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Articles by Sharanya Iyengar in JoVE

 JoVE Clinical and Translational Medicine

Screening for Melanoma Modifiers using a Zebrafish Autochthonous Tumor Model

1Program in Molecular Medicine and Department of Cancer Biology, University of Massachusetts Medical School, 2Departments of Surgery and Medicine, Weill Cornell Medical College, 3Departments of Surgery and Medicine, New York Presbyterian Hospital


JoVE 50086

A rapid way to screen for melanoma modifiers using a zebrafish autochthonous tumor model is presented. It takes advantage of the miniCoopR vector which allows for expression of candidate melanoma genes in melanocytes. A method to obtain melanoma-free survival curves, an invasion assay, a protocol for antibody staining of scale melanocytes and a melanoma transplantation assay are described.

Other articles by Sharanya Iyengar on PubMed

Efficacy and Safety of Tenecteplase in ST Elevation Myocardial Infarction Patients from the Elaxim Indian Registry

to study the efficacy and safety of indigenously developed tenecteplase injection in the management of Indian STEMI patients in clinical practice.

Medium of Exchange Matters: What's Fair for Goods is Unfair for Money

Organized groups face a fundamental problem of how to distribute resources fairly. We found people view it as less fair to distribute resources equally when the allocated resource invokes the market by being a medium of exchange than when the allocated resource is a good that holds value in use. These differences in fairness can be attributed to being a medium of exchange, and not to other essential properties of money (i.e., being a unit of account or a store of value). These findings suggest that egalitarian outcomes have a greater likelihood of being accepted as fair when the resources being distributed take the form of in-kind goods rather than of cash transfers.

Prevalence and Awareness Regarding Diabetes Mellitus in Rural Tamaka, Kolar

The worldwide prevalence of diabetes mellitus has risen dramatically in the developing countries over the past two decades. Regular screening of adults is essential for early detection and care. There are limited studies on diabetes awareness and prevalence in rural communities. Hence this prevalence and knowledge assessment study was undertaken. Such data are extremely important to plan the public health policies with specific reference to implementation of National Diabetic Control Program.

Systems Approaches to Polypharmacology and Drug Discovery

Systems biology uses experimental and computational approaches to characterize large sample populations systematically, process large datasets, examine and analyze regulatory networks, and model reactions to determine how components are joined to form functional systems. Systems biology technologies, data and knowledge are particularly useful in understanding disease processes and drug actions. An important area of integration between systems biology and drug discovery is the concept of polypharmacology: the treatment of diseases by modulating more than one target. Polypharmacology for complex diseases is likely to involve multiple drugs acting on distinct targets that are part of a network regulating physiological responses. This review discusses the current state of the systems-level understanding of diseases and both the therapeutic and adverse mechanisms of drug actions. Drug-target networks can be used to identify multiple targets and to determine suitable combinations of drug targets or drugs. Thus, the discovery of new drug therapies for complex diseases may be greatly aided by systems biology.

Outcome of Patients with Diffuse Large B-cell Lymphoma of the Testis by Era of Treatment: the M. D. Anderson Cancer Center Experience

The purpose of this study was to assess the clinicopathologic characteristics and outcomes in patients with diffuse large B-cell lymphoma (DLBCL) of the testis, and to assess the impact of changes in the therapeutic approach that have occurred over the years. We reviewed the medical records of 75 patients between 1964 and 2008. Factors analyzed included: age, clinical stage, B-symptoms, serum levels of lactate dehydrogenase (LDH), beta(2)-microglobulin, treatment received, and outcome. Immunophenotypic data were available for 43 cases, all of which showed B-cell lineage. On univariate analysis, stages III and IV (p = 0.042), elevated serum LDH (p = 0.014), B-symptoms (p = 0.003), and high-intermediate or high International Prognostic Index (IPI) score (p = 0.010) were associated with a significantly decreased overall survival (OS) and progression-free survival (PFS). The 5-year OS and PFS for patients after 2000, treated predominantly with R-CHOP, intrathecal chemotherapy (ITC), and scrotal radiotherapy (RT), were 86.6% and 59.3%, respectively. This is compared to 56.3% and 51.7%, respectively, for patients treated between 1977 and 1999 with doxorubicin based chemotherapy without rituximab, who were not uniformly treated with ITC. Patients treated prior to 1977 had an OS and PFS of 15.4% and 15.4%, respectively, and were not treated with doxorubicin based chemotherapy or ITC (p = 0.019 for OS and p = 0.138 for PFS). Advanced stage, elevated serum LDH, B-symptoms, and high IPI are poor prognostic markers. R-CHOP based chemotherapy with intrathecal chemotherapy and scrotal RT is associated with an improved OS.

Post-eclosion Odor Experience Modifies Olfactory Receptor Neuron Coding in Drosophila

Olfactory responses of Drosophila undergo pronounced changes after eclosion. The flies develop attraction to odors to which they are exposed and aversion to other odors. Behavioral adaptation is correlated with changes in the firing pattern of olfactory receptor neurons (ORNs). In this article, we present an information-theoretic analysis of the firing pattern of ORNs. Flies reared in a synthetic odorless medium were transferred after eclosion to three different media: (i) a synthetic medium relatively devoid of odor cues, (ii) synthetic medium infused with a single odorant, and (iii) complex cornmeal medium rich in odors. Recordings were made from an identified sensillum (type II), and the Jensen-Shannon divergence (D(JS)) was used to assess quantitatively the differences between ensemble spike responses to different odors. Analysis shows that prolonged exposure to ethyl acetate and several related esters increases sensitivity to these esters but does not improve the ability of the fly to distinguish between them. Flies exposed to cornmeal display varied sensitivity to these odorants and at the same time develop greater capacity to distinguish between odors. Deprivation of odor experience on an odorless synthetic medium leads to a loss of both sensitivity and acuity. Rich olfactory experience thus helps to shape the ORNs response and enhances its discriminative power. The experiments presented here demonstrate an experience-dependent adaptation at the level of the receptor neuron.

Efficacy and Safety of Duloxetine in Patients with Chronic Low Back Pain

This was a randomized, double-blind, placebo-controlled clinical trial.

Treatment of Resistant Depression in Adolescents (TORDIA): Week 24 Outcomes

The purpose of this study was to report on the outcome of participants in the Treatment of Resistant Depression in Adolescents (TORDIA) trial after 24 weeks of treatment, including remission and relapse rates and predictors of treatment outcome.

Mechanisms Controlling Cell Size and Shape During Isotropic Cell Spreading

Cell motility is important for many developmental and physiological processes. Motility arises from interactions between physical forces at the cell surface membrane and the biochemical reactions that control the actin cytoskeleton. To computationally analyze how these factors interact, we built a three-dimensional stochastic model of the experimentally observed isotropic spreading phase of mammalian fibroblasts. The multiscale model is composed at the microscopic levels of three actin filament remodeling reactions that occur stochastically in space and time, and these reactions are regulated by the membrane forces due to membrane surface resistance (load) and bending energy. The macroscopic output of the model (isotropic spreading of the whole cell) occurs due to the movement of the leading edge, resulting solely from membrane force-constrained biochemical reactions. Numerical simulations indicate that our model qualitatively captures the experimentally observed isotropic cell-spreading behavior. The model predicts that increasing the capping protein concentration will lead to a proportional decrease in the spread radius of the cell. This prediction was experimentally confirmed with the use of Cytochalasin D, which caps growing actin filaments. Similarly, the predicted effect of actin monomer concentration was experimentally verified by using Latrunculin A. Parameter variation analyses indicate that membrane physical forces control cell shape during spreading, whereas the biochemical reactions underlying actin cytoskeleton dynamics control cell size (i.e., the rate of spreading). Thus, during cell spreading, a balance between the biochemical and biophysical properties determines the cell size and shape. These mechanistic insights can provide a format for understanding how force and chemical signals together modulate cellular regulatory networks to control cell motility.

Opioid Modulation of Cell Proliferation in the Ventricular Zone of Adult Zebra Finches (Taenopygia Guttata)

Besides modulating pain, stress, physiological functions, motivation, and reward, the opioid system has been implicated in developmental and adult mammalian neurogenesis and gliogenesis. In adult male songbirds including zebra finches, neurons generated from the ventricular zone (VZ) of the lateral ventricles are incorporated throughout the telencephalon, including the song control nuclei, HVC, and area X. Although the endogenous opioid met-enkephalin is present in neurons adjacent to the VZ and is upregulated in song control regions during singing, it is not known whether the opioid system can modulate adult neurogenesis/gliogenesis in zebra finches. We used quantitative RT-PCR and in situ hybridization to demonstrate that μ- and δ-opioid receptors are expressed by the VZ of adult male zebra finches. Treating cultured VZ cells from male birds with the opioid antagonist naloxone led to an increase in cell proliferation measured by 5-bromo-2-deoxyuridine incorporation, whereas administering met-enkephalin had the opposite effect, compared with saline-treated cultures. Systemically administering naloxone (2.5 mg/kg body wt) to adult male zebra finches for 4 d also led to a significant increase in cell proliferation in the ventral VZ of these birds, compared with saline-treated controls. Our results show that cell proliferation is augmented by naloxone in the VZ adjacent to the anterior commissure, suggesting that the endogenous opioids modulate adult neurogenesis/gliogenesis by inhibiting cell proliferation in songbirds.

Left Ventricular Lateral Annulus and Left Atrial Free-wall Velocity Time Integral Indicate Thromboembolism in Patients with Rheumatic Atrial Fibrillation

Low wall motion and stasis increase the likelihood of clot formation. We hypothesized that tissue Doppler indices of left atrial (LA) motion are reduced in the presence of LA thrombi and may be predictive for clot formation in patients with atrial fibrillation (AF).

Marginal Zone Lymphomas: Factors That Affect the Final Outcome

A retrospective review and analysis of 275 patients with marginal zone lymphoma (MZL) was performed to determine prognostic factors. An effort was also made to establish a specific prognostic score for patients with extranodal MZL.

Cutaneous Sporothrix Schenckii of the Human Eyelid

An 87-year-old patient presented with a 6-week history of an isolated progressive destructive nodular eyelid mass, secondary nodular and ulcerative lesions, and regional painful lymphadenopathy. After 4 weeks, fungal cultures demonstrated Sporothrix schenckii. S. schenckii is a rare dimorphic fungus that can occasionally involve the periocular skin. The authors' case demonstrates typical clinical features, emphasizes the delay in diagnosis, and shows effective treatment with oral itraconazole.

Training in Systems Pharmacology: Predoctoral Program in Pharmacology and Systems Biology at Mount Sinai School of Medicine

Our recently developed predoctoral training program in pharmacology and systems biology prepares students to become experts in systems-level models of disease that identify therapeutic targets and predict adverse effects or new uses of existing therapeutics. Multiple computational modeling modes are introduced throughout a curriculum that integrates basic cell and molecular sciences with the physiology and pathophysiology of disease states. Problem-based learning exercises enable students from different experimental and computational backgrounds to design experiments and interpret data quantitatively.

Hodgkin Lymphoma Involving Extranodal and Nodal Head and Neck Sites: Characteristics and Outcomes

Most Hodgkin lymphoma (HL) patients present with disease in nodal regions. However, in a small subset, disease develops in unique anatomic sites such as the head and neck area. This study aims to identify the characteristics and outcomes of patients who develop HL involving extranodal and nodal head and neck sites.

Isotope Dependent, Temperature Regulated, Energy Repartitioning in a Low-barrier, Short-strong Hydrogen Bonded Cluster

We investigate and analyze the vibrational properties, including hydrogen/deuterium isotope effects, in a fundamental organic hydrogen bonded system using multiple experimental (infrared multiple photon dissociation and argon-tagged action spectroscopy) and computational techniques. We note a qualitative difference between the two experimental results discussed here and employ ab initio molecular dynamics simulations to explain these results. A deeper understanding of the differences between the isotopically labeled systems arises from an analysis of the simulated cluster spectroscopy and leads to a system-bath coupling interpretation. Specifically, when a few active modes, involving the shared hydrogen/deuterium stretch, are identified and labeled as "system," with all other molecular vibrational modes being identified as "bath" modes, we find critical differences in the coupling between the system modes for the shared proton and shared deuteron cases. These differences affect the energy repartitioning between these modes resulting in a complex spectral evolution as a function of temperature. Furthermore, intensity borrowing across modes that are widely distributed in the frequency domain plays an important role on the simulated spectra.

Studies on Active Site Mutants of P. Falciparum Adenylosuccinate Synthetase: Insights into Enzyme Catalysis and Activation

Adenylosuccinate synthetase catalyzes a reversible reaction utilizing IMP, GTP and aspartate in the presence of Mg²+ to form adenylosuccinate, GDP and inorganic phosphate. Comparison of similarly liganded complexes of Plasmodium falciparum, mouse and Escherichia coli AdSS reveals H-bonding interactions involving nonconserved catalytic loop residues (Asn429, Lys62 and Thr307) that are unique to the parasite enzyme. Site-directed mutagenesis has been used to examine the role of these interactions in catalysis and structural organization of P. falciparum adenylosuccinate synthetase (PfAdSS). Mutation of Asn429 to Val, Lys62 to Leu and Thr307 to Val resulted in an increase in K(m) values for IMP, GTP and aspartate, respectively along with a 5 fold drop in the k(cat) value for N429V mutant suggesting the role of these residues in ligand binding and/or catalysis. We have earlier shown that the glycolytic intermediate, fructose 1,6 bisphosphate, which is an inhibitor of mammalian AdSS is an activator of the parasite enzyme. Enzyme kinetics along with molecular docking suggests a mechanism for activation wherein F16BP seems to be binding to the Asp loop and inducing a conformation that facilitates aspartate binding to the enzyme active site. Like in other AdSS, a conserved arginine residue (Arg155) is involved in dimer crosstalk and interacts with IMP in the active site of the symmetry related subunit of PfAdSS. We also report on the biochemical characterization of the arginine mutants (R155L, R155K and R155A) which suggests that unlike in E. coli AdSS, Arg155 in PfAdSS influences both ligand binding and catalysis.

Drug Discovery in Academic Settings

Systems Pharmacology

We examine how physiology and pathophysiology are studied from a systems perspective, using high-throughput experiments and computational analysis of regulatory networks. We describe the integration of these analyses with pharmacology, which leads to new understanding of drug action and enables drug discovery for complex diseases. Network studies of drug-target relationships can serve as an indication on the general trends in the approved drugs and the drug-discovery progress. There is a growing number of targeted therapies approved and in the pipeline, which meets a new set of problems with efficacy and adverse effects. The pitfalls of these mechanistically based drugs are described, along with how a systems view of drug action is increasingly important to uncover intricate signaling mechanisms that play an important part in drug action, resistance mechanisms, and off-target effects. Computational methodologies enable the classification of drugs according to their structures and to which proteins they bind. Recent studies have combined the structural analyses with analysis of regulatory networks to make predictions about the therapeutic effects of drugs for complex diseases and possible off-target effects.

A Multistage Ab Initio Quantum Wavepacket Dynamics Formalism for Electronic Structure and Dynamics in Open Systems

We propose a multistage quantum wavepacket dynamical treatment for the study of delocalized electronic systems as well as electron transport through donor-bridge-acceptor systems such as those found in molecular-wire/electrode networks. The full donor-bridge-acceptor system is treated through a rigorous partitioning scheme that utilizes judiciously placed offsetting absorbing and emitting boundary conditions. These facilitate a computationally efficient and potentially accurate treatment of the long-range coupling interactions between the bridge and donor/acceptor systems and the associated open system boundary conditions. Time-independent forms of the associated, partitioned equations are also derived. In the time-independent form corresponding to the bridge system, coupling to donor and acceptor, that is long-range interactions, is completely accounted. For the time-dependent study, the quantum dynamics of the electronic flux through the bridge-donor/acceptor interface is constructed using an accurate and efficient representation of the discretized quantum-mechanical free-propagator. A model for an electrode-molecular wire-electrode system is used to test the accuracy of the scheme proposed. Transmission probability is obtained directly from the probability density of the electronic flux in the acceptor region. Conductivity through the molecular wire is computed using a wavepacket flux correlation function.

The Abduction External Rotation (ABER) View for MRI of the Shoulder

FRNK Inhibition of Focal Adhesion Kinase-dependent Signaling and Migration in Vascular Smooth Muscle Cells

To examine whether interference with FRNK targeting to focal adhesions (FAs) affects its inhibitory activity and tyrosine phosphorylation.

Born to Choose: the Origins and Value of the Need for Control

Belief in one's ability to exert control over the environment and to produce desired results is essential for an individual's wellbeing. It has repeatedly been argued that perception of control is not only desirable, but is also probably a psychological and biological necessity. In this article, we review the literature supporting this claim and present evidence of a biological basis for the need for control and for choice-that is, the means by which we exercise control over the environment. Converging evidence from animal research, clinical studies and neuroimaging suggests that the need for control is a biological imperative for survival, and a corticostriatal network is implicated as the neural substrate of this adaptive behavior.

Genome-wide Association Identifies SKIV2L and MYRIP As Protective Factors for Age-related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. We conducted a genome-wide association study in a series of families enriched for AMD and completed a meta-analysis of this new data with results from reanalysis of an existing study of a late-stage case-control cohort. We tested the top findings for replication in 1896 cases and 1866 controls and identified two novel genetic protective factors for AMD. In addition to the complement factor H (CFH) (P=2.3 × 10⁻⁶⁴) and age-related maculopathy susceptibility 2 (ARMS2) (P=1.2 × 10⁻⁶⁰) loci, we observed a protective effect at rs429608, an intronic SNP in SKIV2L (P=5.3 × 10⁻¹⁵), a gene near the complement component 2 (C2)/complement factor B (BF) locus, that indicates the protective effect may be mediated by variants other than the C2/BF variants previously studied. Haplotype analysis at this locus identified three protective haplotypes defined by the rs429608 protective allele. We also identified a new potentially protective effect at rs2679798 in MYRIP (P=2.9 × 10⁻⁴), a gene involved in retinal pigment epithelium melanosome trafficking. Interestingly, MYRIP was initially identified in the family-based scan and was confirmed in the case-control set. From these efforts, we report the identification of two novel protective factors for AMD and confirm the previously known associations at CFH, ARMS2 and C3.

Comorbid Anxiety in Children and Adolescents with Bipolar Spectrum Disorders: Prevalence and Clinical Correlates

Anxiety disorders are among the most common comorbid conditions in youth with bipolar disorder. We aimed to examine the prevalence and correlates of comorbid anxiety disorders among youth with bipolar disorder.

Effect of Combining Extended-release Carvedilol and Lisinopril in Hypertension: Results of the COSMOS Study

Hypertension treatment commonly requires multiple agents to achieve target blood pressure (BP). β-blockers and angiotensin-converting enzyme inhibitors (ACEIs) are commonly co-prescribed in clinical practice although few data are available that test their additivity on BP lowering. The efficacy and safety of once-daily extended-release carvedilol (carvedilol CR) combined with the ACEI lisinopril in a double-blind, randomized, factorial design study were studied. Patients (N=656) with stage 1 or 2 hypertension were randomized evenly to 1 of 15 groups for 6 weeks: carvedilol CR monotherapy 20 mg, 40 mg, or 80 mg/d; lisinopril monotherapy 10 mg, 20 mg, or 40 mg/d; or 1 of 9 combinations of carvedilol CR plus lisinopril initiated simultaneously. Primary efficacy measures (assessed by ambulatory BP monitoring [ABPM]) were change from baseline in 24-hour mean diastolic BP (DBP) and in trough (20-24 hours) DBP. Continuous efficacy variables were assessed using analysis of covariance. Whether any combination dose was superior to its monotherapy components was assessed using the Hung AVE procedure. Despite the presence of additional BP lowering observed with most of the combinations compared with their monotherapy components, the Hung AVE test was not significant for either primary efficacy measures. Post hoc analyses of the high-dose combination groups (carvedilol CR/lisinopril regimens of 80/10 mg, 80/20 mg, 80/40 mg, 20/40 mg, and 40/40 mg) showed a significant treatment difference compared with both carvedilol CR 80 mg and lisinopril 40 mg for 24-hour mean DBP but not for trough DBP. With the exception of dizziness, individual adverse events did not increase with ascending doses or combinations. The superiority of initiating combination treatment with carvedilol CR and lisinopril compared with the monotherapy components was not demonstrated with the ABPM measurements. Nonetheless, the post hoc assessment combining all high-dose groups did produce significant 24-hour mean BP reduction when compared with the high-dose monotherapy groups. The tolerability profile of initiating combination therapy was generally comparable to the initiation of treatment with monotherapy.

