Whole-exome sequencing for diagnosis of Peters-plus syndrome after prenatal diagnosis of recurrent low PAPP-A and multiple fetal anomalies in two consecutive pregnancies.

 We report a case of two consecutive pregnancies in the same couple presenting with very low pregnancy-associated plasma protein A (PAPP-A), with both pregnancies affected by multiple anomalies of a similar phenotype identified during mid-trimester ultrasound, and eventual diagnosis of Peters-plus syndrome. This case is important in expanding the differential for very low PAPP-A. It also demonstrates the diagnostic value of whole-exome sequencing (WES) after prenatal diagnosis of recurrent fetal ultrasonographic findings. The importance and complexity of providing patient education to enable informed consent for next generation sequencing technologies is discussed.

Whole-exome sequencing for diagnosis of Peters-plus syndrome after prenatal diagnosis of recurrent low PAPP-A and multiple fetal anomalies in two consecutive pregnancies.

 We report a case of two consecutive pregnancies in the same couple presenting with very low pregnancy-associated plasma protein A (PAPP-A), with both pregnancies affected by multiple anomalies of a similar phenotype identified during mid-trimester ultrasound, and eventual diagnosis of Peters-plus syndrome. This case is important in expanding the differential for very low PAPP-A. It also demonstrates the diagnostic value of whole-exome sequencing (WES) after prenatal diagnosis of recurrent fetal ultrasonographic findings. The importance and complexity of providing patient education to enable informed consent for next generation sequencing technologies is discussed.

An Empirical Study of Personality Disorders Among Treatment-Seeking Problem Gamblers.

The primary aims of this study were to examine the prevalence of personality disorders in problem gamblers, to explore the relationship between personality disorders and problem gambling severity, and to explore the degree to which the psychological symptoms highlighted in the biosocial developmental model of borderline personality disorder (impulsivity, distress tolerance, substance use, PTSD symptoms, psychological distress and work/social adjustment) are associated with problem gambling. A secondary aim was to explore the strength of the relationships between these symptoms and problem gambling severity in problem gamblers with and without personality disorder pathology. Participants were 168 consecutively admitted problem gamblers seeking treatment from a specialist outpatient gambling service in Australia. The prevalence of personality disorders using the self-report version of the Iowa Personality Disorders Screen was 43.3 %. Cluster B personality disorders, but not Cluster A or C personality disorders, were associated with problem gambling severity. All psychological symptoms, except alcohol and drug use, were significantly higher among participants with personality disorder pathology compared to those without. Finally, psychological distress, and work and social adjustment were significantly associated with problem gambling severity for problem gamblers with personality disorder pathology, while impulsivity, psychological distress, and work and social adjustment were significantly associated with problem gambling severity for those without personality disorder pathology. High rates of comorbid personality disorders, particularly Cluster B disorders, necessitate routine screening in gambling treatment services. More complex psychological profiles may complicate treatment for problem gamblers with comorbid personality disorders. Future research should examine the applicability of the biosocial developmental model to problem gambling in community studies.

A New Experiment for Investigating Evaporation and Condensation of Cryogenic Propellants.

Passive and active technologies have been used to control propellant boil-off, but the current state of understanding of cryogenic evaporation and condensation in microgravity is insufficient for designing large cryogenic depots critical to the long-term space exploration missions. One of the key factors limiting the ability to design such systems is the uncertainty in the accommodation coefficients (evaporation and condensation), which are inputs for kinetic modeling of phase change. A novel, combined experimental and computational approach is being used to determine the accommodation coefficients for liquid hydrogen and liquid methane. The experimental effort utilizes the Neutron Imaging Facility located at the National Institute of Standards and Technology (NIST) in Gaithersburg, Maryland to image evaporation and condensation of hydrogenated propellants inside of metallic containers. The computational effort includes numerical solution of a model for phase change in the contact line and thin film regions as well as an CFD effort for determining the appropriate thermal boundary conditions for the numerical solution of the evaporating and condensing liquid. Using all three methods, there is the possibility of extracting the accommodation coefficients from the experimental observations. The experiments are the first known observation of a liquid hydrogen menisci condensing and evaporating inside aluminum and stainless steel cylinders. The experimental technique, complimentary computational thermal model and meniscus shape determination are reported. The computational thermal model has been shown to accurately track the transient thermal response of the test cells. The meniscus shape determination suggests the presence of a finite contact angle, albeit very small, between liquid hydrogen and aluminum oxide.

