Evaluating medication response in ADHD: cognitive, behavioral, and single-subject methodology

We introduce a novel application for linkage analysis: using bone marrow donor-recipient sib pairs to search for genes influential in graft-versus-host disease (GVHD), a major cause of morbidity and mortality following allogeneic bone marrow transplantation. In particular, we show that transplant sib pairs in which the recipient developed severe GVHD can be used to map genes in the same way as traditional discordant (affected/unaffected) sib pairs (DSPs). For a plausible GVHD model, we demonstrate that the transplant/discordant sib pair analog of the "possible triangle test" [Holmans (1993) Am J Hum Genet 52:362-374] has similar power to that of the simpler "restricted test" proposed by Risch [(1990b) Am J Hum Genet 46:229-241; (1992) Am J Hum Genet 51:673-675]. Moreover, we show that the restricted test has superior power in much of the DSP possible triangle and significantly inferior power in only a small region. Thus, we conclude that the restricted test is preferable for localizing genes with transplant/discordant sib pairs. Finally, we examine the effects of heterogeneity on the power to detect GVHD loci and demonstrate the gain in efficiency by dividing the sample into genetically more homogeneous subgroups.     

Protein topology of presenilin 1

Mutations in a gene encoding a multitransmembrane protein, termed presenilin 1 (PS1), are causative in the majority of early-onset cases of AD. To determine the topology of PS1, we utilized two strategies: first, we tested whether putative transmembranes are sufficient to export a protease-sensitive substrate across a lipid bilayer; and second, we examined the binding of antibodies to specific PS1 epitopes in cultured cells selectively permeabilized with the pore-forming toxin, streptolysin-O. We document that the "loop," N-terminal, and C-terminal domains of PS1 are oriented toward the cytoplasm.     

Stability of linear discrete switched systems with delays based on average dwell time method

This paper deals with the problem of exponential stability for a class of linear discrete switched systems with constant delays.The switched systems consist of stable and unstable subsystems.Based on the average dwell time method, some switching signals will be found to guarantee exponential stability of these systems.The explicit state decay estimation is also given in the form of the solutions of linear matrix inequalities(LMIs).An example relating to networked control systems(NCSs) illustrates the effect...     

Diagnosis and treatment of aortic valve stenosis

The present review has attempted to summarize the classic symptoms and signs of aortic valve stenosis, especially in an adult. It is emphasized that all the classic signs rarely are present and their absence may mislead an unwary clinician. The diagnostic help provided by noninvasive tests, including echocardiography and phonocardiography, has been emphasized. A need for cardiac catheterization and angiography in most patients prior to corrective surgery is stressed. The natural history of the disease without operative intervention is dim and a significant risk of sudden death exists. The current surgical approach with immediate and long-term results is summarized. Finally, attention has been drawn to the special clinical circumstances when the aortic valve stenosis provides a strinkingly different clinical picture. We cannot find a better way to end this review than by quoting a warning note given by Thomas Lewis in 1920: "It is the faint cry of an anguished and fast failing muscle, which, when it comes, all should strain to hear, for it is not long repeated. A few months, a few years at most, and the end comes."     

Growth of Low-Density Vertical Quantum Dot Molecules with Control in Energy Emission

In this work, we present results on the formation of vertical molecule structures formed by two vertically aligned InAs quantum dots (QD) in which a deliberate control of energy emission is achieved. The emission energy of the first layer of QD forming the molecule can be tuned by the deposition of controlled amounts of InAs at a nanohole template formed by GaAs droplet epitaxy. The QD of the second layer are formed directly on top of the buried ones by a strain-driven process. In this way, either symmetric or asymmetric vertically coupled structures can be obtained. As a characteristic when using a droplet epitaxy patterning process, the density of quantum dot molecules finally obtained is low enough (2 × 10⁸ cm⁻²) to permit their integration as active elements in advanced photonic devices where spectroscopic studies at the single nanostructure level are required.     

In vitro translation of a 2.3-kb splicing variant of the hamster pgp1 gene whose presence in transfectants is associated with decreased drug resistance