A Meta-analysis of Depression During Pregnancy and the Risk of Preterm Birth, Low Birth Weight, and Intrauterine Growth Restriction

Maternal depressive symptoms during pregnancy have been reported in some, but not all, studies to be associated with an increased risk of preterm birth (PTB), low birth weight (LBW), and intrauterine growth restriction (IUGR).

Update on Pediatric Lacrimal Disorders

Selective Release of MicroRNA Species from Normal and Malignant Mammary Epithelial Cells

MicroRNAs (miRNAs) in body fluids are candidate diagnostics for a variety of conditions and diseases, including breast cancer. One premise for using extracellular miRNAs to diagnose disease is the notion that the abundance of the miRNAs in body fluids reflects their abundance in the abnormal cells causing the disease. As a result, the search for such diagnostics in body fluids has focused on miRNAs that are abundant in the cells of origin. Here we report that released miRNAs do not necessarily reflect the abundance of miRNA in the cell of origin. We find that release of miRNAs from cells into blood, milk and ductal fluids is selective and that the selection of released miRNAs may correlate with malignancy. In particular, the bulk of miR-451 and miR-1246 produced by malignant mammary epithelial cells was released, but the majority of these miRNAs produced by non-malignant mammary epithelial cells was retained. Our findings suggest the existence of a cellular selection mechanism for miRNA release and indicate that the extracellular and cellular miRNA profiles differ. This selective release of miRNAs is an important consideration for the identification of circulating miRNAs as biomarkers of disease.

Importance of Blood Pressure Control in Left Ventricular Mass Regression

Blood pressure (BP) reduction to 140/90 mm Hg or lower using renin-angiotensin-system blockers reportedly provides the greatest left ventricular (LV) mass regression; β-blockers have less effect. This study examined whether combination antihypertensive therapy would provide greater benefit. With a double-blind, parallel-group design, the effects of 3 different combinations, carvedilol controlled-release (CR)/lisinopril, atenolol/lisinopril, and lisinopril, on left ventricular mass index (LVMI) were assessed by MRI after 12 months. Patients were treated to achieve guideline-recommended BP (<140 mm Hg/<90 mm Hg; diabetes: <130 mm Hg/<80 mm Hg). Sample size was calculated to achieve 90% power to detect a 5 g/m(2) difference in mean change from baseline in LVMI between the carvedilol CR/lisinopril group and each of the other treatment groups. Of 287 patients randomized, more than 50% were titrated to maximum dosage; 73% reached targeted BP. At month 12 (last observation carried forward ≥ month 9) for 195 evaluable subjects, mean BP was similar in all groups (carvedilol CR/lisinopril: 128.8/77.9; atenolol/lisinopril: 128.7/76.5; lisinopril: 126.3/80.3 mm Hg). Compared with baseline, mean LVMI decreased to a similar extent in all groups (carvedilol CR/lisinopril: -6.3; atenolol/lisinopril: -6.7; lisinopril: -7.9 g/m(2)). Achievement of targeted BP control is more important than treatment regimen in achieving LV mass reduction.

Efficacy and Safety of Tenecteplase in Diabetic and Non-diabetic Patients of STEMI - Indian Registry Data

Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation in Vivo

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

Quantum Wavepacket Ab Initio Molecular Dynamics: Generalizations Using an Extended Lagrangian Treatment of Diabatic States Coupled Through Multireference Electronic Structure

We present a generalization to our previously developed quantum wavepacket ab initio molecular dynamics (QWAIMD) method by using multiple diabatic electronic reduced single particle density matrices, propagated within an extended Lagrangian paradigm. The Slater determinantal wavefunctions associated with the density matrices utilized may be orthogonal or nonorthogonal with respect to each other. This generalization directly results from an analysis of the variance in electronic structure with quantum nuclear degrees of freedom. The diabatic electronic states are treated here as classical parametric variables and propagated simultaneously along with the quantum wavepacket and classical nuclei. Each electronic density matrix is constrained to be N-representable. Consequently two sets of new methods are derived: extended Lagrangian-QWAIMD (xLag-QWAIMD) and diabatic extended Lagrangian-QWAIMD (DxLag-QWAIMD). In both cases, the instantaneous potential energy surface for the quantum nuclear degrees of freedom is constructed from the diabatic states using an on-the-fly nonorthogonal multireference formalism. By introducing generalized grid-based electronic basis functions, we eliminate the basis set dependence on the quantum nucleus. Subsequent reuse of the two-electron integrals during the on-the-fly potential energy surface computation stage yields a substantial reduction in computational costs. Specifically, both xLag-QWAIMD and DxLag-QWAIMD turn out to be about two orders of magnitude faster than our previously developed time-dependent deterministic sampling implementation of QWAIMD. Energy conservation properties, accuracy of the associated potential surfaces, and vibrational properties are analyzed for a family of hydrogen bonded systems.

Patterns of Neural Differentiation in Melanomas

Melanomas, highly malignant tumors arise from the melanocytes which originate as multipotent neural crest cells during neural tube genesis. The purpose of this study is to assess the pattern of neural differentiation in relation to angiogenesis in VGP melanomas using the tumor as a three dimensional system.

Dynamics of an Excitable Glow-discharge Plasma Under External Forcing

Glow discharge plasma in the excitable regime shows rich dynamical behavior under external forcing. By perturbing the plasma with a subthreshold sawtooth periodic signal, we obtained small subthreshold oscillations that showed resonance with the perturbation frequency. The resonance phenomenon can be useful to estimate characteristic of an excitable system. However, for suprathreshold perturbation, frequency entrainment was observed. In this case, the system showed harmonic frequency entrainment for the perturbation frequencies greater than the characteristic frequency of the system and the excitable behavior for the perturbation frequencies well below the characteristic frequency. The experiments were performed in a glow-discharge plasma where excitability was achieved at a suitable discharge voltage and gas pressure.

Dietary Ligands As Determinants of Iron-zinc Interactions at the Absorptive Enterocyte

Iron and zinc interact at the enterocyte and influence the absorption of one another. We have previously reported that zinc noncompetitively inhibits iron uptake in Caco-2 cells, a widely accepted model of the absorptive enterocyte. However, the determinants of this interaction, such as the effect of dietary ligands, remain uncharacterized. Dietary ligands selectively chelate iron and zinc in definite stoichiometric proportions and thus alter the bioavailability from food matrices. Here, we have used common dietary ligands, such as ascorbic acid, phytic acid, tannic acid, tartaric acid, cysteine, histidine, and methionine to characterize iron, zinc uptake individually and in combination, using Caco-2 cells. Selective chelation of zinc, using cysteine, decreased the magnitude of inhibition of iron uptake but could not reverse the inhibition. On the other hand, selective increase in iron uptake in the presence of methionine resulted in increased zinc uptake, rather than inhibition. Taken together, these in vitro results suggest that dietary ligands can modulate iron-zinc interaction and that zinc cannot competitively inhibit iron uptake.

Heritability Estimation for Speech-sound Traits with Developmental Trajectories

Numerous studies have examined genetic influences on developmental problems such as speech sound disorders (SSD), language impairment (LI), and reading disability. Disorders such as SSD are often analyzed using their component endophenotypes. Most studies, however, have involved comparisons of twin pairs or siblings of similar age, or have adjusted for age ignoring effects that are peculiar to age-related trajectories for phenotypic change. Such developmental changes in these skills have limited the usefulness of data from parents or siblings who differ substantially in age from the probands. Employing parent-offspring correlation in heritability estimation permits a more precise estimate of the additive component of genetic variance, but different generations have to be measured for the same trait. We report on a smoothing procedure which fits a series of lines that approximate a curve matching the developmental trajectory. This procedure adjusts for changes in measures with age, so that the adjusted values are on a similar scale for children, adolescents, and adults. We apply this method to four measures of phonological memory and articulation in order to estimate their heritability. Repetition of multisyllabic real words (MSW) showed the best heritability estimate of 45% in this sample. We conclude that differences in measurement scales across the age span can be reconciled through non-linear modeling of the developmental process.

Role of Systems Pharmacology in Understanding Drug Adverse Events

Systems pharmacology involves the application of systems biology approaches, combining large-scale experimental studies with computational analyses, to the study of drugs, drug targets, and drug effects. Many of these initial studies have focused on identifying new drug targets, new uses of known drugs, and systems-level properties of existing drugs. This review focuses on systems pharmacology studies that aim to better understand drug side effects and adverse events. By studying the drugs in the context of cellular networks, these studies provide insights into adverse events caused by off-targets of drugs as well as adverse events-mediated complex network responses. This allows rapid identification of biomarkers for side effect susceptibility. In this way, systems pharmacology will lead to not only newer and more effective therapies, but safer medications with fewer side effects.

Potentiation of EBV-induced B Cell Transformation by CXCR4-tropic, but Not CCR5-tropic, HIV Gp120: Implications for HIV-associated Lymphomagenesis

Abstract R5 and X4 HIV strains use CCR5 or CXCR4 chemokine receptors (CKRs), respectively, for entry. Preferential growth of X4 vs. R5 HIV in cell lines reflects constitutive expression of CXCR4, but not CCR5 (in contrast to dual expression on primary T cells), and CXCR4 is the predominant CKR found on most tumors. Non-Hodgkin's B cell lymphomas (NHL) are increased among HIV(+) patients, and interactions between HIV envelope and CKRs may contribute to lymphomagenesis. Despite strong evidence for a CXCR4-SDF-1 oncogenic axis, no in vitro evaluation of CXCR4-mediated normal lymphocyte transformation has been published. Exposure of normal B cells to EBV in the presence of X4 gp120 (but not R5 gp120) increased proliferation and BLCL outgrowth, comparable to anti-CD40 mAb costimulation. This suggests a role for X4 tropic viral envelope signaling via CXCR4 and/or CXCR7 in HIV-associated lymphomagenesis.

The Importance of Interfacial Design for the Sensitivity of a Label-free Electrochemical Immuno-biosensor for Small Organic Molecules

An immuno-biosensing interface comprising a mixed layer of an oligo(ethylene glycol) (OEG) component, and an oligo(phenylethynylene) molecular wire (MW) is described. The OEG controls the interaction of proteins and electroactive interferences with the surface and the MW allows electrochemical communication to the underlying glassy carbon electrode. The layers are formed from in situ generated-aryl diazonium cations. To the distal end of the MW, a redox probe 1,1'-di(aminomethyl)ferrocene is attached followed by the surface bound epitope (the structural feature the antibody selectively recognizes) to which an antibody would bind. Association or disassociation of the antibody with the sensing interface causes a modulation of the ferrocene electrochemistry. X-ray photoelectron spectroscopy, cyclic voltammetry, and square wave voltammetry have been used to characterize the step-wise fabrication of the sensing interface. The influence of the molar ratio of the MW and OEG deposited onto the sensor interface was explored relative to the final sensor sensitivity. Five combinations of MW/OEG 1:0, 1:20, 1:50, 1:75 and 1:100 were tested on sensor sensitivity detection for a model analyte (biotin) free in solution, via a displacement assay. The ratio of 1:50 was found to give the highest sensitivity. At this ratio, good reproducibility (RSD 6.8%) and repeatability (RSD 9.6%) was achieved. This immuno-biosensor provides an intervention free immuno-biosensing platform for agriculture and biomedical samples.

Tenecteplase in the Treatment of Acute Pulmonary Thrombo-embolism

This is a retrospective study documenting the use of tenecteplase in 41 cases of suspected or confirmed pulmonary embolism receiving in-hospital tenecteplase as per weight-adjusted dosing in addition to standard heparin and oral anticoagulant therapy. The presenting symptoms of dyspnoea, chest pain, hemoptysis and syncope were found in 40 (97.56%), 19 (46.34%), 6 (14.63%) and 9 (21.95%) patients, respectively. There was one case of mortality who was a 26 yrs old female of postpartum pulmonary thrombo-embolism with severe hypotension, cyanosis, bilateral crepitations in lungs and pulmonary hypertension. In the 40 survived patients, there was alleviation of dyspnoea and hemoptysis in all patients. Significant reduction in tachycardia (P < 0.0001) and increase in the oxygen saturation (SaOâ‚‚) (P < 0.0001) were seen at discharge as compared to at the time of presentation. Eighteen patients had hypotension which recovered in all patients till the time of discharge (P < 0.0001). There was a significant reduction in right ventricular systolic pressure in all 18 patients who underwent 2-D echocardiography both before and after the tenecteplase therapy. Resolution of pulmonary embolism on CT pulmonary angiography was documented in only two patients. No bleeding events or any other adverse events were reported during this study. The present study suggests favourable efficacy of tenecteplase in patients with suspected or confirmed acute pulmonary embolism. Although no major adverse events were noted, a large prospective study on the use of tenecteplase in pulmonary embolism is suggested.

Blood Dendritic Cells Suppress NK Cell Function and Increase the Risk of Leukemia Relapse After Hematopoietic Cell Transplantation

NK cells play an important role in hematopoietic stem cell transplantation (HCT) and in cross talk with dendritic cells (DCs) to induce primary T cell response against infection. Therefore, we hypothesized that blood DCs should augment NK cell function and reduce the risk of leukemia relapse after HCT. To test this hypothesis, we conducted laboratory and clinical studies in parallel. We found that although, phenotypically, NK cells could induce DC maturation and DCs could in turn increase activating marker expression on NK cells, paradoxically, both BDCA1(+) myeloid DCs and BDCA4(+) plasmacytoid DCs suppressed the function of NK cells. Patients who received an HLA-haploidentical graft containing a larger number of BDCA1(+) DCs or BDCA4(+) DCs had a higher risk of leukemia relapse and poorer survival. Further experiments indicated that the potent inhibition on NK cell cytokine production and cytotoxicity was mediated in part through the secretion of IL-10 by BDCA1(+) DCs and IL-6 by BDCA4(+) DCs. These results have significant implications for future HCT strategies.

Efficacy and Safety of Carvedilol in Treatment of Heart Failure with Chronic Kidney Disease: a Meta-analysis of Randomized Trials

The safety and efficacy of different types of β-blocker therapy in patients with non-dialysis-dependent chronic kidney disease (CKD) and systolic heart failure (HF) are not well described. We assessed whether treatment of systolic HF with carvedilol is efficacious and safe in adults with CKD.

Phosphatidylinositol-4,5-bisphosphate Regulates Epidermal Growth Factor Receptor Activation

Phosphatidylinositol-4,5-bisphosphate [PI(4,5)P(2) or PIP(2)] is a direct modulator of a diverse array of proteins in eukaryotic cells. The functional integrity of transmembrane proteins, such as ion channels and transporters, is critically dependent on specific interactions with PIP(2) and other phosphoinositides. Here, we report a novel requirement for PIP(2) in the activation of the epidermal growth factor receptor (EGFR). Down-regulation of PIP(2) levels either via pharmacological inhibition of PI kinase activity, or via manipulation of the levels of the lipid kinase PIP5K1α and the lipid phosphatase synaptojanin, reduced EGFR tyrosine phosphorylation, whereas up-regulation of PIP(2) levels via overexpression of PIP5K1α had the opposite effect. A cluster of positively charged residues in the juxtamembrane domain (basic JD) of EGFR is likely to mediate binding of EGFR to PIP(2) and PIP(2)-dependent regulation of EGFR activation. A peptide mimicking the EGFR juxtamembrane domain that was assayed by surface plasmon resonance displayed strong binding to PIP(2). Neutralization of positively charged amino acids abolished EGFR/PIP(2) interaction in the context of this peptide and down-regulated epidermal growth factor (EGF)-induced EGFR auto-phosphorylation and EGF-induced EGFR signaling to ion channels in the context of the full-length receptor. These results suggest that EGFR activation and downstream signaling depend on interactions of EGFR with PIP(2) and point to the basic JD's critical involvement in these interactions. The addition of this very different class of membrane proteins to ion channels and transporters suggests that PIP(2) may serve as a general modulator of the activity of many diverse eukaryotic transmembrane proteins through their basic JDs.

Magnetic Resonance Imaging Tendon Integrity Assessment After Arthroscopic Partial-thickness Rotator Cuff Repair

Our goal was to assess the integrity of the repaired rotator cuff in patients with partial-thickness rotator cuff tears who underwent a technique of tear completion followed by surgical repair, using post-repair magnetic resonance imaging (MRI) at a minimum of 2 years' follow-up.

Toxicity Associated with Postoperative Radiation Therapy for Prostate Cancer

To quantify gastrointestinal (GI) and genitourinary (GU) toxicity associated with postprostatectomy radiation and to determine the relationships between dosimetry parameters and medical comorbidities and toxicity.

A Systematic Review of Locking Plate Fixation of Proximal Humerus Fractures

Technique for the fixation of two, three, and four part proximal humerus fractures has rapidly shifted towards the use of specially contoured proximal humerus locking plates. The purpose of this study is to evaluate the short to medium term functional results and common complications associated with the fixation of proximal humerus fractures with locking plates.

Re: "Radiographic Analysis of Extraocular Muscle Volumetric Changes in Thyroid-related Orbitopathy Following Orbital Decompression"

Antidepressant Exposure As a Predictor of Clinical Outcomes in the Treatment of Resistant Depression in Adolescents (TORDIA) Study

This paper examines the relationship between plasma concentration of antidepressant and both clinical response and adverse effects in treatment-resistant depressed adolescents. Adolescents (n = 334) with major depression who had not responded to a selective serotonin reuptake inhibitor (SSRI) were randomized to 1 of 4 treatments: switch to another SSRI (fluoxetine, citalopram, or paroxetine), switch to venlafaxine, switch to SSRI plus cognitive behavior therapy, or switch to venlafaxine plus cognitive behavior therapy. Adolescents who did not improve by 6 weeks had their dose increased. Plasma concentrations of medication and metabolites were measured at 6 weeks in 244 participants and at 12 weeks in 204 participants. Adolescents treated with citalopram whose plasma concentration was equal to or greater than the geometric mean (GM) showed a higher response rate compared to those with less than the GM, with parallel but nonsignificant findings for fluoxetine. A dose increase of citalopram or fluoxetine at week 6 was most likely to result in response when it led to a change in concentration from less than the GM at 6 weeks to the GM or greater at week 12. Plasma levels of paroxetine, venlafaxine, or O-desmethylvenlafaxine were not related to clinical response. Exposure was associated with more cardiovascular and dermatologic side effects in those receiving venlafaxine. Antidepressant concentration may be useful in optimizing treatment for depressed adolescents receiving fluoxetine or citalopram.

Community Treatment of Posttraumatic Stress Disorder for Children Exposed to Intimate Partner Violence: a Randomized Controlled Trial

To evaluate community-provided trauma-focused cognitive behavior therapy (TF-CBT) compared with usual community treatment for children with intimate partner violence (IPV)-related posttraumatic stress disorder (PTSD) symptoms.

Embryonic Vasculogenesis in Nodular Melanomas and Tumour Differentiation

The relationship of vasculogenic mimicry to pigment in nodular vertical growth phase [VGP] cutaneous melanomas is assessed in this study. 10 nodules each from 27 tumors, 15 pigmented and 12 amelanotic were sampled in proportion to the pigment level. Serial frozen and paraffin sections subjected to HE, Reticulin, PAS to assess the vascular pattern; Dopa Oxidase and Immunopositivity for HMB45, LN5 [laminin 5] & integrin[α(5)β(1)], and EM [electron microscopy] to identify Weibel-Palade bodies within endothelial cells. The vascular pattern, pigment and the immunopositivity was mapped to assess the percentage VM [vasculogenic sinusoids] vs INC [incorporated microvasculature]. In pigmented melanomas, INC from pre-existing stromal vessels is predominant. Amelanotic melanomas show embryonic vasculogenic mimicry, a self-propagating system of spaces within the sheets of tumors cells. Both INC and VM co-exist in tumors with both amelanotic and melanotic nodules. In areas with VM, loci of LN5 and α(5)β(1) integrin positive cells appear within the proliferating columns, positivity in these cells suggesting a switch to a more aggressive form. Irregular spaces appear lined by tumor cells, with initial hemopoeitic activity, coalesce and interlink into tubular networks. Spaces lined by tumor cells extend into an intricate network which then connects with the angiogenetic system. The tumor cells lining the vasculogenic spaces are positive for LN5, α(5)β(1) integrin. Statistically, INC is significantly higher in pigmented melanomas, whereas amelanotic melanomas show significantly higher VM. Pigmentation is correlated positively with INC and negatively with VM. INC and VM are negatively correlated with each other.

