticians, Inc. Jul, 2010  |  Pubmed ID: 20622218

Proventricular dilatation disease (PDD) is a neurologic disease of psittacine birds suspected to be caused by a recently identified Avian bornavirus (ABV). In the current report, data supporting the causal association of ABV with PDD are presented. Immunohistochemistry (IHC) with rabbit polyclonal antiserum raised against ABV nucleocapsid protein was used to identify cell and organ distribution of viral antigen. The ABV antigen was most consistently detected in brain, spinal cord, adrenal gland, pancreas, and kidney. Histopathologic evaluation was correlated with ABV-specific polymerase chain reaction (PCR) and immunohistochemical tests in multiple tissues from 16 psittacine birds with and without PDD. Using histopathologic diagnosis as the gold standard, the sensitivity and specificity of IHC for ABV antigens were found to be 100% and 100%, respectively. Many more tissues were positive for ABV RNA by reverse transcription PCR than were positive for pathologic changes or viral antigens by IHC, indicating the presence of subclinical or asymptomatic infection at many sites.

Cross-species Genomics Matches Driver Mutations and Cell Compartments to Model Ependymoma

Nature. Jul, 2010  |  Pubmed ID: 20639864

Understanding the biology that underlies histologically similar but molecularly distinct subgroups of cancer has proven difficult because their defining genetic alterations are often numerous, and the cellular origins of most cancers remain unknown. We sought to decipher this heterogeneity by integrating matched genetic alterations and candidate cells of origin to generate accurate disease models. First, we identified subgroups of human ependymoma, a form of neural tumour that arises throughout the central nervous system (CNS). Subgroup-specific alterations included amplifications and homozygous deletions of genes not yet implicated in ependymoma. To select cellular compartments most likely to give rise to subgroups of ependymoma, we matched the transcriptomes of human tumours to those of mouse neural stem cells (NSCs), isolated from different regions of the CNS at different developmental stages, with an intact or deleted Ink4a/Arf locus (that encodes Cdkn2a and b). The transcriptome of human supratentorial ependymomas with amplified EPHB2 and deleted INK4A/ARF matched only that of embryonic cerebral Ink4a/Arf(-/-) NSCs. Notably, activation of Ephb2 signalling in these, but not other, NSCs generated the first mouse model of ependymoma, which is highly penetrant and accurately models the histology and transcriptome of one subgroup of human supratentorial tumour. Further, comparative analysis of matched mouse and human tumours revealed selective deregulation in the expression and copy number of genes that control synaptogenesis, pinpointing disruption of this pathway as a critical event in the production of this ependymoma subgroup. Our data demonstrate the power of cross-species genomics to meticulously match subgroup-specific driver mutations with cellular compartments to model and interrogate cancer subgroups.

Decline with a Capital D: Long-term Changes in General Practice Consultation Patterns Across Australia

The Medical Journal of Australia. Jul, 2010  |  Pubmed ID: 20642408

To determine changes in the pattern of use of standard general practice consultations, and the degree to which any changes are offset by the use of special Medicare Benefits Schedule (MBS) items.

Fluoroscopic Study of the Normal Gastrointestinal Motility and Measurements in the Hispaniolan Amazon Parrot (Amazona Ventralis)

Veterinary Radiology & Ultrasound : the Official Journal of the American College of Veterinary Radiology and the International Veterinary Radiology Association. Jul-Aug, 2010  |  Pubmed ID: 20806877

Contrast fluoroscopy is a valuable tool to examine avian gastrointestinal motility. However, the lack of a standardized examination protocol and reference ranges prevents the objective interpretation of motility disorders and other gastrointestinal abnormalities. Our goals were to evaluate gastrointestinal motility in 20 Hispaniolan Amazon parrots (Amazona ventralis) by contrast fluoroscopy. Each parrot was crop-fed an equal part mixture of barium sulfate and hand-feeding formula and placed in a cardboard box for fluoroscopy. Over a 3-h period, 1.5 minute segments of lateral and ventrodorsal fluoroscopy were recorded every 30 min. The gastric cycle and patterns of intestinal motility were described. The frequency of crop contractions, esophageal boluses, and gastric cycles were determined in lateral and ventrodorsal views. A range of 3.4-6.6 gastric cycles/min was noted on the lateral view and 3.0-6.6 gastric cycles/min on the ventrodorsal view. Circular measurements of the proventriculus diameter, ventriculus width, and length were obtained using the midshaft femoral diameter as a standard reference unit. The upper limits of the reference ranges were 3.6 and 4.7 femoral units for the proventriculus diameter in the lateral and ventrodorsal view, respectively. Two consecutive measurements were obtained and the measurement technique was found to have high reproducibility. In this study, we established a standardized protocol for contrast fluoroscopic examination of the gastrointestinal tract and a reliable measurement method of the proventriculus and ventriculus using femoral units in the Hispaniolan Amazon parrot.

Polymer Surface Functionalities That Control Human Embryoid Body Cell Adhesion Revealed by High Throughput Surface Characterization of Combinatorial Material Microarrays

Biomaterials. Dec, 2010  |  Pubmed ID: 20832108

High throughput materials discovery using combinatorial polymer microarrays to screen for new biomaterials with new and improved function is established as a powerful strategy. Here we combine this screening approach with high throughput surface characterization (HT-SC) to identify surface structure-function relationships. We explore how this combination can help to identify surface chemical moieties that control protein adsorption and subsequent cellular response. The adhesion of human embryoid body (hEB) cells to a large number (496) of different acrylate polymers synthesized in a microarray format is screened using a high throughput procedure. To determine the role of the polymer surface properties on hEB cell adhesion, detailed HT-SC of these acrylate polymers is carried out using time of flight secondary ion mass spectrometry (ToF SIMS), X-ray photoelectron spectroscopy (XPS), pico litre drop sessile water contact angle (WCA) measurement and atomic force microscopy (AFM). A structure-function relationship is identified between the ToF SIMS analysis of the surface chemistry after a fibronectin (Fn) pre-conditioning step and the cell adhesion to each spot using the multivariate analysis technique partial least squares (PLS) regression. Secondary ions indicative of the adsorbed Fn correlate with increased cell adhesion whereas glycol and other functionalities from the polymers are identified that reduce cell adhesion. Furthermore, a strong relationship between the ToF SIMS spectra of bare polymers and the cell adhesion to each spot is identified using PLS regression. This identifies a role for both the surface chemistry of the bare polymer and the pre-adsorbed Fn, as-represented in the ToF SIMS spectra, in controlling cellular adhesion. In contrast, no relationship is found between cell adhesion and wettability, surface roughness, elemental or functional surface composition. The correlation between ToF SIMS data of the surfaces and the cell adhesion demonstrates the ability to identify surface moieties that control protein adsorption and subsequent cell adhesion using ToF SIMS and multivariate analysis.

Contribution of Subdomain Structure to the Thermal Stability of the Cholera Toxin A1 Subunit

Biochemistry. Oct, 2010  |  Pubmed ID: 20839789

The catalytic A1 subunit of cholera toxin (CTA1) is an ADP-ribosyltransferase with three distinct subdomains: CTA1(1) forms the catalytic core of the toxin, CTA1(2) is an extended linker between CTA1(1) and CTA1(3), and CTA1(3) is a compact globular region. CTA1 crosses the endoplasmic reticulum (ER) membrane to enter the cytosol where it initiates a cytopathic effect. Toxin translocation involves ER-associated degradation (ERAD), a quality control system that exports misfolded proteins from the ER to the cytosol. At the physiological temperature of 37 °C, the free CTA1 subunit is in a partially unfolded conformation that triggers its ERAD-mediated translocation to the cytosol. Thus, the temperature sensitivity of CTA1 structure is an important determinant of its function. Here, we examined the contribution of CTA1 subdomain structure to the thermal unfolding of CTA1. Biophysical measurements demonstrated that the CTA1(1) subdomain is thermally unstable and that the CTA1(2) subdomain provides a degree of conformational stability to CTA1(1). The CTA1(3) subdomain does not affect the overall stability of CTA1, but the thermal unfolding of CTA1 appears to begin with a local loss of structure in the CTA1(3) subdomain: glycerol and acidic pH both inhibited the thermal disordering of full-length CTA1 but not the disordering of a CTA1 construct lacking the A1(3) subdomain. These observations provide mechanistic insight regarding the thermal unfolding of CTA1, an event which facilitates its subsequent translocation to the cytosol.

DNA Methyltransferase 1-associated Protein (DMAP1) is a Co-repressor That Stimulates DNA Methylation Globally and Locally at Sites of Double Strand Break Repair

The Journal of Biological Chemistry. Nov, 2010  |  Pubmed ID: 20864525

Correction of double strand DNA breaks proceeds in an error-free pathway of homologous recombination (HR), which can result in gene silencing of half of the DNA molecules caused by action by DNA methyltransferase 1 (DNMT1) (Cuozzo, C., Porcellini, A., Angrisano, T., Morano, A., Lee, B., Di Pardo, A., Messina, S., Iuliano, R., Fusco, A., Santillo, M. R., Muller, M. T., Chiariotti, L., Gottesman, M. E., and Avvedimento, E. V. (2007) PLoS Genet. 3, e110). To explore the mechanism that leads to HR-induced silencing, a genetic screen was carried out based on the silencing of a GFP reporter to identify potential partners. DMAP1, a DNMT1 interacting protein, was identified as a mediator of this process. DMAP1 is a potent activator of DNMT1 methylation in vitro, suggesting that DMAP1 is a co-repressor that supports the maintenance and de novo action of DNMT1. To examine critical roles for DMAP1 in vivo, lentiviral shRNA was used to conditionally reduce cellular DMAP1 levels. The shRNA transduced cells grew poorly and eventually ceased their growth. Analysis of the tumor suppressor gene p16 methylation status revealed a clear reduction in methylated CpGs in the shRNA cells, suggesting that reactivation of a tumor suppressor gene pathway caused the slow growth phenotype. Analysis of HR, using a fluorescence-based reporter, revealed that knocking down DMAP1 also caused hypomethylation of the DNA repair products following gene conversion. DMAP1 was selectively enriched in recombinant GFP chromatin based on chromatin immunoprecipitation analysis. The picture that emerges is that DMAP1 activates DNMT1 preferentially at sites of HR repair. Because DMAP1 depleted cells display enhanced HR, we conclude that it has additional roles in genomic stability.

Rapid Diagnosis of Medulloblastoma Molecular Subgroups

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Apr, 2011  |  Pubmed ID: 21325292

Microarray studies indicate medulloblastoma comprises distinct molecular disease subgroups, which offer potential for improved clinical management.

Notification and Support for People Exposed to the Risk of Creutzfeldt-Jakob Disease (CJD) (or Other Prion Diseases) Through Medical Treatment (iatrogenically)

Cochrane Database of Systematic Reviews (Online). 2011  |  Pubmed ID: 21412905

Creutzfeldt-Jakob disease (CJD) and variant CJD (vCJD) are rare and always-fatal diseases transmissible via certain medical procedures. If a person is exposed to the disease risk through medical treatment, they may need to be notified of this to prevent them passing the risk to others in healthcare settings and to enable additional infection control measures to be put in place for certain procedures. As CJD is incurable, and unable to be screened for or effectively treated, communicating this risk information after an exposure incident may have significant implications for the person at risk, their families/ carers and healthcare professionals. The best ways to notify people of their exposure to the risk of CJD or vCJD, and to support them subsequently, are currently unknown.