R-Ras interacts with filamin a to maintain endothelial barrier function.

The molecular mechanisms regulating vascular barrier integrity remain incompletely elucidated. We have previously reported an association between the GTPase R-Ras and repeat 3 of Filamin A (FLNa). Loss of FLNa has been linked to increased vascular permeability. We sought to determine whether FLNa's association with R-Ras affects endothelial barrier function. We report that in endothelial cells endogenous R-Ras interacts with endogenous FLNa as determined by co-immunoprecipitations and pulldowns with the FLNa-GST fusion protein repeats 1-10. Deletion of FLNa repeat 3 (FLNaΔ3) abrogated this interaction. In these cells FLNa and R-Ras co-localize at the plasma membrane. Knockdown of R-Ras and/or FLNa by siRNA promotes vascular permeability, as determined by TransEndothelial Electrical Resistance and FITC-dextran transwell assays. Re-expression of FLNa restored endothelial barrier function in cells lacking FLNa whereas re-expression of FLNaΔ3 did not. Immunostaining for VE-Cadherin in cells with knocked down R-Ras and FLNa demonstrated a disorganization of VE-Cadherin at adherens junctions. Loss of R-Ras and FLNa or blocking R-Ras function via GGTI-2133, a selective R-Ras inhibitor, induced vascular permeability and increased phosphorylation of VE-Cadherin (Y731) and Src (Y416). Expression of dominant negative R-Ras promoted vascular permeability that was blocked by the Src inhibitor PP2. These findings demonstrate that maintaining endothelial barrier function is dependent upon active R-Ras and association between R-Ras and FLNa and that loss of this interaction promotes VE-Cadherin phosphorylation and changes in downstream effectors that lead to endothelial leakiness.

Proinsulin peptide immunotherapy in type 1 diabetes: report of a first-in-man Phase I safety study.

Immunotherapeutic strategies under consideration for type 1 diabetes include modification of the autoimmune response through antigen-specific routes. Administration of short peptides representing T cell epitopes targeted by patients with the disease represents one approach. This study evaluated safety and mechanistic outcomes during first-in-man intradermal administration of a human leucocyte antigen-DR4 (HLA-DR4)-restricted peptide epitope of proinsulin (C19-A3). This randomized, open-label study assessed two major theoretical risks of peptide immunotherapy, namely induction of allergic hypersensitivity and exacerbation of the proinflammatory autoimmune response, using clinical assessment and mechanistic assays in vitro. Patients with long-standing type 1 diabetes and HLA-DRB1*0401 genotype received 30 microg (n = 18) or 300 microg (n = 18) of peptide in three equal doses at 0, 1 and 2 months or no intervention (n = 12). Proinsulin peptide immunotherapy in the dosing regimen used is well tolerated and free from risk of systemic hypersensitivity and induction/reactivation of proinsulin-specific, proinflammatory T cells. Peptide-specific T cells secreting the immune suppressive cytokine interleukin (IL)-10 were observed at month 3 in four of 18 patients in the low-dose group (versus one of 12 in the control group; P = not significant). Mean IL-10 response to peptide in the low-dose group increased between 0 and 3 months (P = 0.05 after stimulation with 5 microM peptide in vitro) and then declined to baseline levels between 3 and 6 months (P = 0.01 at 10 microM peptide in vitro). These studies pave the way for future investigations in new-onset patients designed to examine whether proinsulin peptide immunotherapy has beneficial effects on markers of T cell autoimmunity and preservation of beta cell mass.

Effects of temperature variation on suicide in five U.S. counties, 1991-2001.

Effects of weather variables on suicide are well-documented, but there is still little consistency among the results of most studies. Nevertheless, most studies show a peak in suicides during the spring season, and this is often attributed to increased temperatures. The purpose of this study is to test the relationship between monthly temperature and monthly suicide, independent of months or seasons, for five counties located across the United States. Harmonic analysis shows that four of the five counties display some seasonal components in the suicide data. However, simple linear regression shows no correlation between suicide and temperature, and discriminant analysis shows that monthly departure from mean annual suicide rates is not a useful tool for identifying months with temperatures that are colder or warmer than the annual average. Therefore, it appears that the seasonality of suicides is due to factors other than temperature.

Mechanical resonances of bacteria cells.

