The pallid mouse. A model of genetic alpha 1-antitrypsin deficiency

A single dose pharmacokinetic study with modified human Interleukin-1 Beta (IL-1 beta or DuP 118) was performed by injecting 5 micrograms/kg of drug into the jugular vein of three beagle dogs. Serial 5-ml plasma samples were removed from the dogs over a 120-minute period. DuP 118 plasma levels were measured using a sandwich ELISA technique capable of measuring concentrations ranging from 0.25 to 2 ng/ml with accuracy and precision constraints of less than +/- 20% variability. DuP 118 stored at -20 degrees C in dog plasma was stable for at least 1 month. Pharmacokinetic parameters were determined for the three dogs by standard model independent or non-compartmental methods. DuP 118 was rapidly distributed in the dog. The volume of distribution was approximately two-fold higher than the total body water of a lean dog. The terminal half-life was short, less than 30 minutes. Within approximately an hour after dosing, DuP 118 plasma levels were reduced 20-fold and were below the quantifiable limit of the assay.     

Interaction of thymidylate synthase with pyridoxal 5'-phosphate as studied by UV/visible difference spectroscopy and molecular modeling

Pyridoxal 5'-phosphate (PLP) is an effective inhibitor of Lactobacillus casei thymidylate synthase (TS), competitive with respect to the nucleotide substrate dUMP (Chen et al., 1989). The UV/vis difference spectra of TS-PLP complexes show lambda max at 328 nm due to the specific interaction between Cys 198 of TS and PLP to form a thiohemiacetal, and lambda min at 388 nm due to depletion of free PLP. At high concentrations of PLP a new absorbance at 430 nm forms due to nonspecific Schiff base formation between PLP and lysine residues of the enzyme. Using spectral titration at 328 nm, the binding constant of the specific TS-PLP complex was determined to be 0.5 microM, and the stoichiometry was 2 mol of PLP/mol of TS dimer. The 328-nm absorbance of the TS-PLP complex can be competitively and completely eliminated by addition of dUMP or dTMP; this serves as a convenient binding assay for molecules which bind to the active site of TS. Analogs of PLP which do not contain the phosphate or the aldehyde moieties of PLP bound poorly to the enzyme, thus demonstrating the importance of these functional groups for binding. When treated with PLP, C244T TS, which contains the active site Cys 198 as the sole cysteine residue, showed the same properties as the wild-type enzyme. Treatment of the C198A and C198S mutants with PLP did not produce the absorbance at 328 nm assigned to thiohemiacetal formation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pain mapping during minilaparoscopy in infertile patients without pathology

Multiple myeloma (MM) typically afflicts elderly patients with a median age of 65 years. However, while recently shown to provide superior outcome to standard treatment, high-dose therapy (HDT) has usually been limited to patients up to 65 years. Among 550 patients with MM and a minimum follow-up of 18 months, 49 aged >/=65 years were identified (median age, 67; range, 65 to 76 years). Their outcome was compared with 49 younger pair mates (median, 52; range, 37 to 64 years) selected among the remaining 501 younger patients (<65 years) matched for five previously recognized critical prognostic factors (cytogenetics, beta2-microglobulin, C-reactive protein, albumin, creatinine). Nearly one half had been treated for more than 1 year with standard therapy and about one third had refractory MM. All patients received high-dose melphalan-based therapy; 76% of the younger and 65% of the older group completed a second transplant (P =.3). Sufficient peripheral blood stem cells to support two HDT cycles (CD34 > 5 x 10(6)/kg) were available in 83% of younger and 73% of older patients (P =.2). After HDT, hematopoietic recovery to critical levels of granulocytes (>500/microL) and of platelets (>50,000/microL) proceeded at comparable rates among younger and older subjects with both first and second HDT. The frequency of extramedullary toxicities was comparable. Treatment-related mortality with the first HDT cycle was 2% in younger and 8% among older subjects, whereas no mortality was encountered with the second transplant procedure. Comparing younger/older subjects, median durations of event-free and overall survival were 2.8/1.5 years (P =.2) and 4.8/3.3 years (P =.4). Multivariate analysis showed pretransplant cytogenetics and beta2-microglobulin levels as critical prognostic features for both event-free and overall survival, whereas age was insignificant for both endpoints (P =.2/.8). Thus, age is not a biologically adverse parameter for patients with MM receiving high-dose melphalan-based therapy with peripheral blood stem cell support and, hence, should not constitute an exclusion criterion for participation in what appears to be superior therapy for symptomatic MM.     