Pediatric and Adult Sonic Hedgehog Medulloblastomas Are Clinically and Molecularly Distinct

Acta Neuropathologica. Aug, 2011  |  Pubmed ID: 21681522

Recent integrative genomic approaches have defined molecular subgroups of medulloblastoma that are genetically and clinically distinct. Sonic hedgehog (Shh) medulloblastomas account for one-third of all cases and comprise the majority of infant and adult medulloblastomas. To discern molecular heterogeneity among Shh-medulloblastomas, we analyzed transcriptional profiles from four independent Shh-medulloblastoma expression datasets (n = 66). Unsupervised clustering analyses demonstrated a clear distinction between infant and adult Shh-medulloblastomas, which was reliably replicated across datasets. Comparison of transcriptomes from infant and adult Shh-medulloblastomas revealed deregulation of multiple gene families, including genes implicated in cellular development, synaptogenesis, and extracellular matrix maintenance. Furthermore, metastatic dissemination is a marker of poor prognosis in adult, but not in pediatric Shh-medulloblastomas. Children with desmoplastic Shh-medulloblastomas have a better prognosis than those with Shh-medulloblastomas and classic histology. Desmoplasia is not prognostic for adult Shh-medulloblastoma. Cytogenetic analysis of a large, non-overlapping cohort of Shh-medulloblastomas (n = 151) revealed significant over-representation of chromosome 10q deletion (P < 0.001) and MYCN amplification (P < 0.05) in pediatric Shh cases compared with adults. Adult Shh-medulloblastomas harboring chromosome 10q deletion, 2 gain, 17p deletion, 17q gain, and/or GLI2 amplification have a much worse prognosis as compared to pediatric cases exhibiting the same aberrations. Collectively, our data demonstrate that pediatric and adult Shh-medulloblastomas are clinically, transcriptionally, genetically, and prognostically distinct.

Detection of Legionella Species in Potting Mixes Using Fluorescent in Situ Hybridisation (FISH)

Journal of Microbiological Methods. Sep, 2011  |  Pubmed ID: 21683098

This study used Fluorescent in situ Hybridisation (FISH) with rRNA targeted oligonucleotide probes combined with scanning confocal laser microscopy to successfully detect Legionella spp. in commercially available potting mix. A range of techniques were explored to optimise the FISH method by reducing background fluorescence and preventing non-specific binding of probes. These techniques included the use of a blocking agent, UV light treatment, image subtraction of a nonsense probe and spectral unmixing of specific probes fluorescence and autofluorescence dependent on the specific emission spectra of probe fluorophores. Spectral unmixing was the best microscopy technique for reducing background fluorescence and non-specific binding of probes was not observed. The rapid turnaround time and increased sensitivity of the FISH provides as an alternative to traditional culture methods, which are tedious and often give varied results. FISH is also advantageous compared to PCR methods as it provides information on the structure of the microbial community the bacteria is situated in. This study demonstrates that FISH could provide an alternative method for Legionella detection and enumeration in environmental samples.

Mouse Models of Medulloblastoma

Chinese Journal of Cancer. Jul, 2011  |  Pubmed ID: 21718590

Medulloblastoma is the most common malignant pediatric brain tumor. Despite its prevalence and importance in pediatric neuro-oncology, the genes and pathways responsible for its initiation, maintenance, and progression remain poorly understood. Genetically engineered mouse models are an essential tool for uncovering the molecular and cellular basis of human diseases, including cancer, and serve a valuable role as preclinical models for testing targeted therapies. In this review, we summarize how such models have been successfully applied to the study of medulloblastoma over the past decade and what we might expect in the coming years.

Assessment of Out-of-field Doses in Radiotherapy of Brain Lesions in Children

International Journal of Radiation Oncology, Biology, Physics. Mar, 2011  |  Pubmed ID: 20732763

To characterize the out-of-field doses in pediatric radiotherapy and to identify simple methods by which out-of-field dose might be minimized, with a view to reducing the risk of secondary cancers.

Medulloblastoma Comprises Four Distinct Molecular Variants

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Apr, 2011  |  Pubmed ID: 20823417

Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups.

Consideration of the Radiation Dose Delivered Away from the Treatment Field to Patients in Radiotherapy

Journal of Medical Physics / Association of Medical Physicists of India. Apr, 2011  |  Pubmed ID: 21731221

Radiation delivery to cancer patients for radiotherapy is invariably accompanied by unwanted radiation to other parts of the patient's body. Traditionally, considerable effort has been made to calculate and measure the radiation dose to the target as well as to nearby critical structures. Only recently has attention been focused also on the relatively low doses that exist far from the primary radiation beams. In several clinical scenarios, such doses have been associated with cardiac toxicity as well as an increased risk of secondary cancer induction. Out-of-field dose is a result of leakage and scatter and generally difficult to predict accurately. The present review aims to present existing data, from measurements and calculations, and discuss its implications for radiotherapy.

Meeting Report: 1st International Symposium on Sponge Microbiology

Marine Biotechnology (New York, N.Y.). Dec, 2011  |  Pubmed ID: 21773777

The success of the 1st International Symposium on Sponge Microbiology reflects the growing interest of the scientific community in this new and emerging field. Research themes of the symposium included symbiont diversity, physiology and function, secondary metabolites, metagenomics, single-cell genomics and other -omics approaches, sponge-symbiont interactions, sponge diseases, environmental stress, and many more. This article summarizes the major developments in the field and identifies future foci for research.

Structural and Functional Interactions Between the Cholera Toxin A1 Subunit and ERdj3/HEDJ, a Chaperone of the Endoplasmic Reticulum

Infection and Immunity. Nov, 2011  |  Pubmed ID: 21844235

Cholera toxin (CT) is endocytosed and transported by vesicle carriers to the endoplasmic reticulum (ER). The catalytic CTA1 subunit then crosses the ER membrane and enters the cytosol, where it interacts with its Gsα target. The CTA1 membrane transversal involves the ER chaperone BiP, but few other host proteins involved with CTA1 translocation are known. BiP function is regulated by ERdj3, an ER-localized Hsp40 chaperone also known as HEDJ. ERdj3 can also influence protein folding and translocation by direct substrate binding. In this work, structural and functional assays were used to examine the putative interaction between ERdj3 and CTA1. Cell-based assays demonstrated that expression of a dominant negative ERdj3 blocks CTA1 translocation into the cytosol and CT intoxication. Binding assays with surface plasmon resonance demonstrated that monomeric ERdj3 interacts directly with CTA1. This interaction involved the A1(2) subdomain of CTA1 and was further dependent upon the overall structure of CTA1: ERdj3 bound to unfolded but not folded conformations of the isolated CTA1 subunit. This was consistent with the chaperone function of ERdj3, as was the ability of ERdj3 to mask the solvent-exposed hydrophobic residues of CTA1. Our data identify ERdj3 as a host protein involved with the CT intoxication process and provide new molecular details regarding CTA1-chaperone interactions.

Modulation of Toxin Stability by 4-phenylbutyric Acid and Negatively Charged Phospholipids

PloS One. 2011  |  Pubmed ID: 21887297

AB toxins such as ricin and cholera toxin (CT) consist of an enzymatic A domain and a receptor-binding B domain. After endocytosis of the surface-bound toxin, both ricin and CT are transported by vesicle carriers to the endoplasmic reticulum (ER). The A subunit then dissociates from its holotoxin, unfolds, and crosses the ER membrane to reach its cytosolic target. Since protein unfolding at physiological temperature and neutral pH allows the dissociated A chain to attain a translocation-competent state for export to the cytosol, the underlying regulatory mechanisms of toxin unfolding are of paramount biological interest. Here we report a biophysical analysis of the effects of anionic phospholipid membranes and two chemical chaperones, 4-phenylbutyric acid (PBA) and glycerol, on the thermal stabilities and the toxic potencies of ricin toxin A chain (RTA) and CT A1 chain (CTA1). Phospholipid vesicles that mimic the ER membrane dramatically decreased the thermal stability of RTA but not CTA1. PBA and glycerol both inhibited the thermal disordering of RTA, but only glycerol could reverse the destabilizing effect of anionic phospholipids. In contrast, PBA was able to increase the thermal stability of CTA1 in the presence of anionic phospholipids. PBA inhibits cellular intoxication by CT but not ricin, which is explained by its ability to stabilize CTA1 and its inability to reverse the destabilizing effect of membranes on RTA. Our data highlight the toxin-specific intracellular events underlying ER-to-cytosol translocation of the toxin A chain and identify a potential means to supplement the long-term stabilization of toxin vaccines.

The Genetic Landscape of the Childhood Cancer Medulloblastoma

Science (New York, N.Y.). Jan, 2011  |  Pubmed ID: 21163964

Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.

HIV-associated Neurocognitive Disorders Before and During the Era of Combination Antiretroviral Therapy: Differences in Rates, Nature, and Predictors

Journal of Neurovirology. Feb, 2011  |  Pubmed ID: 21174240

Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV-) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV - participants from the pre-CART era (1988-1995; N = 857) and CART era (2000-2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.

Analysis of Manganese Tracer Kinetics and Target Tissue Dosimetry in Monkeys and Humans with Multi-route Physiologically Based Pharmacokinetic Models

Toxicological Sciences : an Official Journal of the Society of Toxicology. Apr, 2011  |  Pubmed ID: 21205636

Manganese (Mn) is an essential nutrient with the capacity for toxicity from excessive exposure. Accumulation of Mn in the striatum, globus pallidus, and other midbrain regions is associated with neurotoxicity following high-dose Mn inhalation. Physiologically based pharmacokinetic (PBPK) models for ingested and inhaled Mn in rats and nonhuman primates were previously developed. The models contained saturable Mn tissue-binding capacities, preferential fluxes of Mn in specific tissues, and homeostatic control processes such as inducible biliary excretion of Mn. In this study, a nonhuman primate model was scaled to humans and was further extended to include iv, ip, and sc exposure routes so that past studies regarding radiolabeled carrier-free (54)MnCl(2) tracer kinetics could be evaluated. Simulation results accurately recapitulated the biphasic elimination behavior for all exposure routes. The PBPK models also provided consistent cross-species descriptions of Mn tracer kinetics across multiple exposure routes. These results indicate that PBPK models can accurately simulate the overall kinetic behavior of Mn and predict conditions where exposures will increase free Mn in various tissues throughout the body. Simulations with the human model indicate that globus pallidus Mn concentrations are unaffected by air concentrations < 10 μg/m(3) Mn. The use of this human Mn PBPK model can become a key component of future human health risk assessment of Mn, allowing the consideration of various exposure routes, natural tissue background levels, and homeostatic controls to explore exposure conditions that lead to increased target tissue levels resulting from Mn overexposure.

Effects of Central Nervous System Antiretroviral Penetration on Cognitive Functioning in the ALLRT Cohort

AIDS (London, England). Jan, 2011  |  Pubmed ID: 21124201

Differences in antiretroviral distribution into the central nervous system (CNS) may impact neurocognitive status. We assessed the relationship between estimates of antiretroviral therapy penetration into the CNS, using a published ranking system, and neurocognitive status in HIV-positive participants with plasma HIV-1 RNA (vRNA) suppression.

Multiple Sources and Routes of Information Transmission: Implications for Epidemic Dynamics

Mathematical Biosciences. Jun, 2011  |  Pubmed ID: 21397611

In a recent paper, we proposed and analyzed a compartmental ODE-based model describing the dynamics of an infectious disease where the presence of the pathogen also triggers the diffusion of information about the disease. In this paper, we extend this previous work by presenting results based on pairwise and simulation models that are better suited for capturing the population contact structure at a local level. We use the pairwise model to examine the potential of different information generating mechanisms and routes of information transmission to stop disease spread or to minimize the impact of an epidemic. The individual-based simulation is used to better differentiate between the networks of disease and information transmission and to investigate the impact of different basic network topologies and network overlap on epidemic dynamics. The paper concludes with an individual-based semi-analytic calculation of R(0) at the non-trivial disease free equilibrium.