The quality of the natural vibrations of specific bacteria is investigated using a shell model which accounts for the elastic properties of the membrane and the associated viscosities of the cytoplasma and the surrounding fluid. The motion of the membrane is approximated in terms of the distribution of internal forces over the shell thickness, which is assumed to be much less than the size of the cell. Flexural moments and intersecting stresses are neglected. Using experimentally obtained values for the membrane properties, high-quality resonances are predicted for several types of bacteria which have radii greater than 5 microm. Viscous shear waves are the main source of energy dissipation as has been previously reported in other studies on the natural oscillations of red blood cells, drops, and bubbles. Implications for the acoustic mediated destruction of bacteria are discussed.

Echocardiographic characterization of fundamental mechanisms of abnormal diastolic filling in diabetic rats with a parameterized diastolic filling formalism.

Abnormalities of diastolic function (DF) precede systolic dysfunction in diabetic cardiomyopathy. Transmitral Doppler flow analysis is the primary method for noninvasively assessing DF. We used model-based Doppler E-wave analysis to evaluate diastolic function differences between normal and diabetic rat hearts. Control rats and those with diabetes underwent echocardiography with analysis by traditional Doppler indexes and by the parameterized diastolic filling (PDF) formalism, generating 3 parameters, x0, c, and k, that uniquely characterize each E-wave. Significant intergroup differences in the E/A ratios (P <.01), isovolumic relaxation times (P <.01), and the modeling parameter c (P <.05) were found. There were no significant differences in shortening fraction, deceleration time, myocardial collagen content, or the parameters x0 and k between diabetic and control rats. These results indicate that differences in diastolic function may be noninvasively quantified and that diabetic hearts may exhibit defects in uncoupling of the contractile apparatus without concomitant increases in chamber stiffness.

Novel MRI contrast agent for molecular imaging of fibrin: implications for detecting vulnerable plaques.

BACKGROUND: Molecular imaging of thrombus within fissures of vulnerable atherosclerotic plaques requires sensitive detection of a robust thrombus-specific contrast agent. In this study, we report the development and characterization of a novel ligand-targeted paramagnetic molecular imaging agent with high avidity for fibrin and the potential to sensitively detect active vulnerable plaques. METHODS AND RESULTS: The nanoparticles were formulated with 2.5 to 50 mol% Gd-DTPA-BOA, which corresponds to >50 000 Gd(3+) atoms/particle. Paramagnetic nanoparticles were characterized in vitro and evaluated in vivo. In contradistinction to traditional blood-pool agents, T1 relaxation rate as a function of paramagnetic nanoparticle number was increased monotonically with Gd-DTPA concentration from 0.18 mL. s(-1). pmol(-1) (10% Gd-DTPA nanoparticles) to 0.54 mL. s(-1). pmol(-1) for the 40 mol% Gd-DTPA formulations. Fibrin clots targeted in vitro with paramagnetic nanoparticles presented a highly detectable, homogeneous T1-weighted contrast enhancement that improved with increasing gadolinium level (0, 2.5, and 20 mol% Gd). Higher-resolution scans and scanning electron microscopy revealed that the nanoparticles were present as a thin layer over the clot surface. In vivo contrast enhancement under open-circulation conditions was assessed in dogs. The contrast-to-noise ratio between the targeted clot (20 mol% Gd-DTPA nanoparticles) and blood was approximately 118+/-21, and that between the targeted clot and the control clot was 131+/-37. CONCLUSIONS: These results suggest that molecular imaging of fibrin-targeted paramagnetic nanoparticles can provide sensitive detection and localization of fibrin and may allow early, direct identification of vulnerable plaques, leading to early therapeutic decisions.

Contextual influences on the internal structure of phonetic categories: a distinction between lexical status and speaking rate.

Previous research has shown that phonetic categories have a graded internal structure that is highly dependent on acoustic-phonetic contextual factors, such as speaking rate; these factors alter not only the location of phonetic category boundaries, but also the location of a category's best exemplars. The purpose of the present investigation, which focused on the voiceless category as specified by voice onset time (VOT), was to determine whether a higher order linguistic contextual factor, lexical status, which is known to alter the location of the voiced-voiceless phonetic category boundary, also alters the location of the best exemplars of the voiceless category. The results indicated that lexical status has a more limited and qualitatively different effect on the category's best exemplars than does the acoustic-phonetic factor of speaking rate. This dissociation is discussed in terms of a production-based account in which perceived best exemplars of a category track contextual variation in speech production.