A sparse Bayesian approach for joint feature selection and classifier learning

In this paper we present a new method for Joint Feature Selection and Classifier Learning using a sparse Bayesian approach. These tasks are performed by optimizing a global loss function that includes a term associated with the empirical loss and another one representing a feature selection and regularization constraint on the parameters. To minimize this function we use a recently proposed technique, the Boosted Lasso algorithm, that follows the regularization path of the empirical risk associated with our loss function. We develop the algorithm for a well known non-parametrical classification method, the relevance vector machine, and perform experiments using a synthetic data set and three databases from the UCI Machine Learning Repository. The results show that our method is able to select the relevant features, increasing in some cases the classification accuracy when feature selection is performed.     

An Acceptability Trial of Desiccated Beef Liver and Meat Powder as Potential Fortifiers of Complementary Diets of Young Children in Indonesia

The addition of desiccated beef liver to infant and young child complementary foods can be used to overcome nutrient deficits, however its acceptability is unknown. We conducted a series of studies to test the acceptability of complementary foods fortified with either powdered beef liver, beef meat, beef liver + meat or placebo among 96 Indonesian children aged 12 to 23 mo. This was achieved by determining liking of a single test food with added study powder, followed by a 2‐wk home trial and focus group discussions to assess liking during repeated consumption of the study powders added to daily meals. The test food with added beef powders were well liked by mothers, with liking scores never falling below neutral on a 7‐point scale. After home use, mothers reported that their children moderately liked their meals with added powder, with scores ranging between 3.3 and 3.5 on a 5‐point scale. With the exception of lower liking for the combination beef liver + meat powder, there were no detectable differences in mothers’ overall perception of child's liking between the placebo and any of the study powders. The low disappearance rate of the study powders during the home trial was a concern, with mothers reporting a strong smell and fishy odor as the major reason why children did not like their meals. Nonetheless, mothers declared they would continue using the powder on account of the nutritional value and perceived health benefits. Strategies are underway to minimize the level of fishy odor in the beef liver powder.     

On CS Image Reconstruction Using LDPC Code Over Radio Mobile Channel

In this work, the effect of additive white Gaussian noise and fading channel on the compressed sensing or compressive sampling (CS) image reconstruction process are demonstrated. First, the work suggests encoding of the sensed samples by low density parity check code (LDPC) before transmission. It is well known that longer is the length of the LDPC codes better (lower) is the bit error rate (BER) performance. Thus to improve CS reconstruction a method to construct a larger length but 4 cycle free irregular LDPC code structure is also proposed. The code construction is based on the LDPC code in IEEE WiMAX standard. The proposed CS-LDPC structure is then extended for \(4^n\)-QAM to find an optimal set of thresholds by minimizing BER (equivalently symbol error rate) using differential evolution (DE). The algorithm works on the log likelihood ratio values obtained by LDPC decoding. Extensive simulation results show the efficacy of the use of LDPC codes and the trade-off in code rate and measurements on reconstruction quality. Improved performance with the proposed DE based demodulation is also demonstrated.     