Application of Magnetic Particle Tracking Velocimetry to Quadrupole Magnetic Sorting of Porcine Pancreatic Islets

Biotechnology and Bioengineering. Sep, 2011  |  Pubmed ID: 21495008

Magnetic isolation is a promising method for separating and concentrating pancreatic islets of Langerhans for transplantation in Type 1 diabetes patients. We are developing a continuous magnetic islet sorter to overcome the restrictions of current purification methods that result in limited yield and viability. In Quadrupole Magnetic Sorting (QMS) islets are magnetized by infusing superparamagnetic microbeads into islets' vasculature via arteries that serve the pancreas. The performance of the islet sorter depends on the resulting speed of the islets in an applied magnetic field, a property known as magnetophoretic mobility. Essential to the design and successful operation of the QMS is a method to measure the magnetophoretic mobilities of magnetically infused islets. We have adapted a Magnetic Particle Tracking Velocimeter (MPTV) to measure the magnetophoretic mobility of particles up to 1,000 µm in diameter. Velocity measurements are performed in a well-characterized uniform magnetic energy gradient using video imaging followed by analysis of the video images with a computer algorithm that produces a histogram of absolute mobilities. MPTV was validated using magnetic agarose beads serving as islet surrogates and subjecting them to QMS. Mobility distributions of labeled porcine islets indicated that magnetized islets have sufficient mobility to be captured by the proposed sorting method, with this result confirmed in test isolations of magnetized islets.

A Therapeutic Chemical Chaperone Inhibits Cholera Intoxication and Unfolding/translocation of the Cholera Toxin A1 Subunit

PloS One. 2011  |  Pubmed ID: 21526142

Cholera toxin (CT) travels as an intact AB(5) protein toxin from the cell surface to the endoplasmic reticulum (ER) of an intoxicated cell. In the ER, the catalytic A1 subunit dissociates from the rest of the toxin. Translocation of CTA1 from the ER to the cytosol is then facilitated by the quality control mechanism of ER-associated degradation (ERAD). Thermal instability in the isolated CTA1 subunit generates an unfolded toxin conformation that acts as the trigger for ERAD-mediated translocation to the cytosol. In this work, we show by circular dichroism and fluorescence spectroscopy that exposure to 4-phenylbutyric acid (PBA) inhibited the thermal unfolding of CTA1. This, in turn, blocked the ER-to-cytosol export of CTA1 and productive intoxication of either cultured cells or rat ileal loops. In cell culture studies PBA did not affect CT trafficking to the ER, CTA1 dissociation from the holotoxin, or functioning of the ERAD system. PBA is currently used as a therapeutic agent to treat urea cycle disorders. Our data suggest PBA could also be used in a new application to prevent or possibly treat cholera.

Neurosurgical Management of Extraaxial Central Nervous System Infections in Children

Journal of Neurosurgery. Pediatrics. May, 2011  |  Pubmed ID: 21529183

Extraaxial infections of the CNS, including subdural empyema and epidural abscess, are rare but potentially life-threatening conditions. Symptoms are usually progressive, and early diagnosis is therefore important. Early intervention with appropriate treatment offers the best opportunity for eradicating the infection and promoting maximal neurological recovery.

Clinical Factors Related to Brain Structure in HIV: the CHARTER Study

Journal of Neurovirology. Jun, 2011  |  Pubmed ID: 21544705

Despite the widening use of combination antiretroviral therapy (ART), neurocognitive impairment remains common among HIV-infected (HIV+) individuals. Associations between HIV-related neuromedical variables and magnetic resonance imaging indices of brain structural integrity may provide insight into the neural bases for these symptoms. A diverse HIV+ sample (n = 251) was studied through the CNS HIV Antiretroviral Therapy Effects Research initiative. Multi-channel image analysis produced volumes of ventricular and sulcal cerebrospinal fluid (CSF), cortical and subcortical gray matter, total cerebral white matter, and abnormal white matter. Cross-sectional analyses employed a series of multiple linear regressions to model each structural volume as a function of severity of prior immunosuppression (CD4 nadir), current CD4 count, presence of detectable CSF HIV RNA, and presence of HCV antibodies; secondary analyses examined plasma HIV RNA, estimated duration of HIV infection, and cumulative exposure to ART. Lower CD4 nadir was related to most measures of the structural brain damage. Higher current CD4, unexpectedly, correlated with lower white and subcortical gray and increased CSF. Detectable CSF HIV RNA was related to less total white matter. HCV coinfection was associated with more abnormal white matter. Longer exposure to ART was associated with lower white matter and higher sulcal CSF. HIV neuromedical factors, including lower nadir, higher current CD4 levels, and detectable HIV RNA, were associated with white matter damage and variability in subcortical volumes. Brain structural integrity in HIV likely reflects dynamic effects of current immune status and HIV replication, superimposed on residual effects associated with severe prior immunosuppression.

Demographically Corrected Norms for African Americans and Caucasians on the Hopkins Verbal Learning Test-Revised, Brief Visuospatial Memory Test-Revised, Stroop Color and Word Test, and Wisconsin Card Sorting Test 64-Card Version

Journal of Clinical and Experimental Neuropsychology. Aug, 2011  |  Pubmed ID: 21547817

Memory and executive functioning are two important components of clinical neuropsychological (NP) practice and research. Multiple demographic factors are known to affect performance differentially on most NP tests, but adequate normative corrections, inclusive of race/ethnicity, are not available for many widely used instruments. This study compared demographic contributions for widely used tests of verbal and visual learning and memory (Brief Visual Memory Test-Revised, Hopkins Verbal Memory Test-Revised) and executive functioning (Stroop Color and Word Test, Wisconsin Card Sorting Test-64) in groups of healthy Caucasians (n = 143) and African Americans (n = 103). Demographic factors of age, education, gender, and race/ethnicity were found to be significant factors on some indices of all four tests. The magnitude of demographic contributions (especially age) was greater for African Americans than for Caucasians on most measures. New, demographically corrected T-score formulas were calculated for each race/ethnicity. The rates of NP impairment using previously published normative standards significantly overestimated NP impairment in African Americans. Utilizing the new demographic corrections developed and presented herein, NP impairment rates were comparable between the two race/ethnicities and were unrelated to the other demographic characteristics (age, education, gender) in either race/ethnicity group. Findings support the need to consider extended demographic contributions to neuropsychological test performance in clinical and research settings.

Regional Areas and Widths of the Midsagittal Corpus Callosum Among HIV-infected Patients on Stable Antiretroviral Therapies

Journal of Neurovirology. Aug, 2011  |  Pubmed ID: 21556960

Recent reports suggest that a growing number of human immunodeficiency virus (HIV)-infected persons show signs of persistent cognitive impairment even in the context of combination antiretroviral therapies (cART). The basis for this finding remains poorly understood as there are only a limited number of studies examining the relationship between CNS injury, measures of disease severity, and cognitive function in the setting of stable disease. This study examined the effects of HIV infection on cerebral white matter using quantitative morphometry of the midsagittal corpus callosum (CC) in 216 chronically infected participants from the multisite HIV Neuroimaging Consortium study currently receiving cART and 139 controls. All participants underwent MRI assessment, and HIV-infected subjects also underwent measures of cognitive function and disease severity. The midsagittal slice of the CC was quantified using two semi-automated procedures. Group comparisons were accomplished using ANOVA, and the relationship between CC morphometry and clinical covariates (current CD4, nadir CD4, plasma and CSF HIV RNA, duration of HIV infection, age, and ADC stage) was assessed using linear regression models. HIV-infected patients showed significant reductions in both the area and linear widths for several regions of the CC. Significant relationships were found with ADC stage and nadir CD4 cell count, but no other clinical variables. Despite effective treatment, significant and possibly irreversible structural loss of the white matter persists in the setting of chronic HIV disease. A history of advanced immune suppression is a strong predictor of this complication and suggests that antiretroviral intervention at earlier stages of infection may be warranted.

Physiologically Based Pharmacokinetic Modeling of Fetal and Neonatal Manganese Exposure in Humans: Describing Manganese Homeostasis During Development

Toxicological Sciences : an Official Journal of the Society of Toxicology. Aug, 2011  |  Pubmed ID: 21622944

Concerns for potential vulnerability to manganese (Mn) neurotoxicity during fetal and neonatal development have been raised due to increased needs for Mn for normal growth, different sources of exposure to Mn, and pharmacokinetic differences between the young and adults. A physiologically based pharmacokinetic (PBPK) model for Mn during human gestation and lactation was developed to predict Mn in fetal and neonatal brain using a parallelogram approach based upon extrapolation across life stages in rats and cross-species extrapolation to humans. Based on the rodent modeling, key physiological processes controlling Mn kinetics during gestation and lactation were incorporated, including alterations in Mn uptake, excretion, tissue-specific distributions, and placental and lactational transfer of Mn. Parameters for Mn kinetics were estimated based on human Mn data for milk, placenta, and fetal/neonatal tissues, along with allometric scaling from the human adult model. The model was evaluated by comparison with published Mn levels in cord blood, milk, and infant blood. Maternal Mn homeostasis during pregnancy and lactation, placenta and milk Mn, and fetal/neonatal tissue Mn were simulated for normal dietary intake and with inhalation exposure to environmental Mn. Model predictions indicate similar or lower internal exposures to Mn in the brains of fetus/neonate compared with the adult at or above typical environmental air Mn concentrations. This PBPK approach can assess expected Mn tissue concentration during early life and compares contributions of different Mn sources, such as breast or cow milk, formula, food, drinking water, and inhalation, with tissue concentration.

Characterising the Dynamics of Expirated Bloodstain Pattern Formation Using High-speed Digital Video Imaging

International Journal of Legal Medicine. Nov, 2011  |  Pubmed ID: 20668870

During forensic investigations, it is often important to be able to distinguish between impact spatter patterns (blood from gunshots, explosives, blunt force trauma and/or machinery accidents) and bloodstain patterns generated by expiration (blood from the mouth, nose or lungs). These patterns can be difficult to distinguish on the basis of the size of the bloodstains. In this study, high-speed digital video imaging has been used to investigate the formation of expirated bloodstain patterns generated by breathing, spitting and coughing mechanisms. Bloodstain patterns from all three expiration mechanisms were dominated by the presence of stains less than 0.5 mm in diameter. Video analysis showed that in the process of coughing blood, high-velocity, very small blood droplets were ejected first. These were followed by lower velocity, larger droplets, strands and plumes of liquid held together in part by saliva. The video images showed the formation of bubble rings and beaded stains, traditional markers for classifying expirated patterns. However, the expulsion mechanism, the distance travelled by the blood droplets, and the type of surface the blood was deposited on were all factors determining whether beaded stains were generated.

A Contemporary Review of Stereotactic Radiotherapy: Inherent Dosimetric Complexities and the Potential for Detriment

Acta Oncologica (Stockholm, Sweden). May, 2011  |  Pubmed ID: 21288161

The advantages of highly localised, conformal treatments achievable with stereotactic radiotherapy (SRT) are increasingly being extended to extracranial sites as stereotactic body radiotherapy with advancements in imaging and beam collimation. One of the challenges in stereotactic treatment lies in the significant complexities associated with small field dosimetry and dose calculation. This review provides a comprehensive overview of the complexities associated with stereotactic radiotherapy and the potential for detriment.