Passive and Active Shaping of Unitary Responses from Associational/commissural and Perforant Path Synapses in Hippocampal CA3 Pyramidal Cells

Although associational/commissural (A/C) and perforant path (PP) inputs to CA3b pyramidal cells play a central role in hippocampal mnemonic functions, the active and passive processes that shape A/C and PP AMPA and NMDA receptor-mediated unitary EPSP/EPSC (AMPA and NMDA uEPSP/uEPSC) have not been fully characterized yet. Here we find no differences in somatic amplitude between A/C and PP for either AMPA or NMDA uEPSPs. However, larger AMPA uEPSCs were evoked from proximal than from distal A/C or PP. Given the space-clamp constraints in CA3 pyramidal cells, these voltage clamp data suggest that the location-independence of A/C and PP AMPA uEPSP amplitudes is achieved in part through the activation of voltage dependent conductances at or near the soma. Moreover, similarity in uEPSC amplitudes for distal A/C and PP points to the additional participation of unclamped active conductances. Indeed, the pharmacological blockade of voltage-dependent conductances eliminates the location-independence of these inputs. In contrast, the location-independence of A/C and PP NMDA uEPSP/uEPSC amplitudes is maintained across all conditions indicating that propagation is not affected by active membrane processes. The location-independence for A/C uEPSP amplitudes may be relevant in the recruitment of CA3 pyramidal cells by other CA3 pyramidal cells. These data also suggest that PP excitation represents a significant input to CA3 pyramidal cells. Implication of the passive data on local synaptic properties is further investigated in the companion paper with a detailed computational model.

Long-term Outcome of Adolescent Depression Initially Resistant to Selective Serotonin Reuptake Inhibitor Treatment: a Follow-up Study of the TORDIA Sample

We examined the long-term outcome of participants in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study, a randomized trial of 334 adolescents (aged 12-18 years) with DSM-IV-defined major depressive disorder initially resistant to selective serotonin reuptake inhibitor (SSRI) treatment who were subsequently treated for 12 weeks with another SSRI, venlafaxine, another SSRI + cognitive-behavioral therapy (CBT), or venlafaxine + CBT. Responders then continued with the same treatment through week 24, while nonresponders were given open treatment.

EZH2 Y641 Mutations in Follicular Lymphoma

Utility of the APACHE IV, PPI, and Combined APACHE IV with PPI for Predicting Overall and Disease-specific ICU and ACU Mortality

The Acute Physiology and Chronic Health Evaluation (APACHE) IV and Palliative Performance Index (PPI) are scales commonly used to assess prognosis in intensive care units (ICUs) and acute care units (ACUs).

Performance Factors of Mobile Rich Media Job Aids for Community Health Workers

To study and analyze the possible benefits on performance of community health workers using point-of-care clinical guidelines implemented as interactive rich media job aids on small-format mobile platforms.

Signaling Network Triggers and Membrane Physical Properties Control the Actin Cytoskeleton-driven Isotropic Phase of Cell Spreading

Cell spreading is regulated by signaling from the integrin receptors that activate intracellular signaling pathways to control actin filament regulatory proteins. We developed a hybrid model of whole-cell spreading in which we modeled the integrin signaling network as ordinary differential equations in multiple compartments, and cell spreading as a three-dimensional stochastic model. The computed activity of the signaling network, represented as time-dependent activity levels of the actin filament regulatory proteins, is used to drive the filament dynamics. We analyzed the hybrid model to understand the role of signaling during the isotropic phase of fibroblasts spreading on fibronectin-coated surfaces. Simulations showed that the isotropic phase of spreading depends on integrin signaling to initiate spreading but not to maintain the spreading dynamics. Simulations predicted that signal flow in the absence of Cdc42 or WASP would reduce the spreading rate but would not affect the shape evolution of the spreading cell. These predictions were verified experimentally. Computational analyses showed that the rate of spreading and the evolution of cell shape are largely controlled by the membrane surface load and membrane bending rigidity, and changing information flow through the integrin signaling network has little effect. Overall, the plasma membrane acts as a damper such that only ∼5% of the actin dynamics capability is needed for isotropic spreading. Thus, the biophysical properties of the plasma membrane can condense varying levels of signaling network activities into a single cohesive macroscopic cellular behavior.

Impact of Physical and Sexual Abuse on Treatment Response in the Treatment of Resistant Depression in Adolescent Study (TORDIA)

We previously reported that a history of abuse was associated with a poorer response to combination treatment in the Treatment of Resistant Depression in Adolescents study (TORDIA). We now report on the nature and correlates of abuse that might explain these findings.

Multistage Ab Initio Quantum Wavepacket Dynamics for Electronic Structure and Dynamics in Open Systems: Momentum Representation, Coupled Electron-nuclear Dynamics, and External Fields

We recently proposed a multistage ab initio wavepacket dynamics (MS-AIWD) treatment for the study of delocalized electronic systems as well as electron transport through donor-bridge-acceptor systems such as those found in molecular-wire/electrode networks. In this method, the full donor-bridge-acceptor open system is treated through a rigorous partitioning scheme that utilizes judiciously placed offsetting absorbing and emitting boundary conditions. In this manner, the electronic coupling between the bridge molecule and surrounding electrodes is accounted. Here, we extend MS-AIWD to include the dynamics of open-electronic systems in conjunction with (a) simultaneous treatment of nuclear dynamics and (b) external electromagnetic fields. This generalization is benchmarked through an analysis of wavepackets propagated on a potential modeled on an Al(27) - C(7) - Al(27) nanowire. The wavepacket results are inspected in the momentum representation and the dependence of momentum of the wavepacket as well as its transmission probabilities on the magnitude of external bias are analyzed.

Functional Analysis of KAP1 Genomic Recruitment

TRIM28 (KAP1) is upregulated in many cancers and has been implicated in both transcriptional activation and repression. Using chromatin immunoprecipitation and sequencing, we show that KAP1 binding sites fall into several categories, specifically, the 3' coding exons of zinc finger (ZNF) genes and promoter regions of ZNFs and other genes. The currently accepted model is that KAP1 is recruited to the genome via interaction of its N-terminal RBCC domain with KRAB ZNFs (KRAB domain containing ZNFs). To determine whether the interaction of KAP1 with KRAB ZNFs is the mechanism by which KAP1 is recruited to genomic binding sites, we analyzed stable cell lines that express tagged wild-type and mutant KAP1. Surprisingly, deletion of the RBCC domain abolished KAP1 binding to the 3' exons of ZNF genes but KAP1 binding to promoter regions was unaffected. Using KAP1 knockdown cells, we showed that the genes most responsive to KAP1 were not ZNF genes but instead were either indirect targets or had KAP1 bound 10 to 100 kb from the transcription start site. Therefore, our studies suggest that KAP1 plays a role distinct from transcriptional regulation at the majority of its strongest binding sites.

Characterization of the Contradictory Chromatin Signatures at the 3' Exons of Zinc Finger Genes

The H3K9me3 histone modification is often found at promoter regions, where it functions to repress transcription. However, we have previously shown that 3' exons of zinc finger genes (ZNFs) are marked by high levels of H3K9me3. We have now further investigated this unusual location for H3K9me3 in ZNF genes. Neither bioinformatic nor experimental approaches support the hypothesis that the 3' exons of ZNFs are promoters. We further characterized the histone modifications at the 3' ZNF exons and found that these regions also contain H3K36me3, a mark of transcriptional elongation. A genome-wide analysis of ChIP-seq data revealed that ZNFs constitute the majority of genes that have high levels of both H3K9me3 and H3K36me3. These results suggested the possibility that the ZNF genes may be imprinted, with one allele transcribed and one allele repressed. To test the hypothesis that the contradictory modifications are due to imprinting, we used a SNP analysis of RNA-seq data to demonstrate that both alleles of certain ZNF genes having H3K9me3 and H3K36me3 are transcribed. We next analyzed isolated ZNF 3' exons using stably integrated episomes. We found that although the H3K36me3 mark was lost when the 3' ZNF exon was removed from its natural genomic location, the isolated ZNF 3' exons retained the H3K9me3 mark. Thus, the H3K9me3 mark at ZNF 3' exons does not impede transcription and it is regulated independently of the H3K36me3 mark. Finally, we demonstrate a strong relationship between the number of tandemly repeated domains in the 3' exons and the H3K9me3 mark. We suggest that the H3K9me3 at ZNF 3' exons may function to protect the genome from inappropriate recombination rather than to regulate transcription.

Accuracy of Liver Function Tests for Predicting Adverse Maternal and Fetal Outcomes in Women with Preeclampsia: a Systematic Review

Liver function tests are routinely performed in women as part of a battery of investigations to assess severity at admission and later to guide appropriate management.

Evaluation and Management of Proximal Humerus Fractures

Fractures of the proximal humerus occur frequently, and are primarily insufficiency fractures that occur in the elderly. Thorough clinical evaluation is essential in identifying associated neurovascular injury, which warrants emergent surgical referral. Good quality radiographs remain a necessary diagnostic tool in the evaluation of proximal humerus injuries. An appreciation of the relevant anatomy and predictable patterns of deformation aid in understanding the basic classification of proximal humerus fractures. Most of these fractures are minimally displaced and can be treated nonoperatively with acceptable clinical outcomes. Familiarity with the basic surgical treatment modalities is helpful to physicians involved in the pre- and postoperative management. Significantly displaced proximal humerus fractures are typically treated with surgical reduction and internal fixation. Complex fractures in the elderly and fracture dislocations are indications for humeral head prosthetic replacement. Proximal humerus fractures are strongly associated with decreased bone mineral density and future fracture risk, and should prompt a referral for medical management of osteoporosis.

Should We Always Plan a Fontan Completion After a Kawashima Procedure?

To determine the late incidence of pulmonary arteriovenous malformations after bidirectional Glenn in patients with azygos continuation of the inferior vena cava (Kawashima operation).

Incremental Cost-effectiveness of Combined Therapy Vs Medication Only for Youth with Selective Serotonin Reuptake Inhibitor-resistant Depression: Treatment of SSRI-resistant Depression in Adolescents Trial Findings

Many youth with depression do not respond to initial treatment with selective serotonin reuptake inhibitors (SSRIs), and this is associated with higher costs. More effective treatment for these youth may be cost-effective.

MEDRank: Using Graph-based Concept Ranking to Index Biomedical Texts

As the volume of biomedical text increases exponentially, automatic indexing becomes increasingly important. However, existing approaches do not distinguish central (or core) concepts from concepts that were mentioned in passing. We focus on the problem of indexing MEDLINE records, a process that is currently performed by highly trained humans at the National Library of Medicine (NLM). NLM indexers are assisted by a system called the Medical Text Indexer (MTI) that suggests candidate indexing terms.

Identification of Serines 201 and 209 As Sites of Pax3 Phosphorylation and the Altered Phosphorylation Status of Pax3-FOXO1 During Early Myogenic Differentiation

Pax3, a member of the paired class homeodomain family of transcription factors, is essential for early skeletal muscle development and is key in the development of the childhood solid muscle tumor alveolar rhabdomyosarcoma (ARMS). ARMS is primarily characterized by a t(2;13)(q35;q14) chromosomal translocation, which fuses the 5'-coding sequences of Pax3 with the 3'-coding sequence of the forkhead transcription factor FOXO1 generating the oncogenic fusion protein Pax3-FOXO1. We previously demonstrated that Pax3 and Pax3-FOXO1 are phosphorylated by the protein kinase CK2 at serine 205 in proliferating primary myoblasts and that this phosphorylation event is rapidly lost from Pax3, but not Pax3-FOXO1 upon the induction of differentiation. However, reports suggested that additional sites of phosphorylation might be present on Pax3. In this report we use in vitro and in vivo analyses to identify serines 201 and 209 as additional sites of phosphorylation and along with serine 205 are the only sites of phosphorylation on Pax3. We provide solid evidence supporting the role of the protein kinase GSK3β as phosphorylating Pax3 at serine 201. Using phospho-specific antibodies we demonstrate a changing pattern of phosphorylation at serines 201, 205, and 209 throughout early myogenic differentiation and that this pattern of phosphorylation is different for Pax3-FOXO1 in primary myoblasts and in several ARMS cell lines. Taken together, our results allow us to propose a molecular model to describe the changing pattern of phosphorylation for Pax3 and the altered phosphorylation for Pax3-FOXO1 during early myogenic differentiation.

Genomewide Linkage Scan for Diabetic Renal Failure and Albuminuria: the FIND Study

Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals.

Photon Counting, Censor Corrections, and Lifetime Imaging for Improved Detection in Two-photon Microscopy

We present a high-speed photon counter for use with two-photon microscopy. Counting pulses of photocurrent, as opposed to analog integration, maximizes the signal-to-noise ratio so long as the uncertainty in the count does not exceed the gain-noise of the photodetector. Our system extends this improvement through an estimate of the count that corrects for the censored period after detection of an emission event. The same system can be rapidly reconfigured in software for fluorescence lifetime imaging, which we illustrate by distinguishing between two spectrally similar fluorophores in an in vivo model of microstroke.

A Procedural Framework for Good Imaging Practice in Pharmacological FMRI Studies Applied to Drug Development #2: Protocol Optimization and Best Practices

Functional magnetic resonance imaging (fMRI) experiments are more complex compared with standard radiological imaging, involving additional data streams and hardware along with complex analysis methods. Here, we propose guidelines based around mitigating risks associated with the complexities of the technique at the level of the individual imaging protocol, including workable and effective quality assurance/quality control procedures and rigorous, predefined, analysis pipelines. Our aim is to provide a framework for 'good imaging practice' (GIP), enabling these requirements to be addressed at an appropriate level of detail. The development of a procedural framework for GIP in pharmaceutical fMRI studies could lead to greater acceptance of the method within industry and facilitate validation and, eventually, qualification of the technique as an imaging biomarker.

Quantum Wavepacket Ab Initio Molecular Dynamics for Extended Systems

In this paper, we introduce a symmetry-adapted quantum nuclear propagation technique that utilizes distributed approximating functionals for quantum wavepacket dynamics in extended condensed-phase systems. The approach is developed with a goal for implementation in quantum-classical methods such as the recently developed quantum wavepacket ab intio molecular dynamics (QWAIMD) to facilitate the study of extended systems. The method has been numerically benchmarked for extended electronic systems as well as protonic conducting systems that benefit from quantum nuclear treatment. Vibrational properties are computed for the case of the protonic systems through use of a novel velocity-flux correlation function. The treatment is found to be numerically accurate and efficient.

Irreducible Shoulder Dislocation - a Word of Caution

Anterior dislocation of shoulder is usually amenable to closed manipulation. Failure to achieve satisfactory reduction can be due to soft tissue or osseous interposition. We report a case of irreducible anterior shoulder dislocation with the interposition of the musculocutaneous nerve. This required open reduction and release of the musculocutaneous nerve; which was found to be further trapped by the torn long head of biceps.

Design of a Smart Biomarker for Bioremediation: a Machine Learning Approach

Many trace elements (TE) occur naturally in marine environments and accomplish decisive functions in humans to maintain good health. Mytilus galloprovincialis (MG) is a rich source of TE, but since it is grown near industrial outfalls, they become polluted with elevated levels of TE concentration and serve as biomarkers of pollution. As bioremediation is increasingly reliant on machine learning data processing techniques, we propose the information theoretic concept of using MG for bioremediation. The in situ bioremediation in MG is accomplished by reduction in concentration of TE by the technique of determinant inequalities and the maximization of Mutual Information (MI) without adding any chemical element externally. We bring out the superiority of our technique of MI over that of Principal Component Analysis (PCA) in predicting lower concentration for bioremediation of Cd and Pb in MG.

Pediatric Functional Magnetic Resonance Neuroimaging: Tactics for Encouraging Task Compliance

Neuroimaging technology has afforded advances in our understanding of normal and pathological brain function and development in children and adolescents. However, noncompliance involving the inability to remain in the magnetic resonance imaging (MRI) scanner to complete tasks is one common and significant problem. Task noncompliance is an especially significant problem in pediatric functional magnetic resonance imaging (fMRI) research because increases in noncompliance produces a greater risk that a study sample will not be representative of the study population.

Imaging in Prostate Cancer

Prostate cancer is the most common malignancy in men, in general. Most patients diagnosed with prostate cancer have localized disease confined to the prostate. A small percentage of patients with aggressive tumors will progress to develop local, extracapsular tumor extension and distant metastases. The aim of prostate cancer management is to identify and treat those patients with aggressive disease before they develop locally advanced or metastatic disease, and to avoid overtreating indolent tumors, which are unlikely to be life threatening. Imaging has been shown to be valuable in local staging of prostate cancer and as an aid to the management of clinically significant disease. In this article, we discuss the different established imaging modalities and emerging techniques for prostate cancer imaging in patients with clinically localized disease who may be suitable for radical treatment.

Development of Internal Amplification Controls for DNA Profiling with the AmpFℓSTR(®) SGM Plus(®) Kit

DNA extracted from forensic samples can be degraded and also contain co-extracted contaminants that inhibit PCR. The effects of DNA degradation and PCR inhibition are often indistinguishable when examining a DNA profile. Two internal amplification controls (IACs) were developed to improve quality control of PCR using the AmpFℓSTR® SGM Plus® kit. The co-amplification of these controls with DNA samples was used to monitor amplification efficiency and detect PCR inhibitors. IAC fragments of 90 and 410 bp (IAC₉₀ and IAC₄₁₀) were generated from the plasmid pBR322 using tailed primers and then amplified with ROX-labelled primers. Co-amplification of IAC₉₀ and IAC₄₁₀ was performed with varying amounts of template DNA, degraded DNA and DNA contaminated with humic acid, heme and indigo dye. Both IAC₉₀ and IAC₄₁₀ were successfully amplified with human DNA without significantly affecting the quality of the DNA profile, even with DNA amounts lower than 0.5 ng. In the presence of inhibitors, the IAC₉₀ signal was still present after all human DNA loci fail to amplify; in contrast, the IAC₄₁₀ signal was reduced or absent at low levels of inhibition. Amplification of the two IACs provided an internal PCR control and allowed partial profiles caused by inhibition to be distinguished from degraded DNA profiles.

Identification of New Gβγ Interaction Sites in Adenylyl Cyclase 2

The role of Gβγ in adenylyl cyclase (AC) signaling is complicated due to its role as a conditional activator (AC2, AC4 and AC7) and an inhibitor (AC1, AC3 and AC8). AC2 is stimulated by Gα(s) and if Gβγ is present the stimulation is synergistic. The precise mechanism of this synergistic activation is still not known. In order to further elucidate the role of Gβγ in AC2 activation by Gα(s), peptides derived from the C1 domains of AC2 were synthesized and the ability of the various peptides to regulate AC2 function was tested. Our results identify two new Gβγ-binding sites in the AC2 C1 domain, AC2 C1a 339-360 and AC2 C1b 578-602 that are involved with stimulation of AC2 by Gβγ. These two regions are different from the previously described QEHA motif in the C2 domain of AC2. Further, the recently discovered PFAHL motif was confirmed to bind and to be involved with stimulation of AC2 by Gβγ. These functional studies indicate that multiple regions of AC2 are involved in the interaction with Gβγ.

Characteristics of a Subset of Patients with Reversible Systolic Dysfunction in Chronic Kidney Disease

There exists a subgroup of uremic cardiomyopathy patients who experience resolution of heart failure symptoms with recovery of normal cardiac geometry following hemodialysis. The authors studied 52 patients with chronic kidney disease on hemodialysis over a period of 190 days. There were 29 patients with systolic dysfunction (left ventricular ejection fraction <40%). Twenty-three patients with preserved systolic function had diastolic dysfunction. Of the 29 patients with systolic dysfunction, 10 patients had significant improvement in New York Heart Association functional class and left ventricular internal diameter in diastole (LVIDd: 59.8 ± 2.6-55.92 mm and left ventricular internal diameter in systole [LVIDs]: 51.8 ± 1.8-34 ± 1.2 mm; P < .001) with significant increases in left ventricular ejection fraction (30.55%-50.14%; P < .001). These patients had the highest baseline serum levels of troponin I (P = .024), which decreased significantly with recovery of cardiac function. When the entire study group was regrouped as those below and those above the median change of C-reactive protein (CRP), patients with CRP greater than the median change had significant improvements in LVIDs and ejection fraction. A subgroup of patients with uremic cardiomyopathy who demonstrated reversible left ventricular systolic dysfunction had high levels of serum troponin I levels at presentation, which regressed with recovery of ventricular function in parallel with CRP levels.