Shell waves and acoustic scattering from ultrasound contrast agents.

Ultrasound contrast agents are encapsulated microbubbles, filled either with air or a higher weight molecular gas, ranging in size from 1 to 10 microns in diameter. The agents are modeled as air-filled spherical elastic shells of variable thickness and material properties. The scattered acoustic field is computed from a modal series solution, and reflectivity and angular scattering are then determined from the computed fields for agents of various properties. We show that contrast agents also support shell resonance responses in addition to the monopole response, which has been the focus of previous contrast agent studies. Lamb waves appear to be the source of these additional responses. A shell or curvature Lamb wave generates dipole peaks in the 1- to 40-MHz range for 2.5 to 3.5 microns radius agents with elastic properties approximating those of albumin protein. The inclusion of damping affects the lower frequency dipole peaks but is less important for responses occurring above approximately 30 MHz. Moreover, these responses hold untapped potential for clinical ultrasound applications such as tissue perfusion studies and high frequency contrast agent imaging.

Optical and acoustical dynamics of microbubble contrast agents inside neutrophils.

Acoustically active microbubbles are used for contrast-enhanced ultrasound assessment of organ perfusion. In regions of inflammation, contrast agents are captured and phagocytosed by activated neutrophils adherent to the venular wall. Using direct optical observation with a high-speed camera and acoustical interrogation of individual bubbles and cells, we assessed the physical and acoustical responses of both phagocytosed and free microbubbles. Optical analysis of bubble radial oscillations during insonation demonstrated that phagocytosed microbubbles experience viscous damping within the cytoplasm and yet remain acoustically active and capable of large volumetric oscillations during an acoustic pulse. Fitting a modified version of the Rayleigh-Plesset equation that describes mechanical properties of thin shells to optical radius-time data of oscillating bubbles provided estimates of the apparent viscosity of the intracellular medium. Phagocytosed microbubbles experienced a viscous damping approximately sevenfold greater than free microbubbles. Acoustical comparison between free and phagocytosed microbubbles indicated that phagocytosed microbubbles produce an echo with a higher mean frequency than free microbubbles in response to a rarefaction-first single-cycle pulse. Moreover, this frequency increase is predicted using the modified Rayleigh-Plesset equation. We conclude that contrast-enhanced ultrasound can detect distinct acoustic signals from microbubbles inside of neutrophils and may provide a unique tool to identify activated neutrophils at sites of inflammation.

Cross-cultural analysis of eventfulness in the lives of people with schizophrenia.

Eventfulness as a strategy for creating a meaningful life is an important component of the attempts of people with schizophrenia to present a positive self-image. This study of patients with schizophrenia shows that the phenomenon of creating eventfulness through normalcy accounts is relevant cross-culturally, with common themes occurring in the speech of participants from Papua New Guinea and New Zealand. Both patient (n = 23) and nonpatient (n = 27) participants from these two countries were interviewed as part of a larger research project. Conversational speech of participants was analyzed for passages that could be defined as normalcy accounts. A total of 61 such accounts were obtained from the conversational samples. The three most common themes of normalcy accounts (educational achievement and goals, national pride, and travel) were characteristic of the self-presentation of nonpatient subjects as well as patients with schizophrenia. Normalcy themes varied slightly depending on nationality and patient or nonpatient status. The similarity of both normalcy account themes and presentation, however, was remarkably consistent across cultures.

Effects of chewing betel nut (Areca catechu) on the symptoms of people with schizophrenia in Palau, Micronesia.

BACKGROUND: Although millions of people with schizophrenia live in betel chewing regions, the effects of betel chewing on their symptoms are unknown. Betel nut alkaloids include potent muscarinic cholinomimetics: recent research suggests that these agents may be therapeutic in schizophrenia. AIMS: To compare the primary and extrapyramidal symptom profiles and substance-using habits of betel chewing v. non-chewing people with schizophrenia. METHOD: A cross-sectional study of 70 people with schizophrenia. Symptom ratings measured by the Positive and Negative Syndrome Scale (PANSS) and Extrapyramidal Symptom Rating Scale (ESRS), and demographic and substance-use data, were compared for 40 chewers and 30 non-chewers of betel nut. RESULTS: Betel chewers with schizophrenia scored significantly lower on the positive (P = 0.001) and negative (P = 0.002) sub-scales of the PANSS than did non-chewers. There were no significant differences in extrapyramidal symptoms or tardive dyskinesia. CONCLUSIONS: Betel chewing is associated with milder symptomatology and avoidance of more harmful recreational drugs. These initial results indicate that longitudinal research is merited.