Presence of Mechanical Dyssynchrony in Duchenne Muscular Dystrophy

Journal of Cardiovascular Magnetic Resonance : Official Journal of the Society for Cardiovascular Magnetic Resonance. 2011  |  Pubmed ID: 21288342

Cardiac dysfunction in boys with Duchenne muscular dystrophy (DMD) is a leading cause of death. Cardiac resynchronization therapy (CRT) has been shown to dramatically decrease mortality in eligible adult population with congestive heart failure. We hypothesized that mechanical dyssynchrony is present in DMD patients and that cardiovascular magnetic resonance (CMR) may predict CRT efficacy.

Persistence of HIV-associated Cognitive Impairment, Inflammation, and Neuronal Injury in Era of Highly Active Antiretroviral Treatment

AIDS (London, England). Mar, 2011  |  Pubmed ID: 21297425

To determine whether cognitive impairment and brain injury as measured by proton magnetic resonance spectroscopy (MRS) persist in the setting of HAART.

Quantification of Accuracy and Precision of Multi-center DTI Measurements: a Diffusion Phantom and Human Brain Study

NeuroImage. Jun, 2011  |  Pubmed ID: 21316471

The inter-site and intra-site variability of system performance of MRI scanners (due to site-dependent and time-variant variations) can have significant adverse effects on the integration of multi-center DTI data. Measurement errors in accuracy and precision of each acquisition determine both the inter-site and intra-site variability. In this study, multiple scans of an identical isotropic diffusion phantom and of the brain of a traveling human volunteer were acquired at MRI scanners from the same vendor and with similar configurations at three sites. We assessed the feasibility of multi-center DTI studies by direct quantification of accuracy and precision of each dataset. Accuracy was quantified via comparison to carefully constructed gold standard datasets while precision (the within-scan variability) was estimated by wild bootstrap analysis. The results from both the phantom and human data suggest that the inter-site variation in system performance, although relatively small among scanners of the same vendor, significantly affects DTI measurement accuracy and precision and therefore the effectiveness for the integration of multi-center DTI measurements. Our results also highlight the value of a DTI-specific phantom in identifying and quantifying measurement errors due to site-dependent variations in the system performance, and its usefulness for quality assurance/quality control in multi-center DTI studies. In addition, we observed that the within-scan variability of each data acquisition, as assessed by wild bootstrap analysis, is of the same magnitude as the inter-site and intra-site variability. We propose that by weighing datasets based on their variability, as evaluated by wild bootstrap analysis, one can improve the quality of the dataset. This approach will provide a more effective integration of datasets from multi-center DTI studies.

Left Ventricular Noncompaction in Sotos Syndrome

American Journal of Medical Genetics. Part A. May, 2011  |  Pubmed ID: 21484993

Sotos syndrome is an autosomal dominant condition characterized by pre- and postnatal overgrowth (tall stature and macrocephaly), a typical facial appearance, advanced bone age, and developmental delay. The syndrome is caused by mutations or deletions of the nuclear receptor binding SET domain protein 1 (NSD1) gene, which encodes a histone methyltransferase implicated in the regulation of chromatin. Left ventricular noncompaction (LVNC), also called left ventricular (LV) hypertrabeculation, is a rare disorder classified as a primary genetic cardiomyopathy by the American Heart Association. This condition is characterized by an altered myocardial wall due to arrest of embryonic compaction of the loose interwoven meshwork that makes up the fetal myocardial primordium. The cardiac manifestations of this cardiomyopathy are variable, ranging from an absence of symptoms to a progressive deterioration in cardiac function, with heart failure, arrhythmias, and systemic thromboemboli. We describe two unrelated patients who had LVNC, as based on echocardiographic findings, and Sotos syndrome, as based on physical features and molecular analysis. To our knowledge, the literature contains no previous reports of concomitant LVNC and Sotos syndrome. In the light of these two cases, we suggest that patients with Sotos syndrome be evaluated for LVNC cardiomyopathy when being screened for heart defects.

The Effect of Firearm Muzzle Gases on the Backspatter of Blood

International Journal of Legal Medicine. Sep, 2011  |  Pubmed ID: 20461525

Injuries caused by gunshots can produce what bloodstain pattern analysts know as "backspatter." Observations about the presence or absence of backspatter on an individual may be used in court as evidence of guilt or innocence. The discharge of three firearms (.22 caliber revolver, .38 caliber revolver, and .308 caliber rifle) and the resulting impact of bullets on a blood source were recorded using high-speed digital video imaging. Blood droplets, firearm muzzle gases, and ballistic shock waves were visualized using standard reflected light and shadowgraphy imaging techniques. A significant interaction between air currents, muzzle gases, and particulate material emanating from the firearms upon discharge with backspattered blood was observed. Blood droplets, initially spattered back toward the firearm and the shooter, were observed to change direction under the influence of firearm-induced air currents and were blown forward toward and beyond their original source location. Implications for experts testifying in court and for bloodstain pattern instructors are discussed.

Effects of Traumatic Brain Injury on Cognitive Functioning and Cerebral Metabolites in HIV-infected Individuals

Journal of Clinical and Experimental Neuropsychology. Mar, 2011  |  Pubmed ID: 21229435

We explored the possible augmenting effect of traumatic brain injury (TBI) history on HIV (human immunodeficiency virus) associated neurocognitive complications. HIV-infected participants with self-reported history of definite TBI were compared to HIV patients without TBI history. Groups were equated for relevant demographic and HIV-associated characteristics. The TBI group evidenced significantly greater deficits in executive functioning and working memory. N-acetylaspartate, a putative marker of neuronal integrity, was significantly lower in the frontal gray matter and basal ganglia brain regions of the TBI group. Together, these results suggest an additional brain impact of TBI over that from HIV alone. One clinical implication is that HIV patients with TBI history may need to be monitored more closely for increased risk of HIV-associated neurocognitive disorder signs or symptoms.

Chemokines in Cerebrospinal Fluid Correlate with Cerebral Metabolite Patterns in HIV-infected Individuals

Journal of Neurovirology. Feb, 2011  |  Pubmed ID: 21246320

Chemokines influence HIV neuropathogenesis by affecting the HIV life cycle, trafficking of macrophages into the nervous system, glial activation, and neuronal signaling and repair processes; however, knowledge of their relationship to in vivo measures of cerebral injury is limited. The primary objective of this study was to determine the relationship between a panel of chemokines in cerebrospinal fluid (CSF) and cerebral metabolites measured by proton magnetic resonance spectroscopy (MRS) in a cohort of HIV-infected individuals. One hundred seventy-one stored CSF specimens were assayed from HIV-infected individuals who were enrolled in two ACTG studies that evaluated the relationship between neuropsychological performance and cerebral metabolites. Concentrations of six chemokines (fractalkine, IL-8, IP-10, MCP-1, MIP-1β, and SDF-1) were measured and compared with cerebral metabolites individually and as composite neuronal, basal ganglia, and inflammatory patterns. IP-10 and MCP-1 were the chemokines most strongly associated with individual cerebral metabolites. Specifically, (1) higher IP-10 levels correlated with lower N-acetyl aspartate (NAA)/creatine (Cr) ratios in the frontal white matter and higher MI/Cr ratios in all three brain regions considered and (2) higher MCP-1 levels correlated with lower NAA/Cr ratios in frontal white matter and the parietal cortex. IP-10, MCP-1, and IL-8 had the strongest associations with patterns of cerebral metabolites. In particular, higher levels of IP-10 correlated with lower neuronal pattern scores and higher basal ganglia and inflammatory pattern scores, the same pattern which has been associated with HIV-associated neurocognitive disorders (HAND). Subgroup analysis indicated that the effects of IP-10 and IL-8 were influenced by effective antiretroviral therapy and that memantine treatment may mitigate the neuronal effects of IP-10. This study supports the role of chemokines in HAND and the validity of MRS as an assessment tool. In particular, the findings identify relationships between the immune response-particularly an interferon-inducible chemokine, IP-10-and cerebral metabolites and suggest that antiretroviral therapy and memantine modify the impact of the immune response on neurons.

Exact Epidemic Models on Graphs Using Graph-automorphism Driven Lumping

Journal of Mathematical Biology. Apr, 2011  |  Pubmed ID: 20425114

The dynamics of disease transmission strongly depends on the properties of the population contact network. Pair-approximation models and individual-based network simulation have been used extensively to model contact networks with non-trivial properties. In this paper, using a continuous time Markov chain, we start from the exact formulation of a simple epidemic model on an arbitrary contact network and rigorously derive and prove some known results that were previously mainly justified based on some biological hypotheses. The main result of the paper is the illustration of the link between graph automorphisms and the process of lumping whereby the number of equations in a system of linear differential equations can be significantly reduced. The main advantage of lumping is that the simplified lumped system is not an approximation of the original system but rather an exact version of this. For a special class of graphs, we show how the lumped system can be obtained by using graph automorphisms. Finally, we discuss the advantages and possible applications of exact epidemic models and lumping.

Effects of Steroids and Angiotensin Converting Enzyme Inhibition on Circumferential Strain in Boys with Duchenne Muscular Dystrophy: a Cross-sectional and Longitudinal Study Utilizing Cardiovascular Magnetic Resonance

Journal of Cardiovascular Magnetic Resonance : Official Journal of the Society for Cardiovascular Magnetic Resonance. 2011  |  Pubmed ID: 22011358

Steroid use has prolonged ambulation in Duchenne muscular dystrophy (DMD) and combined with advances in respiratory care overall management has improved such that cardiac manifestations have become the major cause of death. Unfortunately, there is no consensus for DMD-associated cardiac disease management. Our purpose was to assess effects of steroid use alone or in combination with angiotensin converting enzyme inhibitors (ACEI) or angiotension receptor blocker (ARB) on cardiovascular magnetic resonance (CMR) derived circumferential strain (εcc).

The Daubert Standard As Applied to Exposure Assessment Modeling Using the Two-zone (NF/FF) Model Estimation of Indoor Air Breathing Zone Concentration As an Example

Journal of Occupational and Environmental Hygiene. Nov, 2011  |  Pubmed ID: 22017382

WIP1 Enhances Tumor Formation in a Sonic Hedgehog-Dependent Model of Medulloblastoma

Neurosurgery. Oct, 2011  |  Pubmed ID: 22037313

BACKGROUND: A significant number of medulloblastomas (MB) originate from abnormal activation of the Sonic Hedgehog/Patched (SHH/PTC) signaling pathway.Although p53deficiency enhances tumor formation in mice, inactivation of the p53 gene is seen in a minority ofMB.Wild-type P53-induced phosphatase 1 (WIP1) downregulates p53 expression and has been shown to be overexpressed in MB. OBJECTIVE: We tested the hypothesis that overexpression of WIP1 enhances tumor formation in a SHH-dependent model of MB. METHODS: We used the RCAS/Ntv-a system to study the effect of WIP1in vitro and in vivo. We transfected A375-TVA cells with RCAS-WIP1 and then exposed these cells to cisplatin to determine the effect on p53 expression. We modeled ectopic WIP1expression independently and in combination with SHH in the cerebella of newborn mice to assess the effect on tumor formation.Mice were observed for 12 weeks or until they developed neurological symptoms.The brains were examined for tumor formation. RESULTS: A375-TVA cells infected with RCAS-WIP1 demonstrated reduced p53 expression after exposure to cisplatin when compared to controls.We detected tumors in 12/35 (34%) mice injected with RCAS-WIP1 and RCAS-SHH.Tumors were detected in 3/40 (8%) mice injected with RCAS-SHH alone.The difference in tumor formation rates was significant (chi squared test, p=<0.01).Mice injected with RCAS-WIP1 alone did not form tumors. CONCLUSION: We show that ectopic expression of WIP1 cooperates with SHH to enhance formation of MB, although it is insufficient to induce tumors independently.Our results verify the role of WIP1 in MB formation and provide a crucial link to the inactivation of p53 in MB.