A Unique Deep Inferior Epigastric Artery Perforator and Implications for a Muscle and Fascia Sparing Vertical Rectus Abdominis Myocutaneous Flap: a Case Report

Despite the sacrifice of rectus abdominis muscle, the vertical rectus abdominis musculocutaneous (VRAM) flap is still a preferred option for perineal reconstruction. This journal has previously reported on the utility of preoperative computed tomographic angiography (CTA) in this setting to identify cases that are both suitable and unsuitable for rectus abdominis flaps after previous surgery. We report a case which highlights a unique example of the benefits of such imaging, with the largest deep inferior epigastric artery (DIEA) perforator described to date identified on imaging, and used to potentiate a donor-site sparing procedure. The use of this dominant perforator was able to limit donor site harvest to only a small cuff of anterior rectus sheath and a small segment of rectus abdominis, potentiating a muscle-sparing and fascia-sparing VRAM flap for perineal reconstruction. As such, preoperative CTA was found to be a useful tool in identifying a unique anatomical variant in the largest DIEA perforator described to date, and was used to potentiate a muscle-sparing and fascia-sparing VRAM flap for perineal reconstruction.

A Procedural Framework for Good Imaging Practice in Pharmacological FMRI Studies Applied to Drug Development #1: Processes and Requirements

There is increasing interest in the application of quantitative magnetic resonance imaging (MRI) methods to drug development, but as yet little standardization or best practice guidelines for its use in this context. Pharmaceutical trials are subject to regulatory constraints and sponsor company processes, including site qualification and expectations around study oversight, blinding, quality assurance and quality control (QA/QC), analysis and reporting of results. In this article, we review the processes on the sponsor side and also the procedures involved in data acquisition at the imaging site. We then propose summary recommendations to help guide appropriate imaging site qualification, as part of a framework of 'good imaging practice' for functional (f)MRI studies applied to drug development.

KAP1 Protein: an Enigmatic Master Regulator of the Genome

In mammalian cells, multiple cellular processes, including gene silencing, cell growth and differentiation, pluripotency, neoplastic transformation, apoptosis, DNA repair, and maintenance of genomic integrity, converge on the evolutionarily conserved protein KAP1, which is thought to regulate the dynamic organization of chromatin structure via its ability to influence epigenetic patterns and chromatin compaction. In this minireview, we discuss how KAP1 might execute such pleiotropic effects, focusing on genomic targeting mechanisms, protein-protein interactions, specific post-translational modifications of both KAP1 and associated histones, and transcriptome analyses of cells deficient in KAP1.

Nonoperative Treatment of Proximal Humerus Fractures: a Systematic Review

Proximal humerus fractures are common in the setting of osteopenia and osteoporosis and can often be treated nonoperatively. There are few studies that evaluate the long-term outcomes of nonoperative treatment of these fractures. We performed a systematic review of the literature to examine the results of nonoperative treatment of proximal humerus fractures.

Laser-textured Silicon Photodiode with Broadband Spectral Response

A femtosecond-laser-textured Si photodetector is reported. Broadband spectral optical response is detected from UV to NIR. A quantum efficiency of greater than 80% from 490  nm to 780  nm has been achieved. The quantum efficiency at 245  nm is 62%, which is comparable to UV-enhanced Si photodiodes. The bandwidth of a 250-μm-diameter device is 60  MHz.

Computational Approaches for Translational Clinical Research in Disease Progression

Today, there is an ever-increasing amount of biological and clinical data available that could be used to enhance a systems-based understanding of disease progression through innovative computational analysis. In this article, we review a selection of published research regarding computational methods, primarily from systems biology, which support translational research from the molecular level to the bedside, with a focus on applications in trauma and critical care. Trauma is the leading cause of mortality in Americans younger than 45 years, and its rapid progression offers both opportunities and challenges for computational analysis of trends in molecular patterns associated with outcomes and therapeutic interventions.This review presents methods and domain-specific examples that may inspire the development of new algorithms and computational methods that use both molecular and clinical data for diagnosis, prognosis, and therapy in disease progression.

Epidemiology of Sudden Cardiac Death in Rural South India - Insights from the Andhra Pradesh Rural Health Initiative

Sudden cardiac death (SCD) is a common initial presentation of coronary artery disease (CAD). Despite the growing epidemic of CAD in India, the epidemiology of SCD is largely unknown.

Classical and Neonatal Marfan Syndrome Mutations in Fibrillin-1 Cause Differential Protease Susceptibilities and Protein Function

Mutations in fibrillin-1 give rise to Marfan syndrome (MFS) characterized by vascular, skeletal, and ocular abnormalities. Fibrillins form the backbone of extracellular matrix microfibrils in tissues including blood vessels, bone, and skin. They are crucial for regulating elastic fiber biogenesis and growth factor bioavailability. To compare the molecular consequences of mutations causing the severe neonatal MFS with mutations causing the milder classical MFS, we introduced representative point mutations from each group in a recombinant human fibrillin-1 fragment. Structural effects were analyzed by circular dichroism spectroscopy and analytical gel filtration chromatography. Proteolytic susceptibility was probed with non-physiological and physiological proteases, including plasmin, thrombin, matrix metalloproteinases, and cathepsins. All mutant proteins showed a similar gross secondary structure and no differences in heat stability as compared with the wild-type protein. Proteins harboring neonatal mutations were typically more susceptible to proteolytic cleavage compared with those with classical mutations and the wild-type protein. Proteolytic neo-cleavage sites were found both in close proximity and distant to the mutations, indicating small but significant structural changes exposing cryptic cleavage sites. We also report for the first time that cathepsin K and V cleave non-mutated fibrillin-1 at several domain boundaries. Compared with the classical mutations and the wild type, the group of neonatal mutations more severely affected the ability of fibrillin-1 to interact with heparin/heparan sulfate, which plays a role in microfibril assembly. These results suggest differential molecular pathogenetic concepts for neonatal and classical MFS including enhanced proteolytic susceptibility for physiologically relevant enzymes and loss of function for heparin binding.

Recombination-mediated Changes in Coreceptor Usage Confer an Augmented Pathogenic Phenotype in a Nonhuman Primate Model of HIV-1-induced AIDS

Evolution of the env gene in transmitted R5-tropic human immunodeficiency virus type 1 (HIV-1) strains is the most widely accepted mechanism driving coreceptor switching. In some infected individuals, however, a shift in coreceptor utilization can occur as a result of the reemergence of a cotransmitted, but rapidly controlled, X4 virus. The latter possibility was studied by dually infecting rhesus macaques with X4 and R5 chimeric simian simian/human immunodeficiency viruses (SHIVs) and monitoring the replication status of each virus using specific primer pairs. In one of the infected monkeys, both SHIVs were potently suppressed by week 12 postinoculation, but a burst of viremia at week 51 was accompanied by an unrelenting loss of total CD4+ T cells and the development of clinical disease. PCR analyses of plasma viral RNA indicated an env gene segment containing the V3 region from the inoculated X4 SHIV had been transferred into the genetic background of the input R5 SHIV by intergenomic recombination, creating an X4 virus with novel replicative, serological, and pathogenic properties. These results indicate that the effects of retrovirus recombination in vivo can be functionally profound and may even occur when one of the recombination participants is undetectable in the circulation as cell-free virus.

Risk for Suicidal Ideation Among the Offspring of Bipolar Parents: Results from the Bipolar Offspring Study (BIOS)

The objective of the study was to examine rates and identify risk factors for suicidal ideation among offspring of parents with bipolar disorder. Subjects included 388 offspring of parents with bipolar disorder and 250 offspring of matched community controls enrolled in the Pittsburgh Bipolar Offspring Study (BIOS). Offspring of bipolar probands displayed greater rates of lifetime suicidal ideation than offspring of controls (33% versus 20%). Factors most strongly associated with lifetime suicidal ideation in offspring of bipolar parents included offspring mood disorder, hostility, recent sexual abuse, and family conflict. Offspring of parents with bipolar disorder are at elevated risk for suicidal ideation as compared with offspring of controls. Suicide risk assessment in this population should attend to specific risk factors identified.

Imaging Drugs with and Without Clinical Analgesic Efficacy

The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy for pain. The pharmacological/functional magnetic resonance imaging (phMRI/fMRI) methodology can be used to objectively evaluate drug action on the CNS. In this context, we aimed to evaluate two drugs that had been developed as analgesics: one that is efficacious for pain (buprenorphine (BUP)) and one that failed as an analgesic in clinical trials aprepitant (APREP). Using phMRI, we observed that activation induced solely by BUP was present in regions with μ-opioid receptors, whereas APREP-induced activation was seen in regions expressing NK(1) receptors. However, significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration. By implementing an evoked pain fMRI paradigm, these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain. We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration. This investigation demonstrates how CNS-acting drugs can be compared, and how the phMRI/fMRI methodology may be used with conventional measures to better evaluate candidate analgesics in small subject cohorts.

Focal Adhesion Kinase-related Nonkinase Inhibits Vascular Smooth Muscle Cell Invasion by Focal Adhesion Targeting, Tyrosine 168 Phosphorylation, and Competition for P130(Cas) Binding

Focal adhesion kinase-related nonkinase (FRNK), the C-terminal domain of focal adhesion kinase (FAK), is a tyrosine-phosphorylated, vascular smooth muscle cell (VSMC)-specific inhibitor of cell migration. FRNK inhibits both FAK and proline-rich tyrosine kinase 2 (PYK2) in cultured VSMCs, and both kinases may be involved in VSMC invasion during vascular remodeling.

Hsp90-Cdc37 Chaperone Complex Regulates Ulk1- and Atg13-mediated Mitophagy

Autophagy, the primary recycling pathway of cells, plays a critical role in mitochondrial quality control under normal growth conditions and in the response to cellular stress. The Hsp90-Cdc37 chaperone complex coordinately regulates the activity of select kinases to orchestrate many facets of the stress response. Although both maintain mitochondrial integrity, the relationship between Hsp90-Cdc37 and autophagy has not been well characterized. Ulk1, one of the mammalian homologs of yeast Atg1, is a serine-threonine kinase required for mitophagy. Here we show that the interaction between Ulk1 and Hsp90-Cdc37 stabilizes and activates Ulk1, which in turn is required for the phosphorylation and release of Atg13 from Ulk1, and for the recruitment of Atg13 to damaged mitochondria. Hsp90-Cdc37, Ulk1, and Atg13 phosphorylation are all required for efficient mitochondrial clearance. These findings establish a direct pathway that integrates Ulk1- and Atg13-directed mitophagy with the stress response coordinated by Hsp90 and Cdc37.

Preterm Delivery Disrupts the Developmental Program of the Cerebellum

A rapid growth in human cerebellar development occurs in the third trimester, which is impeded by preterm delivery. The goal of this study was to characterize the impact of preterm delivery on the developmental program of the human cerebellum. Still born infants, which meant that all development up to that age had taken place in-utero, were age paired with preterm delivery infants, who had survived in an ex-utero environment, which meant that their development had also taken place outside the uterus. The two groups were assessed on quantitative measures that included molecular markers of granule neuron, purkinje neuron and bergmann glia differentiation, as well as the expression of the sonic hedgehog signaling pathway, that is important for cerebellar growth. We report that premature birth and development in an ex-utero environment leads to a significant decrease in the thickness and an increase in the packing density of the cells within the external granular layer and the inner granular layer well, as a reduction in the density of bergmann glial fibres. In addition, this also leads to a reduced expression of sonic hedgehog in the purkinje layer. We conclude that the developmental program of the cerebellum is specifically modified by events that follow preterm delivery.

Candidate Gene Association Study for Diabetic Retinopathy in Persons with Type 2 Diabetes: the Candidate Gene Association Resource (CARe)

To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).

Urinary Indices During Relapse of Childhood Nephrotic Syndrome

Sodium retention is the hallmark of idiopathic nephrotic syndrome (INS). Sodium retention could be secondary to activation of renin-angiotensin-aldosterone axis or due to an intrinsic activation of Na(+)K(+) ATPase in the cortical collecting duct. Urine potassium/urine potassium + urine sodium (UK(+)/UK(+) + UNa(+)) is a surrogate marker for aldosterone activity and can be useful in differentiating primary sodium retention from secondary sodium retention in children with INS. This was a cross-sectional study of children with INS, presenting to our center from June 2007 to June 2008. Children were categorized into those with steroid responsive and steroid nonresponsive nephrotic syndrome. One hundred and thirty-four children with nephrotic syndrome were analyzed. The FeNa(+) was significantly lower during relapse than in remission but no such difference was observed with UK(+)/UK(+) + UNa(+). The values of FeNa(+) and UK(+)/UK(+) + UNa(+) across various categories of nephrotic syndrome were similar. Correlating FeNa(+) and UK(+)/UK(+) + UNa(+) with cut-off of 0.5 and 60%, respectively, we found 50% of steroid responsive children and 36% of steroid nonresponders having a corresponding UK(+)/UK(+) + UNa(+) of <60% along with low FeNa(+) of <0.5%, favoring primary sodium retention. Urinary indices did not vary with the type of steroid response. In early relapse, the urinary indices revealed an overlap of both primary and secondary sodium retention in most stable edematous children with nephrotic syndrome.

Optimizing Medical Resources for Spaceflight Using the Integrated Medical Model

Efficient allocation of medical resources for spaceflight is important for crew health. The Integrated Medical Model (IMM) was developed to estimate medical event occurrences, mitigation, and resource requirements. An optimization module was created for IMM that uses a systematic process of elimination and preservation to maximize crew health outcomes subject to resource constraints.

Silencing Synaptic Communication Between Random Interneurons During Drosophila Larval Locomotion

Genetic manipulation of individual neurons provides a powerful approach toward understanding their contribution to stereotypic behaviors. We describe and evaluate a method for identifying candidate interneurons and associated neuropile compartments that mediate Drosophila larval locomotion. We created Drosophila larvae that express green fluorescent protein (GFP) and a shibire(ts1) (shi(ts1)) transgene (a temperature-sensitive neuronal silencer) in small numbers of randomly selected cholinergic neurons. These larvae were screened for aberrant behavior at an elevated temperature (31-32°C). Among larvae with abnormal locomotion or sensory-motor responses, some had very small numbers of GFP-labeled temperature-sensitive interneurons. Labeled ascending interneurons projecting from the abdominal ganglia to specific brain neuropile compartments emerged as candidates for mediation of larval locomotion. Random targeting of small sets of neurons for functional evaluation, together with anatomical mapping of their processes, provides a tool for identifying the regions of the central nervous system that are required for normal locomotion. We discuss the limitations and advantages of this approach to discovery of interneurons that regulate motor behavior.

Systems Biology--biomedical Modeling

Because of the complexity inherent in biological systems, many researchers frequently rely on a combination of global analysis and computational approaches to gain insight into both (i) how interacting components can produce complex system behaviors, and (ii) how changes in conditions may alter these behaviors. Because the biological details of a particular system are generally not taught along with the quantitative approaches that enable hypothesis generation and analysis of the system, we developed a course at Mount Sinai School of Medicine that introduces first-year graduate students to these computational principles and approaches. We anticipate that such approaches will apply throughout the biomedical sciences and that courses such as the one described here will become a core requirement of many graduate programs in the biological and biomedical sciences.

Evolutionary History and Identification of Conservation Units in the Giant Otter, Pteronura Brasiliensis

The giant otter, Pteronura brasiliensis, occupies a range including the major drainage basins of South America, yet the degree of structure that exists within and among populations inhabiting these drainages is unknown. We sequenced portions of the mitochondrial DNA (mtDNA) cytochrome b (612bp) and control region (383 bp) genes in order to determine patterns of genetic variation within the species. We found high levels of mtDNA haplotype diversity (h = 0.93 overall) and support for subdivision into four distinct groups of populations, representing important centers of genetic diversity and useful units for prioritizing conservation within the giant otter. We tested these results against the predictions of three hypotheses of Amazonian diversification (Pleistocene Refugia, Paleogeography, and Hydrogeology). While the phylogeographic pattern conformed to the predictions of the Refugia Hypothesis, molecular dating using a relaxed clock revealed the phylogroups diverged from one another between 1.69 and 0.84 Ma, ruling out the influence of Late Pleistocene glacial refugia. However, the role of Plio-Pleistocene climate change could not be rejected. While the molecular dating also makes the influence of geological arches according to the Paleogeography Hypothesis extremely unlikely, the recent Pliocene formation of the Fitzcarrald Arch and its effect of subsequently altering drainage pattern could not be rejected. The data presented here support the interactions of both climatic and hydrological changes resulting from geological activity in the Plio-Pleistocene, in shaping the phylogeographic structure of the giant otter.

Literacy Outcomes of Children with Early Childhood Speech Sound Disorders: Impact of Endophenotypes

To demonstrate that early childhood speech sound disorders (SSD) and later school-age reading, written expression, and spelling skills are influenced by shared endophenotypes that may be in part genetic.

Evaluation of a Tele-education Programme in Brazil

We evaluated a tele-education programme for primary care staff in Pernambuco State, Brazil. During 2008 and 2009, tele-education sessions occurred four times each week for one hour per day. The topics included public health, child and adolescent health, mental health and nursing. After each session, participants completed an evaluation questionnaire. A total of 73 municipalities and 141 health centres participated in the programme. There were 254 tele-education sessions scheduled during the 20-month study period; of these, 224 sessions were successfully performed and 30 were cancelled. We collected 3504 responses from the satisfaction survey. There was high acceptance of the programme: 97% rated it as excellent or good.

Solitary Fibrous Tumor Presenting As a Mass in the Parotid Gland

Membrane-associated RING-CH 10 (MARCH10 Protein) is a Microtubule-associated E3 Ubiquitin Ligase of the Spermatid Flagella

Spermiogenesis is a complex and dynamic process of the metamorphosis of spermatids into spermatozoa. There is a great deal that is still unknown regarding the regulatory mechanisms for the formation of the sperm flagellum. In this study, we determined that the membrane-associated RING-CH 10 (March10) gene is predominantly expressed in rat testis. We isolated two March10 isoforms encoding MARCH10a and MARCH10b, which are generated by alternative splicing. MARCH10a is a long RING finger protein, and MARCH10b is a short RING finger-less protein. Immunohistochemical staining revealed that the MARCH10 proteins are specifically expressed in elongating and elongated spermatids, and the expression is absent in epididymal spermatozoa. MARCH10 immunoreactivity was observed in the cytoplasmic lobes as well as the principal piece and annulus of the flagella. When overexpressed in COS7 cells, MARCH10a was localized along the microtubules, whereas MARCH10b was distributed throughout the cytoplasm. An in vitro microtubule cosedimentation assay showed that MARCH10a is directly associated with microtubules. An in vitro ubiquitination assay demonstrated that the RING finger domain of MARCH10a exhibits an E3 ubiquitin ligase activity along with the E2 ubiquitin-conjugating enzyme UBE2B. Moreover, MARCH10a undergoes proteasomal degradation by autoubiquitination in transfected COS7 cells, but this activity was abolished upon microtubule disassembly. These results suggest that MARCH10 is involved in spermiogenesis by regulating the formation and maintenance of the flagella in developing spermatids.

Serine-910 Phosphorylation of Focal Adhesion Kinase is Critical for Sarcomere Reorganization in Cardiomyocyte Hypertrophy

Tyrosine-phosphorylated focal adhesion kinase (FAK) is required for the hypertrophic response of cardiomyocytes to growth factors and mechanical load, but the role of FAK serine phosphorylation in this process is unknown. The aims of the present study were to characterize FAK serine phosphorylation in cultured neonatal rat ventricular myocytes (NRVM), analyse its functional significance during hypertrophic signalling, and examine its potential role in the pathogenesis of human dilated cardiomyopathy (DCM).

Course of Subthreshold Bipolar Disorder in Youth: Diagnostic Progression from Bipolar Disorder Not Otherwise Specified

To determine the rate of diagnostic conversion from an operationalized diagnosis of bipolar disorder not otherwise specified (BP-NOS) to bipolar I disorder (BP-I) or bipolar II disorder (BP-II) in youth over prospective follow-up and to identify factors associated with conversion.

Association of Polymorphisms in the Hepatocyte Growth Factor Gene Promoter with Keratoconus

Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease.

Summary of Presentations from the 11th Targeted Therapies for Lung Cancer Meeting: Radiation Oncology

A 32 Kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-related Macular Degeneration

Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N = 293) and AMD cases (White N = 4210 Indian = 134; Malay = 140) and controls (White N = 3229; Indian = 117; Malay = 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p = 8.31×10(-109)); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10(-9)) and by 15.57-fold (P = 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number.