Dynamics of gas bubbles in viscoelastic fluids. II. Nonlinear viscoelasticity.

The nonlinear oscillations of a spherical, acoustically forced gas bubble in nonlinear viscoelastic media are examined. The constitutive equation [Upper-Convective Maxwell (UCM)] used for the fluid is suitable for study of large-amplitude excursions of the bubble, in contrast to the previous work of the authors which focused on the smaller amplitude oscillations within a linear viscoelastic fluid [J. S. Allen and R. A. Roy, J. Acoust. Soc. Am. 107, 3167-3178 (2000)]. Assumptions concerning the trace of the stress tensor are addressed in light of the incorporation of viscoelastic constitutive equations into bubble dynamics equations. The numerical method used to solve the governing system of equations (one integrodifferential equation and two partial differential equations) is outlined. An energy balance relation is used to monitor the accuracy of the calculations and the formulation is compared with the previously developed linear viscoelastic model. Results are found to agree in the limit of small deformations; however, significant divergence for larger radial oscillations is noted. Furthermore, the inherent limitations of the linear viscoelastic approach are explored in light of the more complete nonlinear formulation. The relevance and importance of this approach to biomedical ultrasound applications are highlighted. Preliminary results indicate that tissue viscoelasticity may be an important consideration for the risk assessment of potential cavitation bioeffects.

Lactose digestion capacity in Tokelauans: a case for the role of gene flow and genetic drift in establishing the lactose absorption allele in a Polynesian population.

Throughout the Pacific, lactose absorption occurs at rates of 0-46%. Most authors explain the current rate of lactose absorption in the Pacific in terms of gene flow with Europeans. However, researchers have not been able to determine the exact historical circumstances of the introduction of the lactose absorption gene. The availability of genealogical material, historical information, and mal/absorption frequencies for Tokelau (a Polynesian population) presents a unique opportunity to examine the role of gene flow in establishing lactose absorption in Pacific isolates. In an earlier study, Cheer and Allen ([1997] Am. J. Hum. Biol. 93:1-34) determined lactose digestion capacities for 58 Tokelauans. In the current study, we constructed pedigrees for the same 58 individuals, using the Tokelau Island Migrant Study genealogies (Wessen et al. [1992]). Results indicated that 8 of 13 lactose-absorbing individuals have European ancestors, compared with only 4 of 35 lactose malabsorbers (Chi(2) = 15.75, P < 0.01). Six lactose-absorbing individuals have either American or Portuguese ancestors dating back to the mid-1800s. Historical data were used to establish the contribution of Portuguese and American genetic material to the Tokelau population following massive depopulation after the Peruvian slave raids of 1863. This study provides clear evidence for the role of a population bottleneck followed by gene flow and genetic drift in establishing lactose absorption in the Tokelau population. Furthermore, it is the first study of a Pacific population to directly link lactose absorption with gene flow.

Left ventricular contractility is impaired following myocardial infarction in the pig and rat: assessment by the end systolic pressure-volume relation using a single-beat estimation technique and cine magnetic resonance imaging.

The end systolic pressure-volume relation (ESPVR) has been shown to be a relatively load independent measure of left ventricular (LV) contractility. Recently, several single-beat ESPVR computation methods have been developed, enabling the quantification of LV contractility without the need to alter vascular loading conditions on the heart. Using a single-beat ESPVR method, which has been validated previously in humans and assumes that normalized elastance is constant between individuals of a species, we studied the effects of myocardial infarction on LV contractility in two species, the rat and the pig. In our studies, LV pressure was acquired invasively and LV volume determined noninvasively with magnetic resonance imaging, at one week postinfarction in pigs and at 12 weeks postinfarction in rats. Normalized systolic elastance curves in both animal species were not statistically different from that of humans. Also, the slope of the ESPVR (Ees) decreased significantly following infarction in both species, while the volume-axis intercept (V0) was unaffected. These results indicate that a single-beat ESPVR method can be used to measure the inotropic response of the heart to myocardial infarction, and that the basis for this method (i.e., constant normalized elastance) is applicable to a variety of mammalian species.