Rapid, Reliable, and Reproducible Molecular Sub-grouping of Clinical Medulloblastoma Samples

Acta Neuropathologica. Nov, 2011  |  Pubmed ID: 22057785

The diagnosis of medulloblastoma likely encompasses several distinct entities, with recent evidence for the existence of at least four unique molecular subgroups that exhibit distinct genetic, transcriptional, demographic, and clinical features. Assignment of molecular subgroup through routine profiling of high-quality RNA on expression microarrays is likely impractical in the clinical setting. The planning and execution of medulloblastoma clinical trials that stratify by subgroup, or which are targeted to a specific subgroup requires technologies that can be economically, rapidly, reliably, and reproducibly applied to formalin-fixed paraffin embedded (FFPE) specimens. In the current study, we have developed an assay that accurately measures the expression level of 22 medulloblastoma subgroup-specific signature genes (CodeSet) using nanoString nCounter Technology. Comparison of the nanoString assay with Affymetrix expression array data on a training series of 101 medulloblastomas of known subgroup demonstrated a high concordance (Pearson correlation r = 0.86). The assay was validated on a second set of 130 non-overlapping medulloblastomas of known subgroup, correctly assigning 98% (127/130) of tumors to the appropriate subgroup. Reproducibility was demonstrated by repeating the assay in three independent laboratories in Canada, the United States, and Switzerland. Finally, the nanoString assay could confidently predict subgroup in 88% of recent FFPE cases, of which 100% had accurate subgroup assignment. We present an assay based on nanoString technology that is capable of rapidly, reliably, and reproducibly assigning clinical FFPE medulloblastoma samples to their molecular subgroup, and which is highly suited for future medulloblastoma clinical trials.

Chloroflexi Bacteria Are More Diverse, Abundant, and Similar in High Than in Low Microbial Abundance Sponges

FEMS Microbiology Ecology. Dec, 2011  |  Pubmed ID: 22066885

Some marine sponges harbor dense and phylogenetically complex microbial communities [high microbial abundance (HMA) sponges] whereas others contain only few and less diverse microorganisms [low microbial abundance (LMA) sponges]. We focused on the phylum Chloroflexi that frequently occurs in sponges to investigate the different associations with three HMA and three LMA sponges from New Zealand. By applying a range of microscopical and molecular techniques a clear dichotomy between HMA and LMA sponges was observed: Chloroflexi bacteria were more abundant and diverse in HMA than in LMA sponges. Moreover, different HMA sponges contain similar Chloroflexi communities whereas LMA sponges harbor different and more variable communities which partly resemble Chloroflexi seawater communities. A comprehensive phylogenetic analysis of our own and publicly available sponge-derived Chloroflexi 16S rRNA gene sequences (> 780 sequences) revealed the enormous diversity of this phylum within sponges including 29 sponge-specific and sponge-coral clusters (SSC/SCC) as well as a 'supercluster' consisting of > 250 sponge-derived and a single nonsponge-derived 16S rRNA gene sequence. Interestingly, the majority of sequences obtained from HMA sponges, but only a few from LMA sponges, fell into SSC/SCC clusters. This indicates a much more specific association of Chloroflexi bacteria with HMA sponges and suggests an ecologically important role for these prominent bacteria.

Association Between Left Ventricular Mass Index and Cardiac Function in Pediatric Dialysis Patients

Pediatric Nephrology (Berlin, Germany). Nov, 2011  |  Pubmed ID: 22105968

BACKGROUND: Left ventricular mass index (LVMI) is a surrogate of left ventricular hypertrophy and a predictor of cardiac morbidity and mortality in adults with hypertension. LVMI has not been linked to cardiovascular endpoints in children. The aim of this study was to identify an association between elevated LVMI and echocardiographic markers of systolic and diastolic function. METHODS: The study was a retrospective review of chronic dialysis patients from June 1995 to December 2009 at a single tertiary care children's hospital. The upper limit cutoffs for LVMI were set at >38.6 g/m(2.7), >51 g/m(2.7), and by age and sex-based normative values. Sixty-three patients (mean age 14.1 years, 56% males) were enrolled in the study, with a total of 287 echocardiograms. RESULTS: Post-dialysis hypertension was associated with elevated LVMI in both the >51 g/m(2.7) [odds ratio (OR) 2.9, 95% confidence interval (CI) 1.5-5.5] and normative (OR 3.4, 95% CI 1.5-7.7) models. Elevated LVMI, when defined by the >51 g/m(2.7) and normative models, was significantly associated with decreased shortening fraction (OR 4.1, 95% CI 1.7-9.8 and OR 5.4, 95% CI 1.3-22.9, respectively) and increased mitral E wave to lateral mitral tissue Doppler e' wave velocity ratio (E/e'; OR 3.5, 95% CI 1.1-11.2 and OR 4.5, 95% CI 1.0-21.6, respectively). CONCLUSIONS: Elevated LVMI is associated with decreased systolic and diastolic cardiac function, justifying its use as a surrogate of hypertensive cardiomyopathy in children undergoing chronic dialysis.

Molecular Subgroups of Medulloblastoma: the Current Consensus

Acta Neuropathologica. Dec, 2011  |  Pubmed ID: 22134537

Medulloblastoma, a small blue cell malignancy of the cerebellum, is a major cause of morbidity and mortality in pediatric oncology. Current mechanisms for clinical prognostication and stratification include clinical factors (age, presence of metastases, and extent of resection) as well as histological subgrouping (classic, desmoplastic, and large cell/anaplastic histology). Transcriptional profiling studies of medulloblastoma cohorts from several research groups around the globe have suggested the existence of multiple distinct molecular subgroups that differ in their demographics, transcriptomes, somatic genetic events, and clinical outcomes. Variations in the number, composition, and nature of the subgroups between studies brought about a consensus conference in Boston in the fall of 2010. Discussants at the conference came to a consensus that the evidence supported the existence of four main subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). Participants outlined the demographic, transcriptional, genetic, and clinical differences between the four subgroups. While it is anticipated that the molecular classification of medulloblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, herein we outline the current consensus nomenclature, and the differences between the medulloblastoma subgroups.

MicroRNA-182 Promotes Leptomeningeal Spread of Non-sonic Hedgehog-medulloblastoma

Acta Neuropathologica. Dec, 2011  |  Pubmed ID: 22134538

The contribution of microRNAs to the initiation, progression, and metastasis of medulloblastoma (MB) remains poorly understood. Metastatic dissemination at diagnosis is present in about 30% of MB patients, and is associated with a dismal prognosis. Using microRNA expression profiling, we demonstrate that the retinal miR-183-96-182 cluster on chromosome 7q32 is highly overexpressed in non-sonic hedgehog MBs (non-SHH-MBs). Expression of miR-182 and miR-183 is associated with cerebellar midline localization, and miR-182 is significantly overexpressed in metastatic MB as compared to non-metastatic tumors. Overexpression of miR-182 in non-SHH-MB increases and knockdown of miR-182 decreases cell migration in vitro. Xenografts overexpressing miR-182 invaded adjacent normal tissue and spread to the leptomeninges, phenotypically reminiscent of clinically highly aggressive large cell anaplastic MB. Hence, our study provides strong in vitro and in vivo evidence that miR-182 contributes to leptomeningeal metastatic dissemination in non-SHH-MB. We therefore reason that targeted inhibition of miR-182 may prevent leptomeningeal spread in patients with non-SHH-MB.

FISH and Chips: the Recipe for Improved Prognostication and Outcomes for Children with Medulloblastoma

Cancer Genetics. Nov, 2011  |  Pubmed ID: 22200083

Rapidly evolving genomic technologies have permitted progressively detailed studies of medulloblastoma biology in recent years. These data have increased our understanding of the molecular pathogenesis of medulloblastoma, identified prognostic markers, and suggested future avenues for targeted therapy. Although current randomized trials are still stratified based largely on clinical variables, the use of molecular markers is approaching routine use in the clinic. In particular, integrated genomics has uncovered that medulloblastoma comprises four distinct molecular and clinical variants: WNT, sonic hedgehog (SHH), group 3, and group 4. Children with WNT medulloblastoma have improved survival, whereas those with group 3 medulloblastoma have a dismal prognosis. Additionally, integrated genomics has shown that adult medulloblastoma is molecularly and clinically distinct from the childhood variants. Prognostic and predictive markers identified by genomics should drive changes in stratification of treatment protocols for medulloblastoma patients on clinical trials once they can be demonstrated to be reliable, reproducible, and practical. Cases with excellent prognoses (WNT cases) should be considered for therapy de-escalation, whereas those with bleak prognoses (group 3 cases) should be prioritized for experimental therapy. In this review, we will summarize the genomic data published over the past decade and attempt to interpret its prognostic significance, relevance to the clinic, and use in upcoming clinical trials.

Protein-disulfide Isomerase Displaces the Cholera Toxin A1 Subunit from the Holotoxin Without Unfolding the A1 Subunit

The Journal of Biological Chemistry. Jun, 2011  |  Pubmed ID: 21543321

Protein-disulfide isomerase (PDI) has been proposed to exhibit an "unfoldase" activity against the catalytic A1 subunit of cholera toxin (CT). Unfolding of the CTA1 subunit is thought to displace it from the CT holotoxin and to prepare it for translocation to the cytosol. To date, the unfoldase activity of PDI has not been demonstrated for any substrate other than CTA1. An alternative explanation for the putative unfoldase activity of PDI has been suggested by recent structural studies demonstrating that CTA1 will unfold spontaneously upon its separation from the holotoxin at physiological temperature. Thus, PDI may simply dislodge CTA1 from the CT holotoxin without unfolding the CTA1 subunit. To evaluate the role of PDI in CT disassembly and CTA1 unfolding, we utilized a real-time assay to monitor the PDI-mediated separation of CTA1 from the CT holotoxin and directly examined the impact of PDI binding on CTA1 structure by isotope-edited Fourier transform infrared spectroscopy. Our collective data demonstrate that PDI is required for disassembly of the CT holotoxin but does not unfold the CTA1 subunit, thus uncovering a new mechanism for CTA1 dissociation from its holotoxin.

PCDH10 is a Candidate Tumour Suppressor Gene in Medulloblastoma

Child's Nervous System : ChNS : Official Journal of the International Society for Pediatric Neurosurgery. Aug, 2011  |  Pubmed ID: 21597995

The aim of this study was to investigate the genetic and epigenetic mechanisms contributing to PCDH10 down-regulation in medulloblastoma. We examined the role of PCDH10 as a mediator of medulloblastoma cell proliferation, cell cycle progression, and cell migration.

Design and Synthesis of Highly Reactive Dienophiles for the Tetrazine-trans-cyclooctene Ligation

Journal of the American Chemical Society. Jun, 2011  |  Pubmed ID: 21599005

Computation was used to design a trans-cyclooctene derivative that displays enhanced reactivity in the tetrazine-trans-cycloctene ligation. The optimized derivative is an (E)-bicyclo[6.1.0]non-4-ene with a cis-ring fusion, in which the eight-membered ring is forced to adopt a highly strained 'half-chair' conformation. Toward 3,6-dipyridyl-s-tetrazine in MeOH at 25 °C, the strained derivative is 19 and 27 times more reactive than the parent trans-cyclooctene and 4E-cyclooct-4-enol, respectively. Toward 3,6-diphenyl-s-tetrazine in MeOH at 25 °C, the strained derivative is 160 times more reactive than the parent trans-cyclooctene.