Dimensional Psychopathology in Offspring of Parents with Bipolar Disorder

To compare the dimensional psychopathology in offspring of parents with bipolar disorder (BP) with offspring of community control parents as assessed by the Child Behavior Checklist (CBCL).

Bilateral Recurrent Wrist Flexor Tenosynovitis and Rice Body Formation in a Patient with Sero-negative Rheumatoid Arthritis: A Case Report and Review of Literature

Rice body formation has been traditionally observed in the joint and tendon sheaths of patients with tuberculosis. Few case reports exist that describe rice body formation in patients with rheumatoid arthritis. We describe a case report of bilateral recurrent wrist flexor tenosynovitis with rice body formation in a patient with sero-negative rheumatoid arthritis.

Remission After Acute Treatment in Children and Adolescents with Anxiety Disorders: Findings from the CAMS

To report on remission rates in anxious youth who participated in the Child/Adolescent Anxiety Multimodal Study (CAMS). The CAMS, a multisite clinical trial, randomized 488 children and adolescents (ages 7-17 years; 79% Caucasian; 50% female) with separation, social, and/or generalized anxiety disorder to a 12-week treatment of sertraline (SRT), cognitive behavioral therapy (CBT), their combination (COMB), or clinical management with pill placebo (PBO).

Epigenetic Modulation of MiR-122 Facilitates Human Embryonic Stem Cell Self-renewal and Hepatocellular Carcinoma Proliferation

The self-renewal capacity ascribed to hESCs is paralleled in cancer cell proliferation, suggesting that a common network of genes may facilitate the promotion of these traits. However, the molecular mechanisms that are involved in regulating the silencing of these genes as stem cells differentiate into quiescent cellular lineages remain poorly understood. Here, we show that a differentiated cell specific miR-122 exemplifies this regulatory attribute by suppressing the translation of a gene, Pkm2, which is commonly enriched in hESCs and liver cancer cells (HCCs), and facilitates self-renewal and proliferation. Through a series of gene expression analysis, we show that miR-122 expression is highly elevated in quiescent human primary hepatocytes (hPHs) but lost or attenuated in hESCs and HCCs, while an opposing expression pattern is observed for Pkm2. Depleting hESCs and HCCs of Pkm2, or overexpressing miR-122, leads to a common deficiency in self-renewal and proliferation. Likewise, during the differentiation process of hESCs into hepatocytes, a reciprocal expression pattern is observed between miR-122 and Pkm2. An examination of the genomic region upstream of miR-122 uncovered hyper-methylation in hESCs and HCCs, while the same region is de-methylated and occupied by a transcription initiating protein, RNA polymerase II (RNAPII), in hPHs. These findings indicate that one possible mechanism by which hESC self-renewal is modulated in quiescent hepatic derivatives of hESCs is through the regulatory activity of a differentiated cell-specific miR-122, and that a failure to properly turn "on" this miRNA is observed in uncontrollably proliferating HCCs.

Coverage Assessment and Target Tracking in 3D Domains

Recent advances in integrated electronic devices motivated the use of Wireless Sensor Networks (WSNs) in many applications including domain surveillance and mobile target tracking, where a number of sensors are scattered within a sensitive region to detect the presence of intruders and forward related events to some analysis center(s). Obviously, sensor deployment should guarantee an optimal event detection rate and should reduce coverage holes. Most of the coverage control approaches proposed in the literature deal with two-dimensional zones and do not develop strategies to handle coverage in three-dimensional domains, which is becoming a requirement for many applications including water monitoring, indoor surveillance, and projectile tracking. This paper proposes efficient techniques to detect coverage holes in a 3D domain using a finite set of sensors, repair the holes, and track hostile targets. To this end, we use the concepts of Voronoi tessellation, Vietoris complex, and retract by deformation. We show in particular that, through a set of iterative transformations of the Vietoris complex corresponding to the deployed sensors, the number of coverage holes can be computed with a low complexity. Mobility strategies are also proposed to repair holes by moving appropriately sensors towards the uncovered zones. The tracking objective is to set a non-uniform WSN coverage within the monitored domain to allow detecting the target(s) by the set of sensors. We show, in particular, how the proposed algorithms adapt to cope with obstacles. Simulation experiments are carried out to analyze the efficiency of the proposed models. To our knowledge, repairing and tracking is addressed for the first time in 3D spaces with different sensor coverage schemes.

The Promise of the CCD: Challenges and Opportunity for Quality Improvement and Population Health

Interoperability is a requirement of recent electronic health record (EHR) adoption incentive programs in the United States. One approved structure for clinical data exchange is the continuity of care document (CCD). While primarily designed to promote communication between providers during care transitions, coded data in the CCD can be re-used to aggregate data from different EHRs. This provides an opportunity for provider networks to measure quality and improve population health from a consolidated database. To evaluate such potential, this research collected CCDs from 14 organizations and developed a computer program to parse and aggregate them. In total, 139 CCDs were parsed yielding 680 data in the core content modules of problems, medications, allergies and results. Challenges to interoperability were catalogued and potential quality metrics evaluated based on available content. This research highlights the promise of CCDs for population health and recommends changes for future interoperability standards.

Recovering Protein-protein and Domain-domain Interactions from Aggregation of IP-MS Proteomics of Coregulator Complexes

Coregulator proteins (CoRegs) are part of multi-protein complexes that transiently assemble with transcription factors and chromatin modifiers to regulate gene expression. In this study we analyzed data from 3,290 immuno-precipitations (IP) followed by mass spectrometry (MS) applied to human cell lines aimed at identifying CoRegs complexes. Using the semi-quantitative spectral counts, we scored binary protein-protein and domain-domain associations with several equations. Unlike previous applications, our methods scored prey-prey protein-protein interactions regardless of the baits used. We also predicted domain-domain interactions underlying predicted protein-protein interactions. The quality of predicted protein-protein and domain-domain interactions was evaluated using known binary interactions from the literature, whereas one protein-protein interaction, between STRN and CTTNBP2NL, was validated experimentally; and one domain-domain interaction, between the HEAT domain of PPP2R1A and the Pkinase domain of STK25, was validated using molecular docking simulations. The scoring schemes presented here recovered known, and predicted many new, complexes, protein-protein, and domain-domain interactions. The networks that resulted from the predictions are provided as a web-based interactive application at http://maayanlab.net/HT-IP-MS-2-PPI-DDI/.

A Semi-supervised Hidden Markov Model-based Activity Monitoring System

Most existing human activity classification systems require a large training dataset to construct statistical models for each activity of interest. This may be impractical in many cases. In this paper, we proposed a semi-supervised HMM based activity monitoring system, that adapts the HMM for a specific subject from a general model in order to alleviate the requirement of a large training data set. In addition, using two triaxial accelerometers, our system not only identifies simple events such as sitting, standing and walking, but also recognizes the behavior or a more complex activity by temporally linking the events together. Experimental results demonstrate the feasibility of our proposed system.

Systems Pharmacology of Complex Diseases

Systems pharmacology approaches can be used to identify and predict drug-induced adverse events. Disease-centered networks within the human interactome allow us to predict which drugs may produce a similar pathophysiology. Such predictions can be tested in animal models.

Thrombolysis in the Era of Intervention

Thrombolysis revolutionized the treatment of acute ST - elevation myocardial infarction in the latter part of the last century and has been in use for more than two decades. Use of thrombolytic therapy is widespread owing to its safety, efficacy, ease of use, and affordability. Thrombolytic therapy has several limitations, many of which have been overcome with the adoption of percutaneous coronary intervention techniques in recent years. Primary percutaneous intervention is currently the preferred form of reperfusion therapy in the management of ST elevation myocardial infarction. However, thrombolytic therapy continues to have a role in many situations even in this era of intervention.

The Role of Non-invasive Imaging in Patients with Suspected Acute Coronary Syndrome

This article gives an overview of the role of imaging in the diagnosis and management of acute coronary syndrome.

Subtyping Children With Speech Sound Disorders by Endophenotypes

PURPOSE: The present study examined associations of 5 endophenotypes (i.e., measurable skills that are closely associated with speech sound disorders and are useful in detecting genetic influences on speech sound production), oral motor skills, phonological memory, phonological awareness, vocabulary, and speeded naming, with 3 clinical criteria for classifying speech sound disorders: severity of speech sound disorders, our previously reported clinical subtypes (speech sound disorders alone, speech sound disorders with language impairment, and childhood apraxia of speech), and the comorbid condition of reading disorders. PARTICIPANTS AND METHOD: Children with speech sound disorders and their siblings were assessed at early childhood (ages 4-7 years) on measures of the 5 endophenotypes. Severity of speech sound disorders was determined using the z score for Percent Consonants Correct-Revised (developed by Shriberg, Austin, Lewis, McSweeny, & Wilson, 1997). Analyses of variance were employed to determine how these endophenotypes differed among the clinical subtypes of speech sound disorders. RESULTS AND CONCLUSIONS: Phonological memory was related to all 3 clinical classifications of speech sound disorders. Our previous subtypes of speech sound disorders and comorbid conditions of language impairment and reading disorder were associated with phonological awareness, while severity of speech sound disorders was weakly associated with this endophenotype. Vocabulary was associated with mild versus moderate speech sound disorders, as well as comorbid conditions of language impairment and reading disorder. These 3 endophenotypes proved useful in differentiating subtypes of speech sound disorders and in validating current clinical classifications of speech sound disorders.

Efficacy of Duloxetine in Patients with Chronic Pain Conditions

The primary objective of this study is to review the efficacy of duloxetine in treating chronic pain using the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations for clinical significance across chronic pain states. These include pain intensity, patient ratings of overall improvement, physical functioning, and mental functioning. This review comprised the side-by-side analyses of 12 double-blind, placebo-controlled trials of duloxetine in patients with chronic pain (diabetic peripheral neuropathic pain, fibromyalgia, chronic pain due to osteoarthritis, and chronic low back pain). Patients received duloxetine (60 to 120 mg/day) or placebo. Average pain reduction was assessed over 3 months as the primary efficacy outcome. Other measures used were physical function and Patient Global Impression of Improvement. In 10 of the 12 studies, statistically significant greater pain reduction was observed for duloxetine- compared with placebo-treated patients. The response rates based on average pain reduction, improvement of physical function, and global impression were comparable across all 4 chronic pain states. Compared with patients on placebo, significantly more patients treated with duloxetine reported a moderately important pain reduction (≥30% reduction) in 9 of the 12 studies, a minimally important improvement in physical function in 8 of the 12 studies, and a moderately important to substantial improvement in Patient Global Impression of Improvement rating in 11 of the 12 studies. The analyses reported here show that duloxetine is efficacious in treating chronic pain as demonstrated by significant improvement in pain intensity, physical functioning, and patient ratings of overall improvement.

Meta-analysis of Genome-wide Linkage Scans for Renal Function Traits

Several genome scans have explored the linkage of chronic kidney disease phenotypes to chromosomic regions with disparate results. Genome scan meta-analysis (GSMA) is a quantitative method to synthesize linkage results from independent studies and assess their concordance.

Hypercalcemia in Extremely Low Birth Weight Neonates

Hypercalcemia is rare in neonates but may be associated with hypophosphatemia in Extremely low birth weight (ELBW) neonates who are on parenteral nutrition without adequate phosphate supplementation.

Expression of Sonic Hedgehog During Cell Proliferation in the Human Cerebellum

The regulation of cell proliferation in the external granular layer (EGL) of the developing cerebellum is important for its normal patterning. An important signal that regulates EGL cell proliferation is Sonic hedgehog (Shh). Shh is secreted by the Purkinje cells (PC) and has a mitogenic effect on the granule cell precursors of the EGL. Deregulation of Shh signaling has been associated with abnormal development, and been implicated in medulloblastomas, which are tumors that arise from the cerebellum. Given the importance of the Shh pathway in cerebellum development and disease, there has been no systematic study of its expression pattern during human cerebellum development. In this study, we describe the expression pattern of Shh, its receptor patched, smoothened, and its effectors that belong to the Gli family of transcription factors, during normal human cerebellum development from 10 weeks of gestational age, and in medulloblastomas that represents a case of abnormal cell proliferation in the cerebellum. This expression pattern is compared to equivalent stages in the normal development of cerebellum in mouse, as well as in tumors. Important differences between human and mouse that reflect differences in the normal developmental program between the 2 species are observed. First, in humans there appears to be a stage of Shh signaling within the EGL, when the PC are not yet the source of Shh. Second, unlike in the postnatal mouse cerebellum, expression of Shh in the PC in the postnatal human cerebellum is downregulated. Finally, medulloblastomas in the human but not in patched heterozygote mouse express Shh. These results highlight cross-species differences in the regulation of the Shh signaling pathway.

Systems Biology of Kidney Diseases

Kidney diseases manifest in progressive loss of renal function, which ultimately leads to complete kidney failure. The mechanisms underlying the origins and progression of kidney diseases are not fully understood. Multiple factors involved in the pathogenesis of kidney diseases have made the traditional candidate gene approach of limited value toward full understanding of the molecular mechanisms of these diseases. A systems biology approach that integrates computational modeling with large-scale data gathering of the molecular changes could be useful in identifying the multiple interacting genes and their products that drive kidney diseases. Advances in biotechnology now make it possible to gather large data sets to characterize the role of the genome, epigenome, transcriptome, proteome, and metabolome in kidney diseases. When combined with computational analyses, these experimental approaches will provide a comprehensive understanding of the underlying biological processes. Multiscale analysis that connects the molecular interactions and cell biology of different kidney cells to renal physiology and pathology can be utilized to identify modules of biological and clinical importance that are perturbed in disease processes. This integration of experimental approaches and computational modeling is expected to generate new knowledge that can help to identify marker sets to guide the diagnosis, monitor disease progression, and identify new therapeutic targets.

A Genome-wide Association Study Identifies a Potential Novel Gene Locus for Keratoconus, One of the Commonest Causes for Corneal Transplantation in Developed Countries

Keratoconus is a condition in which the cornea progressively thins over time, and is a major cause for cornea transplantation. To identify keratoconus susceptibility regions, we performed a comprehensive genome-wide association study (GWAS) using a discovery and replication design. A discovery panel of 222 keratoconus Caucasian patients and 3324 Caucasian controls was genotyped using Illumina 370K beadchips. Further associated and fine-mapping single nucleotide polymorphisms (SNPs) (n= 4905) were genotyped in an independent replication case-control panel of 304 cases and 518 controls and a family panel of 307 subjects in 70 families. Logistic regression models implemented in PLINK were performed to test associations in case-control samples with and without principal component (PC) adjustments. Generalized estimation equation models accounting for familial correlations implemented in GWAF were used for association testing in families. No genome-wide associations were identified in the discovery GWAS panel. From the initial testing without adjustments for PCs, the top three SNPs located at 3p26 (rs6442925), 2q21.3 (rs4954218) and 19q13.3 (rs1428642) were identified with unadjusted P-values of 6.5 × 10(-8), 2.4 × 10(-7) and 3.1 × 10(-7), respectively. After adjustments for PCs, rs1428642 became the most significant through the genome with a P-value of 1.4 × 10(-6), while rs6442925 and rs4954218 were less significant (P= 1.9 × 10(-5) and 2.6 × 10(-4)). SNP rs4954218 was confirmed in two independent replication panels with P-values of 0.004 and 0.009, respectively. Meta-analysis revealed a highest association at rs4954218 with adjusted P= 1.6 × 10(-7) (unadjusted P= 1.2 × 10(-9)). These findings suggest SNP rs4954218, located near the RAB3GAP1 gene, previously reported to be associated with corneal malformation, is a potential susceptibility locus for keratoconus.

Expression of Medium and Heavy Chain Neurofilaments in the Developing Human Auditory Cortex

Neurofilament medium (NF-M) and heavy (NF-H) chain proteins have been used as markers for maturity in the developing brain since their accumulation in axons leads to an increase in conduction velocity. Earlier studies have demonstrated immunoreactivity of neurofilaments in Layer I of the human auditory cortex at 22 gestation weeks (GW), whereas that in other layers developed between 1 and 12 postnatal years, suggesting a gradual increase in the processing of sounds. However, third trimester fetuses and infants are fairly sophisticated in their ability to discern different aspects of complex sounds. Given these contradictory findings, we decided to study the expression of neurofilaments in human auditory cortex between 15 GW and adulthood. We found that mRNA and protein for both NF-M and NF-H were present in the presumptive human auditory cortex in the second trimester and during the postnatal period (1 year--adulthood). Axons in all layers of the auditory cortex were immunoreactive for neurofilaments by 25 GW and the density of the neurofilament-rich plexus in the cortical wall became adult-like during the first postnatal year in humans (9 postnatal months). Our results suggest that in terms of neurofilament expression, axons within the preterm human auditory cortex may be more mature than previously thought.

An L₁-regularized Logistic Model for Detecting Short-term Neuronal Interactions

Interactions among neurons are a key component of neural signal processing. Rich neural data sets potentially containing evidence of interactions can now be collected readily in the laboratory, but existing analysis methods are often not sufficiently sensitive and specific to reveal these interactions. Generalized linear models offer a platform for analyzing multi-electrode recordings of neuronal spike train data. Here we suggest an L(1)-regularized logistic regression model (L(1)L method) to detect short-term (order of 3 ms) neuronal interactions. We estimate the parameters in this model using a coordinate descent algorithm, and determine the optimal tuning parameter using a Bayesian Information Criterion. Simulation studies show that in general the L(1)L method has better sensitivities and specificities than those of the traditional shuffle-corrected cross-correlogram (covariogram) method. The L(1)L method is able to detect excitatory interactions with both high sensitivity and specificity with reasonably large recordings, even when the magnitude of the interactions is small; similar results hold for inhibition given sufficiently high baseline firing rates. Our study also suggests that the false positives can be further removed by thresholding, because their magnitudes are typically smaller than true interactions. Simulations also show that the L(1)L method is somewhat robust to partially observed networks. We apply the method to multi-electrode recordings collected in the monkey dorsal premotor cortex (PMd) while the animal prepares to make reaching arm movements. The results show that some neurons interact differently depending on task conditions. The stronger interactions detected with our L(1)L method were also visible using the covariogram method.

A Multicenter Study to Map Genes for Fuchs Endothelial Corneal Dystrophy: Baseline Characteristics and Heritability

To describe the methods for family and case-control recruitment for a multicenter genetic and associated heritability analyses of Fuchs endothelial corneal dystrophy (FECD).

Prevalence of Diagnosed and Undiagnosed Diabetes and Hypertension in India--results from the Screening India's Twin Epidemic (SITE) Study

Despite the rising number of patients with diabetes and hypertension in India, there is a dearth of nationwide, comprehensive prevalence data on these diseases. Our study aimed at collecting data on the prevalence of diabetes and hypertension and the underlying risk factors in various outpatient facilities throughout India.

Use of Oscillometric Devices for the Measurement of Blood Pressure-comparison with the Gold Standard

The study was done to validate the use of automated devices (Datascope Duo) as a screening tool for measuring blood pressure. A cross sectional study was conducted in school children from urban slums of Bangalore. Blood pressure was recorded according to standard guidelines using a mercury sphygmomanometer and an automated device (Datascope Duo). The readings obtained using the two instruments were compared. One thousand four hundred eighty nine school children, both males and females, aged 5-16 y were included in the study. Readings with the Datascope Duo varied significantly when compared to the gold standard. The blood pressure measurements using Datascope Duo cannot be recommended as an accurate substitute for manual readings.

Extra-pulmonary Manifestations of Sarcoidosis

Although, the diagnosis and evaluation of sarcoidosis has traditionally remained confined to the chest, its multi-system nature has been widely recognized. Radiological features of pulmonary sarcoidosis are well known but extra-pulmonary manifestations can produce a plethora of non-specific imaging findings that can affect subcutaneous tissue, and the neurological, cardiac, gastrointestinal, urological, liver, spleen, and skeletal systems. In the literature, there are various case reports and specific system reviews but there are few reviews that encompass all the extra-pulmonary manifestations. In this paper, we comprehensively review the imaging features of extra-pulmonary sarcoidosis with characteristic features as well as atypical presentations. In addition, we discuss the emerging role of nuclear medicine in sarcoidosis.

Genetic Association and Gene-gene Interaction Analyses in African American Dialysis Patients with Nondiabetic Nephropathy

African Americans have increased susceptibility to nondiabetic nephropathy relative to European Americans.