An iterative ITI cancellation method for multi-head multi-track bit-patterned magnetic recording systems

Bit-Patterned Magnetic Recording (BPMR) is one of the emerging data storage technologies, which promises an Areal Density (AD) of about 4 Tb/in². However, a major problem practically encountered in a BPMR system is Inter-Track Interference (ITI) that can deteriorate the overall system performance, especially at high ADs. This paper proposes an iterative ITI cancellation method for an m-head m-track BPMR system, which uses m heads to read m adjacent tracks and decodes them simultaneously. To cancel the ITI, we subtract the weighted readback signals of adjacent tracks, acting as the ITI signals, from the readback signal of the target track, before passing the refined readback signal to a turbo decoder. Then, the decoded data will be employed to reconstruct the ITI signal for the next turbo iteration. Experimental results indicate that the proposed system performs better than the conventional system that uses one head to read one data track. Furthermore, we also find out that the proposed system is more robust to media noise and track misregistration than the conventional system.     

Monitoring Snow Characteristics With Ground-Based Multifrequency Microwave Radiometry

Long-term microwave and infrared radiometric measurements of snowpack were carried out with ground-based sensors in winter 2006-2007 and 2007-2008, together with conventional measurements of snow-cover profiles. The first experiment focused on the behavior of snow emission during the destructive and constructive metamorphisms. The second involved a correlation analysis of the small fluctuations related to diurnal solar cycle in order to obtain the time delay of microwave brightness temperatures Tb with respect to the snow surface temperature. From this analysis, it was possible to estimate an effective (weighed average) temperature and the thickness of the layer that mostly contributed to microwave emission at 19 and 37 GHz. The ratio of the brightness temperature to the effective temperature can be assumed to be an equivalent emissivity of the snowpack. Data collected in both years have been compared with simulations carried out using the advanced Institute of Applied Physics (IFAC) Radiative Advanced Dry Snow Emission (IRIDE) model driven by data collected on ground. The model is based on the advanced integral equation method to represent soil, coupled to a layer of dry snow whose electromagnetic properties are described by the dense medium radiative transfer theory with quasi-crystalline approximation applied to a medium (air) filled with sticky particles. Simulations performed by using ground data as inputs to the model have been found to be well in agreement with experimental data. Moreover, the comparison of model simulations with experimental data allowed one to understand some peculiar characteristics of microwave emission from the snowpack related to its physical conditions.     

An assessment of wide bandgap semiconductors for power devices

An advantage for some wide bandgap materials, that is often overlooked, is that the thermal coefficient of expansion (CTE) is better matched to the ceramics in use for packaging technology. It is shown that the optimal choice for uni-polar devices is clearly GaN. It is further shown that the future optimal choice for bipolar devices is C (diamond) owing to the large bandgap, high thermal conductivity, and large electron and hole mobilities. A new expression relating the critical electric field for breakdown in abrupt junctions to the material bandgap energy is derived and is further used to derive new expressions for specific on-resistance in power semiconductor devices. These new expressions are compared to the previous literature and the efficacy of specific power devices, such as heterojunction MOSFETs, using GaN are discussed.     

Quantitative Systems Pharmacology and Biased Agonism at Opioid Receptors: A Potential Avenue for Improved Analgesics

Chronic pain is debilitating and represents a significant burden in terms of personal and socio-economic costs. Although opioid analgesics are widely used in chronic pain treatment, many patients report inadequate pain relief or relevant adverse effects, highlighting the need to develop analgesics with improved efficacy/safety. Multiple evidence suggests that G protein-dependent signaling triggers opioid-induced antinociception, whereas arrestin-mediated pathways are credited with modulating different opioid adverse effects, thus spurring extensive research for G protein-biased opioid agonists as analgesic candidates with improved pharmacology. Despite the increasing expectations of functional selectivity, translating G protein-biased opioid agonists into improved therapeutics is far from being fully achieved, due to the complex, multidimensional pharmacology of opioid receptors. The multifaceted network of signaling events and molecular processes underlying therapeutic and adverse effects induced by opioids is more complex than the mere dichotomy between G protein and arrestin and requires more comprehensive, integrated, network-centric approaches to be fully dissected. Quantitative Systems Pharmacology (QSP) models employing multidimensional assays associated with computational tools able to analyze large datasets may provide an intriguing approach to go beyond the greater complexity of opioid receptor pharmacology and the current limitations entailing the development of biased opioid agonists as improved analgesics.