Potassium Chloride As a Euthanasia Agent in Psittacine Birds: Clinical Aspects and Consequences for Histopathologic Assessment

The Canadian Veterinary Journal. La Revue Vétérinaire Canadienne. Mar, 2011  |  Pubmed ID: 21629426

Twelve parrots anesthetized with isoflurane were euthanized intravenously (IV) with 3 or 10 mEq/kg body weight (BW) of potassium chloride (KCl) resulting in ventricular asystole at 68.0 s and 32.8 s, respectively. Mild vocalization (1/6 birds, 3 mEq/kg BW) and involuntary muscle tremors (5/6 birds, 10 mEq/kg BW) were noted. Unlike barbiturates or T-61 no histologic artefacts resulted from this technique.

Adult Medulloblastoma Comprises Three Major Molecular Variants

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Jul, 2011  |  Pubmed ID: 21632505

Medulloblastoma is a rare primary brain tumor in adults, whereas it constitutes the most common malignant brain tumor in children. Integrated genomics approaches revealed at least four distinct disease variants in children. The aim of this study was to investigate molecular subtypes and their prognostic implication in a large cohort of adult medulloblastomas as the biology in this age group remains poorly understood.

Changing the Pharmacy Practice Model: a Health-system Executive's View

American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists. Jun, 2011  |  Pubmed ID: 21642566

Multiple Loci Variable Number Tandem Repeat (VNTR) Analysis (MLVA) of Mycobacterium Leprae Isolates Amplified from European Archaeological Human Remains with Lepromatous Leprosy

Microbes and Infection / Institut Pasteur. Oct, 2011  |  Pubmed ID: 21658464

Molecular typing methods based on polymorphisms in single nucleotides and short tandem repeat motifs have been developed as epidemiological typing tools for Mycobacterium leprae. We have used a variable number tandem repeat method based on three variable loci to identify strain variation in archaeological cases of lepromatous leprosy. The panel of polymorphic loci used revealed unique profiles in five cases of leprosy, including those with identical SNP type and subtype. These were also different from profiles of three previously studied lepromatous skeletons. Whilst examination with SNP typing provides evidence for disease origins, dissemination and phylogeny, tandem repeat typing may be useful for studying cases from within a defined area or community where SNP types may be identical due to geographical constraints. We envisage the technique may be useful in studying contemporaneous burials such as those associated with leprosaria and will prove invaluable in authentication of ancient DNA analyses.

From Markovian to Pairwise Epidemic Models and the Performance of Moment Closure Approximations

Journal of Mathematical Biology. Jun, 2011  |  Pubmed ID: 21671029

Many if not all models of disease transmission on networks can be linked to the exact state-based Markovian formulation. However the large number of equations for any system of realistic size limits their applicability to small populations. As a result, most modelling work relies on simulation and pairwise models. In this paper, for a simple SIS dynamics on an arbitrary network, we formalise the link between a well known pairwise model and the exact Markovian formulation. This involves the rigorous derivation of the exact ODE model at the level of pairs in terms of the expected number of pairs and triples. The exact system is then closed using two different closures, one well established and one that has been recently proposed. A new interpretation of both closures is presented, which explains several of their previously observed properties. The closed dynamical systems are solved numerically and the results are compared to output from individual-based stochastic simulations. This is done for a range of networks with the same average degree and clustering coefficient but generated using different algorithms. It is shown that the ability of the pairwise system to accurately model an epidemic is fundamentally dependent on the underlying large-scale network structure. We show that the existing pairwise models are a good fit for certain types of network but have to be used with caution as higher-order network structures may compromise their effectiveness.

Diabetes Performance Measures: Current Status and Future Directions

Diabetes Care. Jul, 2011  |  Pubmed ID: 21709298

Delineation of Two Clinically and Molecularly Distinct Subgroups of Posterior Fossa Ependymoma

Cancer Cell. Aug, 2011  |  Pubmed ID: 21840481

Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa (PF) ependymomas. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death compared with Group B patients. Identification and optimization of immunohistochemical (IHC) markers for PF ependymoma subgroups allowed validation of our findings on a third independent cohort, using a human ependymoma tissue microarray, and provides a tool for prospective prognostication and stratification of PF ependymoma patients.

Inline Real-time Near-infrared Granule Moisture Measurements of a Continuous Granulation-drying-milling Process

AAPS PharmSciTech. Dec, 2011  |  Pubmed ID: 21842310

The purpose of this research was to use inline real-time near-infrared (NIR) to measure the moisture content of granules manufactured using a commercial production scale continuous twin-screw granulator fluid-bed dryer milling process. A central composite response surface statistical design was used to study the effect of inlet air temperature and dew point on granule moisture content. The NIR moisture content was compared to Karl Fischer (KF) and loss on drying (LOD) moisture determinations. Using multivariate analysis, the data showed a statistically significant correlation between the conventional methods and NIR. The R(2) values for predicted moisture content by NIR versus KF and predicted moisture values by NIR versus LOD were 0.94 (p < 0.00001) and 0.85 (p < 0.0002), respectively. The adjusted R(2) for KF versus LOD correlation was 0.85 (p < 0.0001). Analysis of the response surface design data showed that inlet air temperature over a range of 35-55°C had a significant linear impact on granule moisture content as measured by predicted NIR (adjusted R(2) = 0.84, p < 0.02), KF (adjusted R(2) = 0.91, p < 0.0001), and LOD (adjusted R(2) = 0.85, p < 0.0006). The inlet air dew point range of 10-20°C did not have a significant impact on any of the moisture measurements.

Monitoring Powder Blend Homogeneity Using Light-induced Fluorescence

AAPS PharmSciTech. Dec, 2011  |  Pubmed ID: 21842311

Light-induced fluorescence (LIF) was evaluated as a process analytical technology to monitor blend homogeneity and establish a relationship with high-performance liquid chromatography (HPLC). Secondary aims for this study included a determination of blend steady-state, acceptable mixing time interval, and mixing end point. Also, identification of potential "dead spots" in the 124 L intermediate bulk container mixing tote was explored. Individual samples from 13 sample locations were collected at 0.25, 0.5, 0.75, 1, 2, 5, 10, and 20 min and analyzed using LIF and HPLC. LIF and HPLC methods showed similar mixing profiles. A coefficient of determination (R(2)) of 0.86 (p value < 0.0001) was obtained for a second-degree polynomial bivariate fit of LIF counts by HPLC percent label claim (%LC). A significant linear relationship was determined between LIF percent relative standard (%RSD) and HPLC %RSD (R(2) = 0.97, p < 0.0001). The LIF steady-state, acceptable mixing time interval, and mixing end point were determined to be 1-20, 2-20, and 2 min, respectively. The steady-state, acceptable mixing time interval, and mixing end point determined by HPLC were 1-20, 5-10, and 5 min, respectively. The Tukey-Kramer honestly significant difference analysis of HPLC %LC by sample location at 5 and 10 min mixing times showed that there was a statistical difference between the HPLC %LC group means at two blender locations.

Will the Food Safety Modernization Act Help Prevent Outbreaks of Foodborne Illness?

The New England Journal of Medicine. Sep, 2011  |  Pubmed ID: 21848454

Liquefaction Necrosis of Mitral Annular Calcification (LNMAC): Review of Pathology, Prevalence, Imaging and Management: Proposed Diagnostic Imaging Criteria with Detailed Multi-modality and MRI Image Characterization

The International Journal of Cardiovascular Imaging. Aug, 2011  |  Pubmed ID: 21863322

Liquefactive necrosis within a large spheroid zone of mitral annular calcification (LNMAC) is an atypical but increasingly recognized variant of mitral annular calcification (MAC). Proposed MRI, echo, and CT imaging criteria for diagnosis of this unusual disease entity are discussed along with a review of the prognosis, histopathology, and management implications. A comprehensive ECHO, CT, and MRI imaging approach to diagnostic differentiation from other cardiac masses, allowing characterization of the differing components of this unusual lesion is emphasized. Differentiation from surrounding myocardium, and demonstration of peripheral ring type hyperenhancement, or hyperintense signal in the wall of this lesion, seen with specific inversion recovery MRI sequences is presented as a major diagnostic criterion. The relationship of these MRI image findings to underlying pathology is also discussed. An illustrative case vignette is provided for clinical reference.

FSTL5 is a Marker of Poor Prognosis in Non-WNT/non-SHH Medulloblastoma

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Oct, 2011  |  Pubmed ID: 21911727

Integrated genomics approaches have revealed at least four distinct biologic variants of medulloblastoma: WNT (wingless), SHH (sonic hedgehog), group C, and group D. Because of the remarkable clinical heterogeneity of group D tumors and the dismal prognosis of group C patients, it is vital to identify molecular biomarkers that will allow early and effective treatment stratification in these non-WNT/non-SHH tumors.

Molecular Genetics of Ependymoma

Chinese Journal of Cancer. Oct, 2011  |  Pubmed ID: 21959044

Brain tumors are the leading cause of cancer death in children, with ependymoma being the third most common and posing a significant clinical burden. Its mechanism of pathogenesis, reliable prognostic indicators, and effective treatments other than surgical resection have all remained elusive. Until recently, ependymoma research was hindered by the small number of tumors available for study, low resolution of cytogenetic techniques, and lack of cell lines and animal models. Ependymoma heterogeneity, which manifests as variations in tumor location, patient age, histological grade, and clinical behavior, together with the observation of a balanced genomic profile in up to 50% of cases, presents additional challenges in understanding the development and progression of this disease. Despite these difficulties, we have made significant headway in the past decade in identifying the genetic alterations and pathways involved in ependymoma tumorigenesis through collaborative efforts and the application of microarray-based genetic (copy number) and transcriptome profiling platforms. Genetic characterization of ependymoma unraveled distinct mRNA-defined subclasses and led to the identification of radial glial cells as its cell type of origin. This review summarizes our current knowledge in the molecular genetics of ependymoma and proposes future research directions necessary to further advance this field.

Intracerebral Malignant Peripheral Nerve Sheath Tumor in a Child with Neurofibromatosis Type 1 and Middle Cerebral Artery Aneurysm Treated with Endovascular Coil Embolization

Journal of Neurosurgery. Pediatrics. Oct, 2011  |  Pubmed ID: 21961539

Among the neoplastic conditions that affect patients with neurofibromatosis Type 1 (NF1) are malignant peripheral nerve sheath tumors (MPNSTs), which typically arise from peripheral nerves of the limbs, trunk, and lumbar and brachial plexuses. Ionizing radiation is an established risk factor for MPNST development, especially in susceptible patients such as those with NF1. Patients with NF1 are also at risk for intracranial aneurysms, which are increasingly being successfully managed with endovascular therapies. The authors describe the case of a 9-year-old, previously healthy girl who presented in extremis with a right frontal intracerebral hemorrhage resulting from a ruptured right middle cerebral artery (MCA) trifurcation aneurysm. Following urgent decompressive craniectomy, the patient underwent endovascular coil embolization of the MCA aneurysm without complication. Given her mother's history of NF1, the child underwent genetic testing, which disclosed signs positive for NF1. The patient recovered well, but follow-up MR imaging and MR angiography performed at 14 months demonstrated a large frontotemporal mass encasing the right MCA trifurcation. The patient underwent frontotemporal craniotomy and subtotal resection of the mass, which was histologically found to be an intracranial MPNST. The patient received chemotherapy and focal radiation therapy and remains alive at 6 months postresection. To the authors' knowledge, this represents the only known case of intracranial neoplasm arising in the region of an intracranial aneurysm repaired by endovascular coil embolization. While patients with NF1 represent a population with genetic susceptibility to radiation-induced tumors, the pathogenesis of intracerebral MPNSTs remains poorly understood.