Modulation of CNS Pain Circuitry by Intravenous and Sublingual Doses of Buprenorphine

Buprenorphine (BUP) is a partial agonist at μ-, δ- and ORL1 (opioid receptor-like)/nociceptin receptors and antagonist at the κ-opioid receptor site. BUP is known to have both analgesic as well as antihyperalgesic effects via its central activity, and is used in the treatment of moderate to severe chronic pain conditions. Recently, it was shown that intravenous (IV) administration of 0.2mg/70kg BUP modulates the blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) response to acute noxious stimuli in healthy human subjects. The present study extends these observations by investigating the effects of BUP dose and route of administration on central nervous system (CNS) pain circuitry. Specifically, the modulation of evoked pain BOLD responses and resting state functional connectivity was measured following IV (0.1 and 0.2mg/70kg) and sublingual (SL) (2mg) BUP administration in healthy human subjects. While 0.1mg/70kg IV BUP is sub-analgesic, both 0.2mg/70kg IV BUP and 2.0mg SL BUP are analgesic doses of the drug. Evoked BOLD responses were clearly modulated in a dose-dependent manner. The analgesic doses of BUP by both routes of administration yielded a potentiation in limbic/mesolimbic circuitry and attenuation in sensorimotor/sensory-discriminative circuitry. In addition, robust decreases in functional connectivity between the putamen and the sensorimotor/sensory-discriminative structures were observed at the two analgesic doses subsequent to measuring the maximum plasma BUP concentrations (C(max)). The decreases in functional connectivity within the sensorimotor/sensory-discriminative circuitry were also observed to be dose-dependent in the IV administration cohorts. These reproducible and consistent functional CNS measures at clinically effective doses of BUP demonstrate the potential of evoked pain fMRI and resting-state functional connectivity as objective tools that can inform the process of dose selection. Such methods may be useful during early clinical phase evaluation of potential analgesics in drug development.

Coordinate Expression and Localization of Iron and Zinc Transporters Explain Iron-zinc Interactions During Uptake in Caco-2 Cells: Implications for Iron Uptake at the Enterocyte

Iron and zinc have diverse and important physiological functions. Yet, the mechanism of their absorption at the intestine remains controversial and is confounded by the fact that many studies have shown, to varying extents, that they inhibit the absorption of each other. We have studied the expression of iron and zinc transporters and storage proteins, and their regulation, in Caco-2 cells, an established enterocyte model, under normal culture conditions and under conditions of iron and zinc depletion and supplementation using a combination of immunoblotting, confocal microscopy and reverse transcriptase polymerase chain reaction. We show that divalent metal transporter-1 (DMT-1) delocalizes from the plasma membrane upon iron or zinc depletion, but its apical abundance increases with zinc supplementation. This translocation of DMT-1 coincides with an increase in iron uptake upon zinc supplementation, as previously reported by us. FPN-1 expression increases upon zinc supplementation and decreases with iron or zinc depletion, effluxing the excess sequestered iron and thus maintaining cellular iron homeostasis. Zinc influx transporters Zip-1 and Zip-14 and efflux transporters ZnT-1 and ZnT-4 are coordinately regulated under conditions of zinc supplementation and depletion to ensure cellular zinc homeostasis. We have previously reported that iron uptake can entail two transporters and that zinc noncompetitively inhibits iron uptake in Caco-2 cells. We now provide evidence that this inhibition is independent of DMT-1 and that Zip-14 may be a relevant iron transporter. These new observations provide experimental support to this two-transporter model of iron uptake and give mechanistic insight to iron-zinc interactions during uptake at the enterocyte.

Influence of Water on Anharmonicity, Stability, and Vibrational Energy Distribution of Hydrogen-bonded Adducts in Atmospheric Reactions: Case Study of the OH + Isoprene Reaction Intermediate Using Ab Initio Molecular Dynamics

The effect of water on the stability and vibrational states of a hydroxy-isoprene adduct is probed through the introduction of 1-15 water molecules. It is found that when a static nuclear harmonic approximation is invoked there is a substantial red-shift of the alcohol O-H stretch (of the order of 800 cm(-1)) as a result of introduction of water. When potential energy surface sampling and associated anharmonicities are introduced through finite temperature ab initio dynamics, this hydroxy-isoprene OH stretch strongly couples with all the water vibrational modes as well as the hydroxy-isoprene OH bend modes. A new computational technique is introduced to probe the coupling between these modes. The method involves a two-dimensional, time-frequency analysis of the finite temperature vibrational properties. Such an analysis not only provides information about the modes that are coupled as a result of finite-temperature analysis, but also the temporal evolution of such coupling.

Development of an Electrochemical Immunosensor for the Detection of HbA1c in Serum

An electrochemical immuno-biosensor for detecting glycosylated haemoglobin (HbA1c) is reported based on glassy carbon (GC) electrodes with a mixed layer of an oligo(phenylethynylene) molecular wire (MW) and an oligo(ethylene glycol) (OEG). The mixed layer is formed from in situ-generated aryl diazonium cations. To the distal end of the MW, a redox probe 1,1'-di(aminomethyl)ferrocene (FDMA) was attached followed by the covalent attachment of an epitope N-glycosylated pentapeptide (GPP), an analogon to HbA1c, to which an anti-HbA1c monocolonal antibody IgG can selectively bind. HbA1c was detected by a competitive inhibition assay based on the competition for binding to anti-HbA1c IgG antibodies between the analyte in solution, HbA1c, and the surface bound epitope GPP. Exposure of the GPP modified sensing interface to the mixture of anti-HbA1c IgG antibody and HbA1c results in the attenuation of ferrocene electrochemistry due to free antibody binding to the interface. Higher concentrations of analyte led to higher Faradaic currents as less anti-HbA1c IgG is available to bind to the electrode surface. It was observed that there is a good linear relationship between the relative Faradaic current of FDMA and the concentration of HbA1c from 4.5% to 15.1% of total haemoglobin in serum without the need for washing or rinsing steps.

Factors Associated with the Persistence and Onset of New Anxiety Disorders in Youth with Bipolar Spectrum Disorders

Anxiety disorders are among the most common comorbid conditions in youth with bipolar disorder, but, to our knowledge, no studies examined the course of anxiety disorders in youth and adults with bipolar disorder.

Systems Pharmacology: Network Analysis to Identify Multiscale Mechanisms of Drug Action

Systems approaches have long been used in pharmacology to understand drug action at the organ and organismal levels. The application of computational and experimental systems biology approaches to pharmacology allows us to expand the definition of systems pharmacology to include network analyses at multiple scales of biological organization and to explain both therapeutic and adverse effects of drugs. Systems pharmacology analyses rely on experimental "omics" technologies that are capable of measuring changes in large numbers of variables, often at a genome-wide level, to build networks for analyzing drug action. A major use of omics technologies is to relate the genomic status of an individual to the therapeutic efficacy of a drug of interest. Combining pathway and network analyses, pharmacokinetic and pharmacodynamic models, and a knowledge of polymorphisms in the genome will enable the development of predictive models of therapeutic efficacy. Network analyses based on publicly available databases such as the U.S. Food and Drug Administration's Adverse Event Reporting System allow us to develop an initial understanding of the context within which molecular-level drug-target interactions can lead to distal effectors in a process that results in adverse phenotypes at the organ and organismal levels. The current state of systems pharmacology allows us to formulate a set of questions that could drive future research in the field. The long-term goal of such research is to develop polypharmacology for complex diseases and predict therapeutic efficacy and adverse event risk for individuals prior to commencement of therapy.

Oral Immunotherapy and Anti-IgE Antibody-adjunctive Treatment for Food Allergy

One of the most promising therapies for food allergy is oral immunotherapy (OIT), in which small amounts of allergen are administered in increasing amounts, with the immediate goal of desensitization and the long-term goal of tolerance. However, safety and standardization concerns prevent its widespread use, and a subgroup of patients may experience severe allergic reactions. These concerns might be addressed by another promising therapy involving anti-IgE monoclonal antibodies (mAb), which can reduce allergic reactions associated with food administration. A recent pilot study combining anti-IgE mAb with OIT suggests that anti-IgE mAb might improve the safety, rapidity, and efficacy of OIT.

Out of the Black Box: Treatment of Resistant Depression in Adolescents and the Antidepressant Controversy

The purpose of this article is to describe the effects of the pediatric antidepressant controversy on the Treatment of Serotonin-Selective Reuptake Inhibitor (SSRI) Resistant Depression in Adolescents (TORDIA) trial.

Do Sub-syndromal Manic Symptoms Influence Outcome in Treatment Resistant Depression in Adolescents? A Latent Class Analysis from the TORDIA Study

To identify distinct depressive symptom trajectories in the TORDIA study and determine their correlates.

Distal Humerus Fractures: Handling of the Ulnar Nerve

Maternal Oxytocin Response During Mother-infant Interaction: Associations with Adult Temperament

Oxytocin is a neuropeptide associated with social affiliation and maternal caregiving. However, its effects appear to be moderated by various contextual factors and stable individual characteristics. The purpose of this study was to investigate the relationship of self-reported state and trait measures (such as temperament, mood and affect) with peripheral oxytocin response in mothers. Fifty-five first-time mothers participated in a semi-structured procedure, during which time repeated peripheral oxytocin levels were measured before, during and after an episode of mother-infant interaction. The maternal oxytocin response was then calculated, based on the difference in oxytocin concentration between initial baseline and interaction phase. Mothers also completed state measures of positive and negative affect and depression, and trait measures of temperament, personality disturbance and depression across time. Regression analyses determined which factors were independently associated with maternal oxytocin response. The trait measure of adult temperament emerged as a significant predictor of oxytocin response. Two out of four Adult Temperament Questionnaire factor scales were independently associated with oxytocin response: Effortful Control was negatively associated, whereas Orienting Sensitivity was positively associated. No state measure significantly predicted oxytocin response. The results indicate that mothers who show an increased oxytocin response when interacting with their infants are more sensitive of moods, emotions and physical sensations; and less compulsive, schedule driven and task oriented. These findings link differences in individual temperament in new mothers with the peripheral oxytocin response, which may have implications in the pharmacologic treatment of disorders such as maternal neglect, post-partum depression and maternal addiction. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.

Oxytocin Receptor Genetic Variation Promotes Human Trust Behavior

Given that human trust behavior is heritable and intranasal administration of oxytocin enhances trust, the oxytocin receptor (OXTR) gene is an excellent candidate to investigate genetic contributions to individual variations in trust behavior. Although a single-nucleotide polymorphism involving an adenine (A)/guanine (G) transition (rs53576) has been associated with socio-emotional phenotypes, its link to trust behavior is unclear. We combined genotyping of healthy male students (n = 108) with the administration of a trust game experiment. Our results show that a common occurring genetic variation (rs53576) in the OXTR gene is reliably associated with trust behavior rather than a general increase in trustworthy or risk behaviors. Individuals homozygous for the G allele (GG) showed higher trust behavior than individuals with A allele carriers (AA/AG). Although the molecular functionality of this polymorphism is still unknown, future research should clarify how the OXTR gene interacts with other genes and the environment in promoting socio-emotional behaviors.

Treatment of Symptomatic Facial Nerve Paralysis with Lower Eyelid Fascia Lata Suspension

G Protein-regulated Inducer of Neurite Outgrowth (GRIN) Modulates Sprouty Protein Repression of Mitogen-activated Protein Kinase (MAPK) Activation by Growth Factor Stimulation

Gα(o/i) interacts directly with GRIN (G protein-regulated inducer of neurite outgrowth). Using the yeast two-hybrid system, we identified Sprouty2 as an interacting partner of GRIN. Gα(o) and Sprouty2 bind to overlapping regions of GRIN, thus competing for GRIN binding. Imaging experiments demonstrated that Gα(o) expression promoted GRIN translocation to the plasma membrane, whereas Sprouty2 expression failed to do so. Given the role of Sprouty2 in the regulation of growth factor-mediated MAPK activation, we examined the contribution of the GRIN-Sprouty2 interaction to CB1 cannabinoid receptor regulation of FGF receptor signaling. In Neuro-2A cells, a system that expresses all of the components endogenously, modulation of GRIN levels led to regulation of MAPK activation. Overexpression of GRIN potentiated FGF activation of MAPK and decreased tyrosine phosphorylation of Sprouty2. Pretreatment with G(o/i)-coupled CB1 receptor agonist attenuated subsequent FGF activation of MAPK. Decreased expression of GRIN both diminished FGF activation of MAPK and blocked CB1R attenuation of MAPK activation. These observations indicate that Gα(o) interacts with GRIN and outcompetes GRIN from bound Sprouty. Free Sprouty then in turn inhibits growth factor signaling. Thus, here we present a novel mechanism of how G(o/i)-coupled receptors can inhibit growth factor signaling to MAPK.

3-Phenyl-5-isothiazole Carboxamides with Potent MGluR1 Antagonist Activity

The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropanecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which correlated with CNS receptor occupancy.

"Pump-probe" Atom-centered Density Matrix Propagation Studies to Gauge Anharmonicity and Energy Repartitioning in Atmospheric Reactive Adducts: Case Study of the OH + Isoprene and OH + Butadiene Reaction Intermediates

Time-resolved "pump-probe" ab initio molecular dynamics studies are constructed to probe the stability of reaction intermediates, the mechanism of energy transfer, and energy repartitioning, for moieties involved during the interaction of volatile organic compunds with hydroxyl radical. These systems are of prime importance in the atmosphere. Specifically, the stability of reaction intermediates of hydroxyl radical adducts to isoprene and butadiene molecules is used as a case study to develop novel computational techniques involving "pump-probe" ab initio molecular dynamics. Starting with the various possible hydroxyl radical adducts to isoprene and butadiene, select vibrational modes of each of the adducts are populated with excess energy to mimic the initial conditions of an experiment. The flow of energy into the remaining modes is then probed by subjecting the excited adducts to ab initio molecular dynamics simulations. It is found that the stability of the adducts arises directly due to the anhormonically driven coupling of the modes to facilitate repartitioning of the excess vibrational energy. This kind of vibrational repartitioning has a critical influence on the energy density.

The Aromatase Gene CYP19A1: Several Genetic and Functional Lines of Evidence Supporting a Role in Reading, Speech and Language

Inspired by the localization, on 15q21.2 of the CYP19A1 gene in the linkage region of speech and language disorders, and a rare translocation in a dyslexic individual that was brought to our attention, we conducted a series of studies on the properties of CYP19A1 as a candidate gene for dyslexia and related conditions. The aromatase enzyme is a member of the cytochrome P450 super family, and it serves several key functions: it catalyzes the conversion of androgens into estrogens; during early mammalian development it controls the differentiation of specific brain areas (e.g. local estrogen synthesis in the hippocampus regulates synaptic plasticity and axonal growth); it is involved in sexual differentiation of the brain; and in songbirds and teleost fishes, it regulates vocalization. Our results suggest that variations in CYP19A1 are associated with dyslexia as a categorical trait and with quantitative measures of language and speech, such as reading, vocabulary, phonological processing and oral motor skills. Variations near the vicinity of its brain promoter region altered transcription factor binding, suggesting a regulatory role in CYP19A1 expression. CYP19A1 expression in human brain correlated with the expression of dyslexia susceptibility genes such as DYX1C1 and ROBO1. Aromatase-deficient mice displayed increased cortical neuronal density and occasional cortical heterotopias, also observed in Robo1-/- mice and human dyslexic brains, respectively. An aromatase inhibitor reduced dendritic growth in cultured rat neurons. From this broad set of evidence, we propose CYP19A1 as a candidate gene for human cognitive functions implicated in reading, speech and language.

Predictors of Survival After Single-ventricle Palliation: the Impact of Right Ventricular Dominance

This study examined survival after surgical palliation in children with single-ventricle physiology.

Merging Systems Biology with Pharmacodynamics

The emerging discipline of systems pharmacology aims to combine analysis and computational modeling of cellular regulatory networks with quantitative pharmacology approaches to drive the drug discovery processes, predict rare adverse events, and catalyze the practice of personalized precision medicine. Here, we introduce the concept of enhanced pharmacodynamic (ePD) models, which synergistically combine the desirable features of systems biology and current PD models within the framework of ordinary or partial differential equations. ePD models that analyze regulatory networks involved in drug action can account for a drug's multiple targets and for the effects of genomic, epigenomic, and posttranslational changes on the drug efficacy. This new knowledge can drive drug discovery and shape precision medicine.

Antiherpes Virus-Specific Treatment and Cognition in Schizophrenia: A Test-of-Concept Randomized Double-Blind Placebo-Controlled Trial

Objective:To test our hypothesis that valacyclovir, an antiherpes virus-specific medication, added to antipsychotics (APs) would improve cognitive performance and psychopathology among schizophrenia subjects exposed to neurotropic herpes simplex virus, type 1 (HSV1).Methods:Using a double-blind placebo-controlled design, we randomized 24 HSV1-seropositive schizophrenia subjects to receive either valacyclovir (n = 12) or placebo (n = 12) for 18 weeks in addition to stable doses of APs. Valacyclovir dose was stabilized at 1.5 g twice daily orally. At each visit, subjects were evaluated for severity of psychopathology and side effects using standardized scales and a study-specific semistructured checklist. A computerized neurocognitive battery validated on both schizophrenia and healthy subjects was administered at baseline and follow-up. Intent-to-treat analysis, using linear regression models that included all randomized subjects, were used to examine differential changes in cognition and psychopathology scores over 18 weeks between valacyclovir and placebo, accounting for placebo response.Results:Valacyclovir group improved in verbal memory, working memory, and visual object learning compared with placebo group. The effect sizes (Cohen's d) were 0.79 for working memory, 1.14 for immediate verbal memory, and 0.97 for the visual object learning. Psychotic symptom severity did not improve.Conclusions:Supplemental valacyclovir may alleviate impairments in cognitive domains that are often observed in schizophrenia but not psychotic symptoms in those exposed to HSV1. If replicated, this approach could provide a novel strategy to treat cognitive impairments in a subgroup of schizophrenia subjects who can be reliably identified using a blood test.

Locoregional Recurrence After Mastectomy with Immediate Transverse Rectus Abdominis Myocutaneous (TRAM) Flap Reconstruction

The locoregional recurrence (LRR) rate after mastectomy is reported to be similar with immediate reconstruction. We aimed to identify characteristics of LRR after transverse rectus abdominis myocutaneous (TRAM) reconstruction.

Primary Tuberculosis: an Unusual Finding in the Oral Cavity

The unusual involvement of the oral cavity in tuberculosis and the non-specific nature of its presentations mean that diagnosis of tuberculosis is often delayed and is an unexpected finding. The aim of this paper is to present a case of primary tuberculosis and discuss the implications of the manifestations and diagnosis of oral tuberculosis. This paper presents an unusual case of a painless, papillary, erythematous lesion in the anterior region of a maxillary edentulous ridge. When the patient concerned was first seen by the author, the lesion had been present for six months. There was cervical lymphadenopathy and it was diagnosed initially as a malignant lesion. Eventually, after biopsy and ultrasound examination, the diagnosis of primary oral tuberculosis was reached. The patient was managed solely by anti-tubercular drug therapy.

Relationship of Fuchs Endothelial Corneal Dystrophy Severity to Central Corneal Thickness

To define the relationship between Fuchs endothelial corneal dystrophy (FECD) severity and central corneal thickness (CCT).

Edematous Striae Distensae

Phase I Dose-escalation Study to Examine the Safety and Tolerability of LY2603618, a Checkpoint 1 Kinase Inhibitor, Administered 1 Day After Pemetrexed 500 mg/m(2) Every 21 Days in Patients with Cancer

Purpose This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. Experimental design This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40-195 mg/m(2)) were combined with 500 mg/m(2) of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Antitumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. Results A total of 31 patients were enrolled into six cohorts (three at 40 mg/m(2) over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m(2), 70 mg/m(2), and 195 mg/m(2); 13 at 105 mg/m(2); six at 150 mg/m(2)). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m(2)); reversible infusion-related reaction (150 mg/m(2)); thrombocytopenia (195 mg/m(2)); and fatigue (195 mg/m(2)). The maximum tolerated dose was defined as 150 mg/m(2). The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m(2). Conclusion LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles.

Is Bipolar Disorder Specifically Associated with Aggression?

Several studies have suggested that bipolar disorder (BP) in adults is associated with aggressive behaviors. However, most studies have included only inpatients and have not taken into consideration possible confounding factors. The goal of the present study was to compare the prevalence of aggression in subjects with BP compared to subjects with other, non-BP psychopathology and healthy controls.

A Look into Lee's Score: Peri-operative Cardiovascular Risk Assessment in Non-cardiac Surgeries-usefulness of Revised Cardiac Risk Index

The revised cardiac risk index (RCRI/Lee's score) was designed for peri-operative risk assessment before elective major non-cardiac surgeries. Through this article, we report the usefulness of RCRI in our daily practice, while evaluating patients undergoing surgeries of varying risk.

The Relationship of Cataract and Cataract Extraction to Age-related Macular Degeneration: the Beaver Dam Eye Study

To examine the associations of cataract and cataract surgery with early and late age-related macular degeneration (AMD) over a 20-year interval.

Decision-making Using FMRI in Clinical Drug Development: Revisiting NK-1 Receptor Antagonists for Pain

Substance P (SP) and neurokinin-1 receptors (NK-1R) are localized within central and peripheral sensory pain pathways. The roles of SP and NK-1R in pain processing, the anatomical distribution of NK-1R and efficacy observed in preclinical pain studies involving pain and sensory sensitization models, suggested that NK-1R antagonists (NK-1RAs) would relieve pain in patient populations. Despite positive data available in preclinical tests for a role of NK-1RAs in pain, clinical studies across several pain conditions have been negative. In this review, we discuss how functional imaging-derived information on activity in pain-processing brain regions could have predicted that NK-1RAs would have a low probability of success in this therapeutic domain.

Association of an Osteopontin Gene Promoter Polymorphism with Susceptibility to Diabetic Nephropathy in Asian Indians

Genetic predisposition has been proposed to be a major determinant in the development of renal complications of diabetes. Osteopontin (OPN) has been suggested to be associated with renal diseases characterized by tubulointerstitial fibrosis and proteinuria. However, information on association of genetic polymorphisms in OPN with diabetic nephropathy is lacking. Thus, the present study was designed with the aim to examine the association of an OPN gene promoter polymorphism with diabetic nephropathy in Asian Indians. OPN C-443T (rs11730582) polymorphism was determined in 1115 type 2 diabetic patients belonging to two independently ascertained cohorts using Real time PCR based Taqman assay. We observed a nearly threefold elevated risk of diabetic nephropathy among carriers of T allele and TT genotype of OPN C-443T polymorphism. Further, this allele was found to be significantly associated with proteinuria and lower eGFR, a hallmark of diabetic nephropathy, in both our cohorts. This is the first study which suggests that OPN C-443T polymorphism may be a significant risk factor for diabetic nephropathy in type 2 diabetic patients.

Long-term Outcomes After Atrioventricular Valve Operations in Patients Undergoing Single-ventricle Palliation

Outcomes after atrioventricular (AV) valve operations in patients with functional single ventricles are unclear.

Human ESC Self-renewal Promoting MicroRNAs Induce Epithelial-mesenchymal Transition in Hepatocytes by Controlling the PTEN and TGFβ Tumor Suppressor Signaling Pathways

The self-renewal capacity ascribed to embryonic stem cells (ESC) is reminiscent of cancer cell proliferation, raising speculation that a common network of genes may regulate these traits. A search for general regulators of these traits yielded a set of microRNAs for which expression is highly enriched in human ESCs and liver cancer cells (HCC) but attenuated in differentiated quiescent hepatocytes. Here, we show that these microRNAs promote hESC self-renewal, as well as HCC proliferation, and when overexpressed in normally quiescent hepatocytes, induce proliferation and activate cancer signaling pathways. Proliferation in hepatocytes is mediated through translational repression of Pten, Tgfbr2, Klf11, and Cdkn1a, which collectively dysregulates the PI3K/AKT/mTOR and TGFβ tumor suppressor signaling pathways. Furthermore, aberrant expression of these miRNAs is observed in human liver tumor tissues and induces epithelial-mesenchymal transition in hepatocytes. These findings suggest that microRNAs that are essential in normal development as promoters of ESC self-renewal are frequently upregulated in human liver tumors and harbor neoplastic transformation potential when they escape silencing in quiescent human hepatocytes.

Variation in the Lysyl Oxidase (LOX) Gene is Associated with Keratoconus in Family-based and Case-control Studies

Keratoconus is a bilateral noninflammatory progressive corneal disorder with complex genetic inheritance and a common cause for cornea transplantation in young adults. A genomewide linkage scan in keratoconus families identified a locus at 5q23.2, overlapping the gene coding for the lysyl oxidase (LOX). LOX encodes an enzyme responsible for collagen cross-linking in a variety of tissues including the cornea. Corneal collagen cross-linking with long-wave ultraviolet light and riboflavin is a promising new treatment for keratoconus. To determine whether LOX is a genetic determinant of the pathogenesis of keratoconus, we analyzed association results of LOX polymorphisms in two independent case-control samples and in keratoconus families.

Validation of the GRACE Score for Prognosis in Indian Patients with Acute Coronary Syndromes

To validate the global registry of acute coronary events (GRACE) score in acute coronary syndromes (ACS) patients and study its angiographic correlation.

Visceral Adiposity in Young Patients with Coronary Artery Disease-a Case Control Study

Central obesity is associated with an increased cardiovascular risk. We carried out a hospital based case control study in young patients with coronary artery disease (CAD) to assess the importance of visceral fat

Large Scale International Replication and Meta-analysis Study Confirms Association of the 15q14 Locus with Myopia. The CREAM Consortium

Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10(-12) for SNP rs634990 in Caucasians, and 9.65 × 10(-4) for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10(-23) for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10(-2) for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.

Immune Factors In Breastmilk And The Development of Atopic Disease

ABSTRACT: Breastfeeding provides protection against infections and contains numerous factors that modulate and promote the development of the infant immune system. These factors include secretory IgA, anti-microbial proteins like CD14, cytokines, and fatty acids. Studies examining the role of breastfeeding in the development of allergic disease in infants demonstrate potentially protective as well as neutral or non-protective effects, likely due to the heterogeneity in their study design. In this overview, we explore the potential role of immune factors in the breastmilk, as well as selected probiotics, in the development of allergy.

Sequential Evolution and Escape from Neutralization of Simian Immunodeficiency Virus SIVsmE660 Clones in Rhesus Macaques

Simian immunodeficiency virus (SIV) infection of rhesus macaques has become an important surrogate model for evaluating HIV vaccine strategies. The extreme resistance to neutralizing antibody (NAb) of many commonly used strains, such as SIVmac251/239 and SIVsmE543-3, limits their potential relevance for evaluating the role of NAb in vaccine protection. In contrast, SIVsmE660 is an uncloned virus that appears to be more sensitive to neutralizing antibody. To evaluate the role of NAb in this model, we generated full-length neutralization-sensitive molecular clones of SIVsmE660 and evaluated two of these by intravenous inoculation of rhesus macaques. All animals became infected and maintained persistent viremia that was accompanied by a decline in memory CD4(+) T cells in blood and bronchoalveolar lavage fluid. High titers of autologous NAb developed by 4 weeks postinoculation but were not associated with control of viremia, and neutralization escape variants were detected concurrently with the generation of NAb. Neutralization escape was associated with substitutions and insertion/deletion polymorphisms in the V1 and V4 domains of envelope. Analysis of representative variants revealed that escape variants also induced NAbs within a few weeks of their appearance in plasma, in a pattern that is reminiscent of the escape of human immunodeficiency virus type 1 (HIV-1) isolates in humans. Although early variants maintained a neutralization-sensitive phenotype, viruses obtained later in infection were significantly less sensitive to neutralization than the parental viruses. These results indicate that NAbs exert selective pressure that drives the evolution of the SIV envelope and that this model will be useful for evaluating the role of NAb in vaccine-mediated protection.

AAN Epilepsy Quality Measures in Clinical Practice: a Survey of Neurologists

Epilepsy Quality Measures (EQM) were developed by the American Academy of Neurology (AAN) to convey standardization and eliminate gaps and variations in the delivery of epilepsy care (Fountain et al., 2011 [1]). The aim of this study was to identify adherence to these measures and other emerging practice standards in epilepsy care. A 15-item survey was mailed to neurologists in Michigan, USA, inquiring about their practice patterns in relation to EQM. One hundred thirteen of the 792 surveyed Michigan Neurologists responded (14%). The majority (83% to 94%) addressed seizure type and frequency, reviewed EEG and MRI, and provided pregnancy counseling to women of childbearing potential. Our survey identified gaps in practice patterns such as counseling about antiepileptic drug (AED) side effects and knowledge about referral for surgical therapy of intractable epilepsy. Statistical significance in the responses on the AAN EQM was noted in relation to number of years in practice, number of epilepsy patients seen, and additional fellowship training in epilepsy. Practice patterns assessment in relation to other comorbidities revealed that although bone health and sudden unexplained death in epilepsy are addressed mainly in patients at risk, depression is infrequently discussed. The findings in this study indicate that additional educational efforts are needed to increase awareness and to improve quality of epilepsy care at various points of health care delivery.

Relationship Between Fuchs Endothelial Corneal Dystrophy Severity and Glaucoma And/or Ocular Hypertension

OBJECTIVE To investigate whether Fuchs endothelial corneal dystrophy (FECD) severity is associated with glaucoma and/or ocular hypertension (G/OHTN). METHODS A subset of eyes (n = 1610) from the FECD Genetics Multi-Center Study were examined to estimate the association between FECD severity (grades 0-6 based on guttae confluence) and G/OHTN. Logistic regression models that accounted for the correlation between eyes and adjusted for age, sex, central corneal thickness, intraocular pressure, presence of diabetes, and time of day of the initial evaluation were fit. RESULTS A total of 107 eyes (6.6%) had G/OHTN based on the study definition. The prevalence of G/OHTN in the control group was 6.0%. The prevalence was lower in index cases with an FECD grade of 1 through 3 and family members with a grade of 0 or 1 through 3 (0.0% and 2.1%, respectively) but higher in index cases and family members with a grade of 4 through 6 (11.2% and 8.5%, respectively). Adjusting for covariates, eyes with a grade of 4 through 6 were more likely to have concurrent G/OHTN than eyes with no FECD (index cases vs controls: odds ratio [OR] = 2.10, P = .04; affected vs unaffected family members: OR = 7.06, P = .07). Age (OR = 1.06 per 1-year increase, P < .001) and intraocular pressure (OR = 1.15 per 1-mm Hg increase, P < .001) were also associated with an increased prevalence of G/OHTN. Sex, diabetes, time of day of evaluation, and central corneal thickness were not associated with the prevalence of G/OHTN (P ≥ .15). CONCLUSIONS Glaucoma and/or ocular hypertension occurs more often in eyes with severe FECD compared with unaffected eyes. Therefore, it may be beneficial to monitor for the development of glaucoma in these patients.

Modality of Choice for Renal Replacement Therapy for Children with Acute Kidney Injury: Results of a Survey

Information on current practices in India for management of renal replacement therapy (RRT) in acute kidney injury (AKI) is lacking. We mailed a questionnaire to 26 pediatric nephrology centers across India to obtain information on the current choice of dialysis modality for management of AKI in children. Acute intermittent peritoneal dialysis was available at all centers surveyed, whereas intermittent hemodialysis and continuous RRT were available in 86% and 17% centers, respectively. Peritoneal dialysis was the predominant modality (accounting for more than 80% of all dialysis) in 14 of the 22 centers, while 4 centers used hemodialysis more commonly. The most important factors influencing the modality choice were patient size, hemodynamic stability, and duration of AKI. These results provide insight into the choice of modality and factors influencing their selection in the management of pediatric AKI in our country.

Identification of Nephropathy Candidate Genes by Comparing Sclerosis-prone and Sclerosis-resistant Mouse Strain Kidney Transcriptomes

ABSTRACT: BACKGROUND: The genetic architecture responsible for chronic kidney disease (CKD) remains incompletely described. The Oligosyndactyly (Os) mouse models focal and segmental glomerulosclerosis (FSGS), which is associated with reduced nephron number caused by the Os mutation. The Os mutation leads to FSGS in multiple strains including the ROP-Os/+. However, on the C57Bl/6J background the mutation does not cause FSGS, although nephron number in these mice are equivalent to those in ROP-Os/+ mice. We exploited this phenotypic variation to identify genes that potentially contribute to glomerulosclerosis. METHODS: To identify such novel genes, which regulate susceptibility or resistance to renal disease progression, we generated and compared the renal transcriptomes using serial analysis of gene expression (SAGE) from the sclerosis-prone ROP-Os/+ and sclerosis resistant C57-Os/+ mouse kidneys. We confirmed the validity of the differential gene expression using multiple approaches. We also used an INGENUITY PATHWAY ANALYSIS engine to assemble differentially regulated molecular networks. Cell culture techniques were employed to confirm functional relevance of selected genes. RESULTS: A comparative analysis of the kidney transcriptomes revealed multiple genes, with expression levels that were statistically different. These novel, candidate, renal disease susceptibility/resistance genes included neuropilin2 (Nrp2), glutathione-S-transferase theta (Gstt1) and itchy (Itch). Of 34 genes with the most robust statistical difference in expression levels between ROP-Os/+ and C57-Os/+ mice, 13 and 3 transcripts localized to glomerular and tubulointerstitial compartments, respectively, from micro-dissected human FSGS biopsies. Network analysis of all significantly differentially expressed genes identified 13 connectivity networks. The most highly scored network highlighted the roles for oxidative stress and mitochondrial dysfunction pathways. Functional analyses of these networks provided evidence for activation of transforming growth factor beta (TGFbeta) signaling in ROP-Os/+ kidneys despite similar expression of the TGFbeta ligand between the tested strains. CONCLUSIONS: These data demonstrate the complex dysregulation of normal cellular functions in this animal model of FSGS and suggest that therapies directed at multiple levels will be needed to effectively treat human kidney diseases.

Acquisition of CD4-dependence by CD4-independent SIV Passaged in Human Peripheral Blood Mononuclear Cells

Chemokine receptors (CKRs), the primordial receptors for primate lentiviruses, are sufficient to mediate virus-cell fusion. Several different fusogenic CKRs and related receptors provide a broad potential host cell range, presumably advantageous for viral spread within a given infected individual, and across species. By contrast, the additional constraint of obligatory CD4 binding, just prior to CKR engagement, radically restricts potential host cells within an individual (or lymph node microenvironment), and might also limit xenotransmission, as CD4 sequences vary among primates. In spite of these potential drawbacks, CD4 dependent entry for SIV and HIV is the rule rather than the exception, and is generally thought to have evolved by selection for 1) stabilization of virus-cell surface interactions, and 2) conformational shielding of readily neutralized CKR binding epitopes. CD4 binding residues of SIV and HIV envelope are recessed, (relatively hidden from immune detection) and may exhibit a strong degree of automimicry, thus benefitting from self tolerance.Documented evolution, within individual macaques, of neutralization-resistant CD4-dependent SIV, derived from CD4-independent inocula, supports these ideas, but does not explain CD4's exclusive role as the penultimate receptor-even more striking, given the wide diversity of CKRs and other surface molecules that can serve as actual fusion receptors for SIV. We, therefore, explored the additional, non-exclusive, hypothesis that surface CD4 on leukocytes is a marker of a more favorable host cell environment, as compared to CD8, NK, or B cell surface markers.

Apolipoprotein L1 Gene Variants Associate with Hypertension-attributed Nephropathy and the Rate of Kidney Function Decline in African Americans

Despite intensive antihypertensive therapy there was a high incidence of renal end points in participants of the African American Study of Kidney Disease and Hypertension (AASK) cohort. To better understand this, coding variants in the apolipoprotein L1 (APOL1) and the nonmuscle myosin heavy chain 9 (MYH9) genes were evaluated for an association with hypertension-attributed nephropathy and clinical outcomes in a case-control study. Clinical data and DNA were available for 675 AASK participant cases and 618 African American non-nephropathy control individuals. APOL1 G1 and G2, and MYH9 E1 variants along with 44 ancestry informative markers, were genotyped with allele frequency differences between cases and controls analyzed by logistic regression multivariable models adjusting for ancestry, age, and gender. In recessive models, APOL1 risk variants were significantly associated with kidney disease in all cases compared to controls with an odds ratio of 2.57. In AASK cases with more advanced disease, such as a baseline urine protein to creatinine ratio over 0.6 g/g or a serum creatinine over 3 mg/dl during follow-up, the association was strengthened with odds ratios of 6.29 and 4.61, respectively. APOL1 risk variants were consistently associated with renal disease progression across medication classes and blood pressure targets. Thus, kidney disease in AASK participants was strongly associated with APOL1 renal risk variants.Kidney International advance online publication, 25 July 2012; doi:10.1038/ki.2012.263.

Is Reaction Time Variability Consistent Across Sensory Modalities? Insights from Latent Variable Analysis of Single-trial P3b Latencies

Recent years have witnessed a steep increase in cognitive, differential and clinical neuroscience research on the neural basis of intra-subject variability of reaction times. Most theoretical accounts make the implicit assumption that individual differences in intra-subject variability are consistent across sensory modalities, but this remains largely untested. The present EEG study aims to fill this gap by analyzing, for the first time, stimulus- and response-locked single-trial P3bs across visual and auditory sensory modalities, and employing an innovative supra-task latent variables approach. We found unidimensionality of intra-subject variability variables across modalities as well as high correlations between the latency jitter of stimulus- and response-locked P3bs. These findings support the hypothesis that intra-subject variability represents a unitary construct, and that the processes underlying that generalises not only across different cognitive tasks, but also across different sensory modalities.

Early Postpartum Maternal Morbidity Among Rural Women of Rajasthan, India: a Community-based Study

The first postpartum week is a high-risk period for mothers and newborns. Very few community-based studies have been conducted on patterns of maternal morbidity in resource-poor countries in that first week. An intervention on postpartum care for women within the first week after delivery was initiated in a rural area of Rajasthan, India. The intervention included a rigorous system of receiving reports of all deliveries in a defined population and providing home-level postpartum care to all women, irrespective of the place of delivery. Trained nurse-midwives used a structured checklist for detecting and managing maternal and neonatal conditions during postpartum-care visits. A total of 4,975 women, representing 87.1% of all expected deliveries in a population of 58,000, were examined in their first postpartum week during January 2007-December 2010. Haemoglobin was tested for 77.1% of women (n=3,836) who had a postnatal visit. The most common morbidity was postpartum anaemia--7.4% of women suffered from severe anaemia and 46% from moderate anaemia. Other common morbidities were fever (4%), breast conditions (4.9%), and perineal conditions (4.5%). Life-threatening postpartum morbidities were detected in 7.6% of women--9.7% among those who had deliveries at home and 6.6% among those who had institutional deliveries. None had a fistula. Severe anaemia had a strong correlation with perinatal death [p<0.000, adjusted odds ratio (AOR)=1.99, 95% confidence interval (CI) 1.32-2.99], delivery at home [p<0.000, AOR=1.64 (95% CI 1.27-2.15)], socioeconomically-underprivileged scheduled caste or tribe [p<0.000, AOR=2.47 (95% CI 1.83-3.33)], and parity of three or more [p<0.000, AOR=1.52 (95% CI 1.18-1.97)]. The correlation with antenatal care was not significant. Perineal conditions were more frequent among women who had institutional deliveries while breast conditions were more common among those who had a perinatal death. This study adds valuable knowledge on postpartum morbidity affecting women in the first few days after delivery in a low-resource setting. Health programmes should invest to ensure that all women receive early postpartum visits after delivery at home and after discharge from institution to detect and manage maternal morbidity. Further, health programmes should also ensure that women are properly screened for complications before their discharge from hospitals after delivery.

Consequences of Maternal Complications in Women's Lives in the First Postpartum Year: a Prospective Cohort Study

Maternal complications are common during and following childbirth. However, little information is available on the psychological, social and economic consequences of maternal complications on women's lives, especially in a rural setting. A prospective cohort study was conducted in southern Rajasthan, India, among rural women who had a severe or less-severe, or no complication at the time of delivery or in the immediate postpartum period. In total, 1,542 women, representing 93% of all women who delivered in the field area over a 15-month period and were examined in the first week postpartum by nurse-midwives, were followed up to 12 months to record maternal and child survival. Of them, a subset of 430 women was followed up at 6-8 weeks and 12 months to capture data on the physical, psychological, social, or economic consequences. Women with severe maternal complications around the time of delivery and in the immediate postpartum period experienced an increased risk of mortality and morbidity in the first postpartum year: 2.8% of the women with severe complications died within one year compared to none with uncomplicated delivery. Women with severe complications also had higher rates of perinatal mortality [adjusted odds ratio (AOR)=3.98, confidence interval (CI) 1.96-8.1, p=0.000] and mortality of babies aged eight days to 12 months (AOR=3.14, CI 1.4-7.06, p=0.004). Compared to women in the uncomplicated group, women with severe complications were at a higher risk of depression at eight weeks and 12 months with perceived physical symptoms, had a greater difficulty in completing daily household work, and had important financial repercussions. The results suggest that women with severe complications at the time of delivery need to be provided regular follow-up services for their physical and psychological problems till about 12 months after childbirth. They also might benefit from financial support during several months in the postpartum period to prevent severe economic consequences. Further research is needed to identify an effective package of services for women in the first year after delivery.