Biological and Clinical Heterogeneity of MYCN-amplified Medulloblastoma

Acta Neuropathologica. Dec, 2011  |  Pubmed ID: 22160402

Focal high-level amplifications of MYC (or MYCC) define a subset of high-risk medulloblastoma patients. However, the prognostic role of MYCN oncogene amplification remains unresolved. We aimed to evaluate the prognostic value of this alteration alone and in combination with biological modifiers in 67 pediatric medulloblastomas with MYCN amplification (MYCN-MB). Twenty-one MYCN-MB were examined using gene expression profiling and array-CGH, whereas for 46 tumors immunohistochemical analysis and FISH were performed. All 67 tumors were further subjected to mutational analyses. We compared molecular, clinical, and prognostic characteristics both within biological MYCN-MB groups and with non-amplified tumors. Transcriptomic analysis revealed SHH-driven tumorigenesis in a subset of MYCN-MBs indicating a biological dichotomy of MYCN-MB. Activation of SHH was accompanied by variant-specific cytogenetic aberrations including deletion of 9q in SHH tumors. Non-SHH MB were associated with gain of 7q and isochromosome 17q/17q gain. Among clinically relevant variables, SHH subtype and 10q loss for non-SHH tumors comprised the most powerful markers of favorable prognosis in MYCN-MB. In conclusion, we demonstrate considerable heterogeneity within MYCN-MB in terms of genetics, tumor biology, and clinical outcome. Thus, assessment of disease group and 10q copy-number status may improve risk stratification of this group and may delineate MYCN-MB with the same dismal prognosis as MYC amplified tumors. Furthermore, based on the enrichment of MYCN and GLI2 amplifications in SHH-driven medulloblastoma, amplification of these downstream signaling intermediates should be taken into account before a patient is enrolled into a clinical trial using a smoothened inhibitor.

Predicting the Physical Properties of Tablets from ATR-FTIR Spectra Using Partial Least Squares Regression

Pharmaceutical Development and Technology. Apr, 2011  |  Pubmed ID: 20100067

The formulation of a new tablet is a time-consuming activity involving the preparation and testing of many different formulations with the aim of identifying one with the desired properties. In complex formulations it may not be clear which excipient is responsible for eliciting a particular property.

Diels-Alder Cycloaddition for Fluorophore Targeting to Specific Proteins Inside Living Cells

Journal of the American Chemical Society. Jan, 2012  |  Pubmed ID: 22176354

The inverse-electron-demand Diels-Alder cycloaddition between trans-cyclooctenes and tetrazines is biocompatible and exceptionally fast. We utilized this chemistry for site-specific fluorescence labeling of proteins on the cell surface and inside living mammalian cells by a two-step protocol. Escherichia coli lipoic acid ligase site-specifically ligates a trans-cyclooctene derivative onto a protein of interest in the first step, followed by chemoselective derivatization with a tetrazine-fluorophore conjugate in the second step. On the cell surface, this labeling was fluorogenic and highly sensitive. Inside the cell, we achieved specific labeling of cytoskeletal proteins with green and red fluorophores. By incorporating the Diels-Alder cycloaddition, we have broadened the panel of fluorophores that can be targeted by lipoic acid ligase.

P53 Rescue Through HDM2 Antagonism Suppresses Melanoma Growth and Potentiates MEK Inhibition

The Journal of Investigative Dermatology. Feb, 2012  |  Pubmed ID: 21993556

Oncogenesis reflects an orchestrated interaction between misguided growth signals. Although much effort has been launched to pharmacologically disable activated oncogenes, one sidelined approach is the restoration of tumor suppressive signals. As TP53 is often structurally preserved, but functionally crippled, by CDKN2A/ARF loss in melanoma, rescue of p53 function represents an attractive point of vulnerability in melanoma. In this study, we showed that both p53 protein and activity levels in melanoma cells were strongly induced by nutlin-3, a canonical HDM2 antagonist. Among a test panel of 51 cell lines, there was a marked reduction in melanoma viability that was directly linked to TP53 status. Moreover, we also found that the melanoma growth suppression mediated by mitogen-activated protein kinase/extracellular signal-regulated kinase inhibition was potentiated by HDM2 antagonism. These results provide fundamental insights into the intact p53 circuitry, which can be restored through small molecule inhibitors and potentially deployed for therapeutic gain.

Survival Benefit for Pediatric Patients with Recurrent Ependymoma Treated with Reirradiation

International Journal of Radiation Oncology, Biology, Physics. Jan, 2012  |  Pubmed ID: 22245198

PURPOSE: The outcome of recurrent ependymoma in children is dismal. Reirradiation has been proposed as an effective modality for ependymoma at relapse. However, the toxicity and outcome benefits of this approach have not been well established. METHODS AND MATERIALS: We conducted a retrospective population-based study of all patients with recurrent ependymoma treated between 1986 and 2010 in our institution. Demographic, treatment, and outcome data were analyzed for the entire cohort. RESULTS: Of 113 patients with intracranial ependymoma, 47 patients relapsed. At the time of relapse, 29 patients were treated with surgical resection and/or chemotherapy, and 18 patients received full-dose (≥54 Gy focal and/or craniospinal) reirradiation with or without surgery at recurrence. Reirradiation was tolerated well with no severe acute complications noticed. Three-year overall survival was 7% ± 6% and 81% ± 12% for nonreirradiated and reirradiated patients, respectively (p < 0.0001). Time to second progression after reirradiation was significantly longer than time to first progression. This surprising phenomenon was associated with improved progression-free survival for tumors with evidence of DNA damage (n = 15; p = 0.002). At a mean follow-up of 3.73 years, only 2/18 patients had endocrine dysfunction, and 1 patient required special education support. However, a decline in intellectual function from pre- to postreirradiation assessment was observed. CONCLUSIONS: Reirradiation is an effective treatment that may change the natural history of recurrent ependymoma in children. However, this change may be associated with increased neurocognitive toxicity. Additional follow-up is needed to determine the risk of late recurrence, secondary radiation-induced tumors, and long-term functional outcome of these patients.

Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations

Cell. Jan, 2012  |  Pubmed ID: 22265402

Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.

Genetically Encoded Tetrazine Amino Acid Directs Rapid Site-Specific in Vivo Bioorthogonal Ligation with Trans-Cyclooctenes

Journal of the American Chemical Society. Feb, 2012  |  Pubmed ID: 22283158

Bioorthogonal ligation methods with improved reaction rates and less obtrusive components are needed for site-specifically labeling proteins without catalysts. Currently no general method exists for in vivo site-specific labeling of proteins that combines fast reaction rate with stable, nontoxic, and chemoselective reagents. To overcome these limitations, we have developed a tetrazine-containing amino acid, 1, that is stable inside living cells. We have site-specifically genetically encoded this unique amino acid in response to an amber codon allowing a single 1 to be placed at any location in a protein. We have demonstrated that protein containing 1 can be ligated to a conformationally strained trans-cyclooctene in vitro and in vivo with reaction rates significantly faster than most commonly used labeling methods.

Molecular Basis for Clinical Heterogeneity in Inherited Cardiomyopathies Due to Myopalladin Mutations

Human Molecular Genetics. Feb, 2012  |  Pubmed ID: 22286171

Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.

Targeting the Enhancer of Zeste Homologue 2 in Medulloblastoma

International Journal of Cancer. Journal International Du Cancer. Jan, 2012  |  Pubmed ID: 22287205

Enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 that catalyzes the trimethylation of histone H3 on Lys 27, and represses gene transcription. EZH2 enhances cancer-cell proliferation and regulates stem cell maintenance and differentiation. Here, we demonstrate that EZH2 is highly expressed in medulloblastoma, a highly malignant brain tumor of childhood, and this altered expression is correlated with genomic gain of chromosome 7 in a subset of medulloblastoma. Inhibition of EZH2 by RNAi suppresses medulloblastoma tumor cell growth. We show that 3-deazaneplanocin A, a chemical inhibitor of EZH2, can suppress medulloblastoma cell growth partially by inducing apoptosis. Suppression of EZH2 expression diminishes the ability of tumor cells to form spheres in culture and strongly represses the ability of known oncogenes to transform neural stem cells. These findings establish a role of EZH2 in medulloblastoma and identify EZH2 as a potential therapeutic target especially in high-risk tumors. © 2012 Wiley-Liss, Inc.

Blood Donors' Helping Behavior is Driven by Warm Glow: More Evidence for the Blood Donor Benevolence Hypothesis

Transfusion. Feb, 2012  |  Pubmed ID: 22321338

BACKGROUND: The benevolence hypothesis (both donor and recipient gain) suggests that blood donors, compared to non-blood donors have a general altruistic motivational preference based on warm glow (i.e., "I donate because it makes me feel good"). With objective behavioral economics tests of altruism and warm-glow giving, this paper offers the first direct experimental test of this hypothesis. The prediction that blood donors will be motivated in general by warm glow was compared to predictions from other theoretical models: strong reciprocity and empathy. STUDY DESIGN AND METHODS: Four experiments and one prospective study examined blood donors' and nondonors' motivations for general charitable giving and blood donation. Variants of the dictator game (DG; a charity DG [CDG] and a warm-glow version of a CDG) were used to provide objective measures of altruism. RESULTS: Blood donors gave less than nondonors on the CDG, but gave more on the warm-glow version. Blood donors' actual donations (in the CDGs and blood donation) were associated with feelings of warm glow. There was no evidence that blood donors were motivated by strong reciprocity or empathic concerns. CONCLUSIONS: This paper offers objective behavioral evidence that blood donors' charitable giving and blood donation, compared to non-blood donors, is more strongly motivated by warm glow. This provides additional support for the benevolence hypothesis of blood donation.

Monoallelic Expression Determines Oncogenic Progression and Outcome in Benign and Malignant Brain Tumors

Cancer Research. Feb, 2012  |  Pubmed ID: 22144470

Although monoallelic expression (MAE) is a frequent genomic event in normal tissues, its role in tumorigenesis remains unclear. Here we carried out single-nucleotide polymorphism arrays on DNA and RNA from a large cohort of pediatric and adult brain tumor tissues to determine the genome-wide rate of MAE, its role in specific cancer-related genes, and the clinical consequences of MAE in brain tumors. We also used targeted genotyping to examine the role of tumor-related genes in brain tumor development and specifically examined the clinical consequences of MAE at TP53 and IDH1. The genome-wide rate of tumor MAE was higher than in previously described normal tissue and increased with specific tumor grade. Oncogenes, but not tumor suppressors, exhibited significantly higher MAE in high-grade compared with low-grade tumors. This method identified nine novel genes highly associated with MAE. Within cancer-related genes, MAE was gene specific; hTERT was most significantly affected, with a higher frequency of MAE in adult and advanced tumors. Clinically, MAE at TP53 exists only in mutated tumors and increases with tumor aggressiveness. MAE toward the normal allele at IDH1 conferred worse survival even in IDH1 mutated tumors. Taken together, our findings suggest that MAE is tumor and gene specific, frequent in brain tumor subtypes, and may be associated with tumor progression/aggressiveness. Further exploration of MAE at relevant genes may contribute to better understanding of tumor development and determine survival in brain tumor patients. Cancer Res; 72(3); 636-44. ©2011 AACR.

Sponge-specific Clusters Revisited: a Comprehensive Phylogeny of Sponge-associated Microorganisms

Environmental Microbiology. Feb, 2012  |  Pubmed ID: 22151434

Marine sponges often contain diverse and abundant communities of microorganisms including bacteria, archaea and eukaryotic microbes. Numerous 16S rRNA-based studies have identified putative 'sponge-specific' microbes that are apparently absent from seawater and other (non-sponge) marine habitats. With more than 7500 sponge-derived rRNA sequences (from clone, isolate and denaturing gradient gel electrophoresis data) now publicly available, we sought to determine whether the current notion of sponge-specific sequence clusters remains valid. Comprehensive phylogenetic analyses were performed on the 7546 sponge-derived 16S and 18S rRNA sequences that were publicly available in early 2010. Overall, 27% of all sequences fell into monophyletic, sponge-specific sequence clusters. Such clusters were particularly well represented among the Chloroflexi, Cyanobacteria, 'Poribacteria', Betaproteobacteria and Acidobacteria, and in total were identified in at least 14 bacterial phyla, as well as the Archaea and fungi. The largest sponge-specific cluster, representing the cyanobacterium 'Synechococcus spongiarum', contained 245 sequences from 40 sponge species. These results strongly support the existence of sponge-specific microbes and provide a suitable framework for future studies of rare and abundant sponge symbionts, both of which can now be studied using next-generation sequencing technologies.

Frontal White Matter Integrity Predictors of Adult Alcohol Treatment Outcome

Biological Psychiatry. Feb, 2012  |  Pubmed ID: 22047719

Previous research has associated abnormalities in frontal lobe functioning with alcohol relapse. In this study, we used diffusion tensor imaging to investigate whether frontal white matter integrity measured at the start of treatment differs between persons with alcohol use disorders (AUD) who sustain treatment gains and those who return to heavy use after treatment.

CXCR4 Activation Defines a New Subgroup of Sonic Hedgehog-driven Medulloblastoma

Cancer Research. Jan, 2012  |  Pubmed ID: 22052462

Medulloblastoma prognosis tends to be poor, despite aggressive therapy, but defining molecular subgroups may identify patients who could benefit from targeted therapies. This study used human gene array and associated clinical data to identify a new molecular subgroup of medulloblastoma characterized by coactivation of the Sonic hedgehog (SHH) and CXCR4 pathways. SHH-CXCR4 tumors were more common in the youngest patients where they were associated with desmoplastic histology. In contrast to tumors activating SHH but not CXCR4, coactivated tumors exhibited greater expression of Math1 and cyclin D1. Treatment with the CXCR4 antagonist AMD3100 inhibited cyclin D1 expression and maximal tumor growth in vivo. Mechanistic investigations revealed that SHH activation stimulated CXCR4 cell surface localization and effector signaling activity, whereas SHH absence caused CXCR4 to assume an intracellular localization. Taken together, our findings define a new medulloblastoma subgroup characterized by a functional interaction between the SHH and CXCR4 pathways, and they provide a rationale to clinically evaluate combined inhibition of SHH and CXCR4 for medulloblastoma treatment.

Persufflation (or Gaseous Oxygen Perfusion) As a Method of Organ Preservation

Cryobiology. Jan, 2012  |  Pubmed ID: 22301419

Improved preservation techniques have the potential to improve transplant outcomes by better maintaining donor organ quality and by making more organs available for allotransplantation. Persufflation, (PSF, gaseous oxygen perfusion) is potentially one such technique that has been studied for over a century in a variety of tissues, but has yet to gain wide acceptance for a number of reasons. A principal barrier is the perception that ex vivo PSF will cause in vivo embolization post-transplant. This review summarizes the extensive published work on heart, liver, kidney, small intestine and pancreas PSF, discusses the differences between anterograde and retrograde PSF and between PSF and other conventional methods of organ preservation (static cold storage, hypothermic machine perfusion). Prospective implications of PSF within the broader field of organ transplantation, and in the specific application with pancreatic islet isolation and transplant are also discussed. Finally, key issues that need to be addressed before PSF becomes a more widely utilized preservation strategy are summarized and discussed.

Matching Mice to Malignancy: Molecular Subgroups and Models of Medulloblastoma

Child's Nervous System : ChNS : Official Journal of the International Society for Pediatric Neurosurgery. Feb, 2012  |  Pubmed ID: 22315164

INTRODUCTION: Medulloblastoma, the largest group of embryonal brain tumors, has historically been classified into five variants based on histopathology. More recently, epigenetic and transcriptional analyses of primary tumors have subclassified medulloblastoma into four to six subgroups, most of which are incongruous with histopathological classification. DISCUSSION: Improved stratification is required for prognosis and development of targeted treatment strategies, to maximize cure and minimize adverse effects. Several mouse models of medulloblastoma have contributed both to an improved understanding of progression and to developmental therapeutics. In this review, we summarize the classification of human medulloblastoma subtypes based on histopathology and molecular features. We describe existing genetically engineered mouse models, compare these to human disease, and discuss the utility of mouse models for developmental therapeutics. Just as accurate knowledge of the correct molecular subtype of medulloblastoma is critical to the development of targeted therapy in patients, we propose that accurate modeling of each subtype of medulloblastoma in mice will be necessary for preclinical evaluation and optimization of those targeted therapies.

Patterns of Left Ventricular Remodeling in Patients with Duchenne Muscular Dystrophy: a Cardiac MRI Study of Ventricular Geometry, Global Function, and Strain

The International Journal of Cardiovascular Imaging. Jan, 2012  |  Pubmed ID: 21222036

The cardiac disease ubiquitously associated in Duchenne Muscular Dystrophy (DMD) has traditionally been considered a progressive dilated cardiomyopathy (DCM). However, left ventricular (LV) dilatation as measured with cardiac MRI has not been a consistent finding in this population, even as circumferential strain (ε(cc)) declines with advancing disease. We hypothesized that a distinct pattern of changes in LV geometry, during the course of ε(cc) decline, distinguishes DMD associated heart disease from DCM. Using CMR, LV end-diastolic volume (EDV), mass (LVM), ejection fraction, ε(cc) and myocardial delayed enhancement (MDE) were determined in DMD patients and normal control subjects. The LV Remodeling Index (LVRI) was calculated as the ratio of LV Mass to Volume (LVM/EDV). Statistical comparisons between all LV parameters and genotype were also performed. Median LVRI in DMD (n = 127) and control subjects (n = 41) were different (0.75 vs. 0.65, P = 0.0150) but within normal range. Furthermore, the median LVRI in DMD boys with reduced LV systolic function was significantly reduced compared to those with normal LV systolic function (0.64 vs. 0.75, P = 0.0974). However, the presence of MDE was associated with a lower median LVRI (0.57 vs. 0.76, P = 0.0471). Regression analysis showed no significant correlation between ε(cc) and LVRI (r = -0.03). The LVRI of DMD patients is unexpectedly normal and not correlated with ε(cc.) Based on these findings, DMD-associated heart disease exhibits a unique remodeling pattern distinct from DCM.

Assessing the Complex Sponge Microbiota: Core, Variable and Species-specific Bacterial Communities in Marine Sponges

The ISME Journal. Mar, 2012  |  Pubmed ID: 21993395

Marine sponges are well known for their associations with highly diverse, yet very specific and often highly similar microbiota. The aim of this study was to identify potential bacterial sub-populations in relation to sponge phylogeny and sampling sites and to define the core bacterial community. 16S ribosomal RNA gene amplicon pyrosequencing was applied to 32 sponge species from eight locations around the world's oceans, thereby generating 2567 operational taxonomic units (OTUs at the 97% sequence similarity level) in total and up to 364 different OTUs per sponge species. The taxonomic richness detected in this study comprised 25 bacterial phyla with Proteobacteria, Chloroflexi and Poribacteria being most diverse in sponges. Among these phyla were nine candidate phyla, six of them found for the first time in sponges. Similarity comparison of bacterial communities revealed no correlation with host phylogeny but a tropical sub-population in that tropical sponges have more similar bacterial communities to each other than to subtropical sponges. A minimal core bacterial community consisting of very few OTUs (97%, 95% and 90%) was found. These microbes have a global distribution and are probably acquired via environmental transmission. In contrast, a large species-specific bacterial community was detected, which is represented by OTUs present in only a single sponge species. The species-specific bacterial community is probably mainly vertically transmitted. It is proposed that different sponges contain different bacterial species, however, these bacteria are still closely related to each other explaining the observed similarity of bacterial communities in sponges in this and previous studies. This global analysis represents the most comprehensive study of bacterial symbionts in sponges to date and provides novel insights into the complex structure of these unique associations.

Determination of Peripheral Underdosage at the Lung-tumor Interface Using Monte Carlo Radiation Transport Calculations

Medical Dosimetry : Official Journal of the American Association of Medical Dosimetrists. 2012  |  Pubmed ID: 21723112

Prediction of dose distributions in close proximity to interfaces is difficult. In the context of radiotherapy of lung tumors, this may affect the minimum dose received by lesions and is particularly important when prescribing dose to covering isodoses. The objective of this work is to quantify underdosage in key regions around a hypothetical target using Monte Carlo dose calculation methods, and to develop a factor for clinical estimation of such underdosage. A systematic set of calculations are undertaken using 2 Monte Carlo radiation transport codes (egsnrc and geant4). Discrepancies in dose are determined for a number of parameters, including beam energy, tumor size, field size, and distance from chest wall. Calculations were performed for 1-mm(3) regions at proximal, distal, and lateral aspects of a spherical tumor, determined for a 6-MV and a 15-MV photon beam. The simulations indicate regions of tumor underdose at the tumor-lung interface. Results are presented as ratios of the dose at key peripheral regions to the dose at the center of the tumor, a point at which the treatment planning system (TPS) predicts the dose more reliably. Comparison with TPS data (pencil-beam convolution) indicates such underdosage would not have been predicted accurately in the clinic. We define a dose reduction factor (DRF) as the average of the dose in the periphery in the 6 cardinal directions divided by the central dose in the target, the mean of which is 0.97 and 0.95 for a 6-MV and 15-MV beam, respectively. The DRF can assist clinicians in the estimation of the magnitude of potential discrepancies between prescribed and delivered dose distributions as a function of tumor size and location. Calculation for a systematic set of "generic" tumors allows application to many classes of patient case, and is particularly useful for interpreting clinical trial data.

Marine Sponges and Their Microbial Symbionts: Love and Other Relationships

Environmental Microbiology. Feb, 2012  |  Pubmed ID: 21443739

Many marine sponges harbour dense and diverse microbial communities of considerable ecological and biotechnological importance. While the past decade has seen tremendous advances in our understanding of the phylogenetic diversity of sponge-associated microorganisms (more than 25 bacterial phyla have now been reported from sponges), it is only in the past 3-4 years that the in situ activity and function of these microbes has become a major research focus. Already the rewards of this new emphasis are evident, with genomics and experimental approaches yielding novel insights into symbiont function. Key steps in the nitrogen cycle [denitrification, anaerobic ammonium oxidation (Anammox)] have recently been demonstrated in sponges for the first time, with diverse bacteria - including the sponge-associated candidate phylum 'Poribacteria'- being implicated in these processes. In this minireview we examine recent major developments in the microbiology of sponges, and identify several research areas (e.g. biology of viruses in sponges, effects of environmental stress) that we believe are deserving of increased attention.