Gauging the Flexibility of the Active Site in Soybean Lipoxygenase-1 (SLO-1) Through an Atom-Centered Density Matrix Propagation (ADMP) Treatment That Facilitates the Sampling of Rare Events

We present a computational methodology to sample rare events in large biological enzymes that may involve electronically polarizing, reactive processes. The approach includes simultaneous dynamical treatment of electronic and nuclear degrees of freedom, where contributions from the electronic portion are computed using hybrid density functional theory and the computational costs are reduced through a hybrid quantum mechanics/molecular mechanics (QM/MM) treatment. Thus, the paper involves a QM/MM dynamical treatment of rare events. The method is applied to probe the effect of the active site elements on the critical hydrogen transfer step in the soybean lipoxygenase-1 (SLO-1) catalyzed oxidation of linoleic acid. It is found that the dynamical fluctuations and associated flexibility of the active site are critical toward maintaining the electrostatics in the regime where the reactive process can occur smoothly. Physical constraints enforced to limit the active site flexibility are akin to mutations and, in the cases studied, have a detrimental effect on the electrostatic fluctuations, thus adversely affecting the hydrogen transfer process.

Does Sepsis Treatment Differ Between Primary and Overflow Intensive Care Units?

Sepsis is a major cause of death in hospitalized patients. Early goal-directed therapy is the standard of care. When primary intensive care units (ICUs) are full, sepsis patients are cared for in overflow ICUs.

Population Pharmacokinetic/pharmacodynamic Models for Duloxetine in the Treatment of Diabetic Peripheral Neuropathic Pain

BACKGROUND: Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor approved for the treatment of diabetic peripheral neuropathic pain (DPNP). The current analyses aimed to identify and evaluate the effect of any significant covariates on DPNP treatment response, via the development of a continuous descriptive Pharmacokinetics/Pharmacodynamics (PK/PD) model for pain score reduction and a proportional odds PK/PD model describing the proportion of patients achieving pain relief. METHODS: A total of 1139 patients received placebo, 20, 60 or 120 mg duloxetine daily for 12 weeks. The primary efficacy measure was 24-h pain scores collected on the 11-point categorical numerical rating scale averaged over a week. PK/PD models were fitted using non-linear mixed-effects models. RESULTS: Baseline pain severity was found to be an important factor in both PK/PD models. Larger drops in pain scores were observed for patients with more severe pain. The proportional odds PK/PD model used an a priori definition for adequate pain relief, which was a decrease in two points from baseline. Simulations showed that approximately 70% of patients in the highest dose groups would obtain pain relief at week 12, although placebo response was relatively high at 40%. The proportion of patients who obtained pain relief was slightly lower in those with mild pain compared to those with more severe pain. CONCLUSIONS: Patients with more severe pain at study entry had larger treatment responses and were more likely to achieve clinically meaningful pain relief with similar amounts of drug, compared to patients with milder pain.

Contractile Activity Regulates Inducible Nitric Oxide Synthase Expression and NO(i) Production in Cardiomyocytes Via a FAK-Dependent Signaling Pathway

Intracellular nitric oxide (NO(i)) is a physiological regulator of excitation-contraction coupling, but is also involved in the development of cardiac dysfunction during hypertrophy and heart failure. To determine whether contractile activity regulates nitric oxide synthase (NOS) expression, spontaneously contracting, neonatal rat ventricular myocytes (NRVM) were treat with L-type calcium channel blockers (nifedipine and verapamil) or myosin II ATPase inhibitors (butanedione monoxime (BDM) and blebbistatin) to produce contractile arrest. Both types of inhibitors significantly reduced iNOS but not eNOS expression, and also reduced NO(i) production. Inhibiting contractile activity also reduced focal adhesion kinase (FAK) and AKT phosphorylation. Contraction-induced iNOS expression required FAK and phosphatidylinositol 3-kinase (PI(3)K), as both PF573228 and LY294002 (10 μM, 24 h) eliminated contraction-induced iNOS expression. Similarly, shRNAs specific for FAK (shFAK) caused FAK knockdown, reduced AKT phosphorylation at T308 and S473, and reduced iNOS expression. In contrast, shRNA-mediated knockdown of PYK2, the other member of the FAK-family of protein tyrosine kinases, had much less of an effect. Conversely, overexpression of a constitutively active form of FAK (CD2-FAK) or AKT (Myr-AKT) reversed the inhibitory effect of BDM on iNOS expression and NO(i) production. Thus, contraction-induced iNOS expression and NO(i) production in NRVM are mediated via a FAK-PI(3)K-AKT signaling pathway.

Genome-wide Association Analyses Identify Three New Susceptibility Loci for Primary Angle Closure Glaucoma

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10(-12)), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10(-10)) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10(-9)). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.

Mycobacterium Chelonae Hand Infection Following Ferret Bite

We present a case of hand infection caused by Mycobacterium chelonae. The patient was a 58-year-old woman with Type II diabetes mellitus and stage 4 chronic kidney disease. The infection occurred following a ferret bite and had not responded to oral antibiotics in the primary care setting. She developed signs of pyogenic flexor tenosynovitis of the index and middle fingers of her left hand. Laboratory parameters showed high C-reactive protein, raised erythrocyte sedimentation rate and leucocytosis. Ultrasound imaging confirmed the clinical diagnosis. Plain radiographs showed no osseous involvement. The infection was treated with surgical debridement and broad spectrum parenteral antibiotics. The intra-operative tissue specimens were initially negative on aerobic and anaerobic cultures. Following transient improvement of her inflammatory parameters and clinical signs, she developed a recurrence with added features of osteomyelitis of the index and middle finger metacarpal heads on repeat radiographs. A revision surgical debridement of the flexor tenosynovitis and osteomyelitis with specific long-term antibiotic cover has led to resolution of the infection. Extended cultures of the tissue specimens at the regional laboratory confirmed the causative organism to be M. chelonae. To our knowledge, this is the first reported case of M. chelonae infection resulting from a ferret bite. This case reminds us of the need for a high index of suspicion for infection with uncommon pathogens following animal bites, especially in patients with altered immune status.

The Case ∣ a Challenging Case of Severe Rickets

Effect of the Y402H Variant in the Complement Factor H Gene on the Incidence and Progression of Age-related Macular Degeneration: Results from Multistate Models Applied to the Beaver Dam Eye Study

To investigate the effect of age, sex, and the Y402H variant in the complement factor H (CFH) gene on the incidence, progression, and regression of age-related macular degeneration (AMD) as well as the effect of these factors and AMD on mortality, using multistate models.

Prevalence, Risk Factors and Awareness of Hypertension in India: a Systematic Review

Indians have high rates of cardiovascular disease. Hypertension (HTN) is an important modifiable risk factor. There are no comprehensive reviews or a nationally representative study of the burden, treatments and outcomes of HTN in India. A systematic review was conducted to study the trends in prevalence, risk factors and awareness of HTN in India. We searched MEDLINE from January 1969 to July 2011 using prespecified medical subject heading (MeSH) terms. Of 3372 studies, 206 were included for data extraction and 174 were observational studies. Prevalence was reported in 48 studies with sample size varying from 206 to 167 331. A significant positive trend (P<0.0001) was observed over time in prevalence of HTN by region and gender. Awareness and control of HTN (11 studies) ranged from 20 to 54% and 7.5 to 25%, respectively. Increasing age, body mass index, smoking, diabetes and extra salt intake were common risk factors. In conclusion, from this systematic review, we record an increasing trend in prevalence of HTN in India by region and gender. The awareness of HTN in India is low with suboptimal control rates. There are few long-term studies to assess outcomes. Good quality long-term studies will help to understand HTN better and implement effective prevention and management programs.Journal of Human Hypertension advance online publication, 13 September 2012; doi:10.1038/jhh.2012.33.

The Value of Ultrasound in Detecting Extra-Axillary Regional Node Involvement in Patients with Advanced Breast Cancer

Assessment of the regional lymphatics is important for accurate staging and treatment of breast cancer patients. We sought to determine the role of regional ultrasound in providing clinically relevant information. We retrospectively analyzed data from patients who were treated curatively in 1996-2006 at The University of Texas MD Anderson Cancer Center for clinical stage III breast cancer. We compared differences in regional lymph node staging based on ultrasound versus mammography and physical examination in the 865 of 1,200 patients who had external-beam radiation as part of their treatment and regional ultrasound studies as part of their initial evaluation. Ultrasound uniquely identified additional lymph node involvement beyond the level I or II axilla in 37% of the patients (325 of 865), leading to a change in clinical nodal stage. Ninety-one percent of these abnormalities that could be biopsied (266 or 293) were confirmed to contain disease. The sites of additional regional nodal disease were: infraclavicular disease, 32% (275 of 865); supraclavicular disease, 16% (140 of 865); and internal mammary disease, 11% (98 of 865). All patients with involvement in the extra-axillary regional nodal basins received a radiation boost to the involved areas ≥10 Gy. Thus, over one third of patients with advanced breast cancer had their radiation plan altered by the ultrasound findings. Regional ultrasound evaluation in patients with advanced breast cancer commonly revealed abnormalities within and beyond the axilla, which changed the clinical stage of disease and the radiation treatment strategy. Therefore, regional ultrasound is beneficial in the initial staging evaluation for such patients.

Isolated Central Nervous System Progression on Crizotinib: An Achilles Heel of Non-small Cell Lung Cancer with EML4-ALK Translocation?

Advanced non-small lung cancer (NSCLC) remains almost uniformly lethal with marginal long-term survival despite efforts to target specific oncogenic addiction pathways that may drive these tumors with small molecularly targeted agents and biologics. The EML4-ALK fusion gene encodes a chimeric tyrosine kinase that activates the Ras signaling pathway, and this fusion protein is found in approximately 5% of NSCLC. Targeting EML4-ALK with Crizotinib in NSCLC has documented therapeutic efficacy, but the vast majority of patients eventually develop recurrent disease that is often refractory to further treatments. We present the clinicopathologic features of three patients with metastatic NSCLC harboring the EML4-ALK translocation that developed isolated central nervous system (CNS) metastases in the presence of good disease control elsewhere in the body. These cases suggest a differential response of NSCLC to Crizotinib in the brain in comparison to other sites of disease, and are consistent with a previous report of poor CNS penetration of Crizotinib. Results of ongoing clinical trials will clarify whether the CNS is a major sanctuary site for EML4-ALK positive NSCLC being treated with Crizotinib. While understanding molecular mechanisms of resistance is critical to overcome therapeutic resistance, understanding physiologic mechanisms of resistance through analyzing anatomic patterns of failure may be equally crucial to improve long-term survival for patients with EML4-ALK translocation positive NSCLC.

Development of Neurological Disease is Associated with Increased Immune Activation in SIV Infected Macaques

Simian immunodeficiency virus (SIV) infection of macaques can result in central nervous system (CNS) disorders, such as meningitis and encephalitis. We studied ten animals inoculated with brain-derived virus from animals with SIV-encephalitis. Over half of the macaques developed SIV-induced neurologic disease. Elevated levels of systemic immune activation were observed to correlate with viral RNA in the cerebral spinal fluid but not with plasma viral load, consistent with a role in the pathogenesis of neurologic disease.

Degenerate Recognition of MHC Class I Molecules with Bw4 and Bw6 Motifs by a Killer Cell Ig-like Receptor 3DL Expressed by Macaque NK Cells

The killer cell Ig-like receptors (KIRs) expressed on the surface of NK cells recognize specific MHC class I (MHC-I) molecules and regulate NK cell activities against pathogen-infected cells and neoplasia. In HIV infection, survival is linked to host KIR and MHC-I genotypes. In the SIV macaque model, however, the role of NK cells is unclear due to the lack of information on KIR-MHC interactions. In this study, we describe, to our knowledge, the first in-depth characterization of KIR-MHC interactions in pigtailed macaques (Macaca nemestrina). Initially, we identified three distinct subsets of macaque NK cells that stained ex vivo with macaque MHC-I tetramers loaded with SIV peptides. We then cloned cDNAs corresponding to 15 distinct KIR3D alleles. One of these, KIR049-4, was an inhibitory KIR3DL that bound MHC-I tetramers and prevented activation, degranulation, and cytokine production by macaque NK cells after engagement with specific MHC-I molecules on the surface of target cells. Furthermore, KIR049-4 recognized a broad range of MHC-I molecules carrying not only the Bw4 motif, but also Bw6 and non-Bw4/Bw6 motifs. This degenerate, yet peptide-dependent, MHC reactivity differs markedly from the fine specificity of human KIRs.

Identification of CK2 As the Kinase That Phosphorylates Pax3 at Ser209 in Early Myogenic Differentiation

The myogenic transcription factor Pax3, a member of the paired class homeodomain family of transcription factors, plays an essential role in early skeletal muscle development. We previously demonstrated that Pax3 is phosphorylated at three specific residues (Ser201, Ser205, and Ser209) and that the pattern of phosphorylation at these sites changes throughout early myogenesis. Further, we demonstrated that the protein kinase CK2 phosphorylates Pax3 at Ser205 and that this phosphorylation event is required for the subsequent phosphorylation of Ser201 by GSK3β. However, the kinase that phosphorylates Pax3 at Ser209 has yet to be identified. In the present work we use standard purification methods and in vitro biochemical analyses to provide solid evidence identifying the protein kinase CK2 as phosphorylating Pax3 at Ser209. Further, we qualitatively demonstrate that the phosphorylation of Pax3 at Ser209 by CK2 is enhanced when Ser205 is previously phosphorylated. Taken together, our results allow us to propose a mechanism to describe the ordered phosphorylation of Pax3 throughout early myogenesis.

Poor Outcomes After Surgery for Coarctation Repair with Hypoplastic Arch Warrants More Extensive Initial Surgery and Close Long-term Follow-up

OBJECTIVESLate outcomes of repair of coarctation with arch hypoplasia have not yet been described. Hypertension and arch reobstruction frequently occur after standard coarctation repair and thus we sought to determine the long-term results of repair in the subset of patients with arch hypoplasia at a single institution over a 20-year period.METHODSWe reviewed the files of the 305 consecutive patients quoted to have arch hypoplasia who had undergone a coarctation repair in a single institution between 1984 and 2004. Repair was performed through a sternotomy in 74 patients (24%), 58 of them undergoing a repair consisting of an end-to-side anastomosis.RESULTSEarly mortality was 9% but there was only 1 death among patients without a major associated anomaly. Eight patients required reintervention before discharge due to residual obstruction. The follow-up was available in 96% of the patients. Only 45% of the patients over 15 years of age had cardiology review in the last 2 years. Survival at 10 and 20 years was 94% (95% CI: 91-97%) and 92% (95% CI: 86-95%), respectively. There were a total of 66 late reinterventions in 49 (18%) patients. Ten- and 20-year freedom from reintervention was 84% (95% CI: 78-88%) and 72% (95% CI: 63-80%), respectively. Ten- and 20-year freedom from reobstruction was 75% (95% CI: 69-80%) and 45% (95% CI: 34-55%), respectively. Patients undergoing end-to-side repair from sternotomy had less arch reobstruction than those undergoing extended end-to-end repair by thoracotomy (92 vs 61% freedom from reobstruction at 10 years, P < 0.001). Only 68% of the patients were normotensive at the last follow-up. Arch obstruction on echocardiogram was associated with an increased prevalence of hypertension (P = 0.018).CONCLUSIONSAfter coarctation repair, half of the patients with hypoplasia of the transverse arch will develop arch reobstruction and a third will become hypertensive. The technique of end-to-side repair performed through a sternotomy seems to alleviate these issues, and could be offered to a larger proportion of patients with hypoplasia of the aortic arch. Many of these patients are lost to follow-up during adolescence, at a time when ongoing care seems mandatory.

An Intelligent Knowledge Mining Model for Kidney Cancer Using Rough Set Theory

Medical diagnosis processes vary in the degree to which they attempt to deal with different complicating aspects of diagnosis such as relative importance of symptoms, varied symptom pattern and the relation between diseases themselves. Rough set approach has two major advantages over the other methods. First, it can handle different types of data such as categorical, numerical etc. Secondly, it does not make any assumption like probability distribution function in stochastic modeling or membership grade function in fuzzy set theory. It involves pattern recognition through logical computational rules rather than approximating them through smooth mathematical functional forms. In this paper we use rough set theory as a data mining tool to derive useful patterns and rules for kidney cancer faulty diagnosis. In particular, the historical data of twenty five research hospitals and medical college is used for validation and the results show the practical viability of the proposed approach.

Feasibility of Screening for Urinary Abnormalities As a Part of School Health Appraisal

Role of Omega-3 Ethyl Ester Concentrate in Reducing Sudden Cardiac Death Following Myocardial Infarction and in Management of Hypertriglyceridemia: An Indian Consensus Statement

Sudden cardiac death (SCD) is the most lethal manifestation of heart disease. In an Indian study the SCDs contribute about 10% of the total mortality and SCD post ST elevation myocardial infarction (MI) constitutes for about half of total deaths.

MARCH7 E3 Ubiquitin Ligase is Highly Expressed in Developing Spermatids of Rats and Its Possible Involvement in Head and Tail Formation

Spermatogenesis is a highly complicated metamorphosis process of male germ cells. Recent studies have provided evidence that the ubiquitin-proteasome system plays an important role in sperm head shaping, but the underlying mechanism is less understood. In this study, we localized membrane-associated RING-CH (MARCH)7, an E3 ubiquitin ligase, in rat testis. Northern blot analysis showed that March7 mRNA is expressed ubiquitously but highly in the testis and ovary. In situ hybridization of rat testis demonstrated that March7 mRNA is expressed weakly in spermatogonia and its level is gradually increased as they develop. Immunohistochemical analysis detected MARCH7 protein expression in spermiogenic cells from late round spermatids to elongated spermatids and in epididymal spermatozoa. Moreover, MARCH7 was found to be localized to the caudal end of the developing acrosome of late round and elongating spermatids, colocalizing with β-actin, a component of the acroplaxome. In addition, MARCH7 was also detected in the developing flagella and its expression levels were prominent in elongated spermatids. We also showed that MARCH7 catalyzes lysine 48 (K48)-linked ubiquitination. Immunolocalization studies revealed that K48-linked ubiquitin chains were detected in the heads of elongating spermatids and in the acrosome/acroplaxome, neck, midpiece and cytoplasmic lobes of elongated spermatids. These results suggest that MARCH7 is involved in spermiogenesis by regulating the structural and functional integrity of the head and tail of developing spermatids.

Automated Quantification of Locomotion, Social Interaction, and Mate Preference in Drosophila Mutants

Automated tracking methods facilitate screening for and characterization of abnormal locomotion or more complex behaviors in Drosophila. We developed the Iowa Fly Locomotion and Interaction Tracker (IowaFLI Tracker), a MATLAB-based video analysis system, to identify and track multiple flies in a small arena. We report altered motor activity in the K(+) and Na(+) channel mutants, Hk1 and parats1, which had previously been shown to display abnormal larval locomotion. Environmental factors influencing individual behavior, such as available "social space," were studied by using IowaFLI Tracker to simultaneously track multiple flies in the same arena. We found that crowding levels affect individual fly activity, with the total movement of individual flies attenuated around a particular density. This observation may have important implications in the design of activity chambers for studying particular kinds of social interactions. IowaFLI Tracker also directly quantifies social interactions by tracking the amount of time individuals are in proximity to one another-visualized as an "interactogram." This feature enables the development of a "target-preference" assay to study male courtship behavior where males are presented with a choice between two immobilized, decapitated females, and their locomotion and interactions quantified. We used this assay to study the chemosensory mutants olf D (paraolf D, sbl 2) and Gr32a and their preferences towards virgin or mated females. Male olf D flies showed reduced courtship levels, with no clear preference towards either, whereas Gr32a males preferentially courted with virgin females over mated females in this assay. These initial results demonstrate that IowaFLI Tracker can be employed to explore motor coordination and social interaction phenomena in behavioral mutants of Drosophila.

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