Adherent macrophage populations derived from monocytes isolated from peripheral blood were evaluated for their ability to "shed" the membrane-associated receptor for TNF-alpha (TNFR) following exposure to a calcium ionophor (A23187) and a synthetic chemotactic peptide (fMLP) reagent. A soluble fraction of TNFR was detected in "cell-free" supernatant produced by stimulated macrophage populations applying 125I-TNF-alpha and biotinylated TNF-alpha ligand-binding analysis (96-well format) in combination with conventional autoradiographic techniques. Approximate molecular weight of the shed TNFR glycoprotein fraction was estimated to be 75 kDa based on interpretation of nondenaturing PAGE gels transferred laterally onto sheets of nitrocellulose membrane subsequently probed by ligand-binding analysis applying 125I-TNF-alpha and biotinylated TNF-alpha as detection modalities. Immunorecognition techniques were also employed to detect TNFR fragments shed from macrophages using biotinylated anti-TNFR Type II (75 kDa) monoclonal antibody in combination with conjugated strepavidin:HRPO and a chemiluminescent substrate reagent. In an effort to identify the class of enzyme directly mediating TNFR Type II (75 kDa) shedding, a spectrum of carboxyl- (e.g., aspartate), hydroxyl- (e.g., serine), thiol (e.g., cysteine), and metalo- (e.g., Ca2+, Mg2+) protease-inhibiting agents were evaluated. Experimental findings implied that a carboxy (aspartate) peptidase, and possibly to a lesser extent, serine (hydroxyl), and thiol (cysteine) peptidases participate in macrophage TNFR Type II (75 kDa) shedding phenomena. Subsequent investigations demonstrated that the carboxy (aspartate) peptidase cathepsin-D promoted liberation of TNFR Type II (75 kDa) in unactivated populations of adherent macrophages. In an effort to complement these observations, a protein fraction with presumed carboxy (aspartate) protease activity was isolated from the cell-free supernatant generated by activated populations of adherent macrophages using immobilized pepstatin-A beaded agarose. Exposure of unstimulated populations of adherent macrophages to the partially purified pepstatin-A binding protein fractions resulted in the liberation of a soluble TNFR Type II (75 kDa) fragment based on interpretation of ligand-binding and immunorecognition analysis of samples developed by SDS-PAGE/PAGE format and transferred onto sheets of nitrocellulose membrane. The molecular weight of the macrophage pepstatin-A binding protein fraction was estimated to be 47-52 kDa with lesser bands also visible at approximately 26-32 kDa, and 100 kDa based on SDS-PAGE analysis. Nondenaturing hemoglobin-PAGE substrate gel analysis of protein fractions possessing pepstatin-A binding-avidity detected a protease with a molecular weight of approximately 47-52 kDa that proteolytically digested hemoglobin, in addition to a synthetic cathepsin-D specific peptide substrate. Collective interpretation of these experimental findings directly corresponds with many of the physical (molecular) and functional (biochemical) characteristics known to be associated with the leukocyte carboxy (aspartate) peptidase cathepsin-D, which is a non-metaloprotease known to exert relatively limited proteolytic activity.     

Coding mammograms using the classification "probably benign finding--short interval follow-up suggested"

OBJECTIVE: Many benign breast lesions revealed by mammography show features indicating that the lesions have a high, but not complete, likelihood of being benign. The Breast Imaging Reporting and Data System (BI-RADS) allows radiologists to classify these mammograms as "probably benign finding-short interval follow-up suggested" (category 3). We explored whether certain factors are associated with the use of category 3 in a national cancer detection program. MATERIALS AND METHODS: We analyzed data from the National Breast and Cervical Cancer Early Detection Program, a comprehensive nationwide program that provides cancer screening for low-income and medically underserved women. The study population included all women at least 40 years old who had undergone mammography on or before September 30, 1996 (n = 372,760). RESULTS: Of the 372,760 mammograms, 7.7% were classified as category 3. The probability of receiving a category 3 classification decreased as patients' ages increased. Women who were symptomatic were nearly twice as likely as women who were asymptomatic to receive a category 3 classification, and women whose clinical breast examinations had abnormal findings were more than twice as likely as women with examinations having normal findings to receive a category 3 classification. The percentage of mammograms classified as category 3 by state or tribal organization ranged from 1.4% to 14.0%. CONCLUSION: Several patient variables, including patient symptomatology, were associated with the probability of having a mammogram classified as category 3. One of the most important determinants was where the patient underwent mammography, which suggests that variability exists among radiologists themselves in using this BI-RADS code for "probably benign" mammographic lesions.     

The effectiveness of early endoscopy for upper gastrointestinal hemorrhage: a community-based analysis

OBJECTIVES: The effectiveness of upper endoscopy in unselected patients with upper gastrointestinal hemorrhage has not been well studied. This study was undertaken to identify factors associated with the performance of early endoscopy (ie, within 1 day of hospitalization) and, after adjusting for these factors, to determine associations between early endoscopy and in-hospital mortality, length of stay, and performance of surgery. METHODS: Subjects in this observational cohort study were 3,801 consecutive admissions with upper gastrointestinal hemorrhage to 30 hospitals in a large metropolitan region. Demographic and clinical data were abstracted from hospital records. A multivariable model based on factors that potentially could relate to the decision to perform endoscopy was developed to determine the propensity (0 to 100%) for early endoscopy in each patient. RESULTS: Early endoscopy was performed in 2,240 patients (59%), and although it was not associated with mortality after adjusting for severity of illness among all patients, it was associated with a higher risk of death for patients in the lowest propensity group. Early endoscopy was associated with a lower likelihood of upper gastrointestinal surgery in all patients and in the two highest propensity groups and with a shorter length of stay in the entire cohort and in all subgroups. CONCLUSIONS: In the absence of specific contraindications, early endoscopy should be considered because of associated reductions in length of stay and surgical intervention. Further studies are needed to identify subgroups in whom the procedure may be associated with adverse effects on survival.     

Laboratory investigation of the mass stability of sampling cassettes from inhalable aerosol samplers

A study was conducted to evaluate the mass stability of the materials used in the construction of samplers with internal cassettes for the gravimetric measurement of inhalable aerosol exposures. The internal cassettes from IOM samplers were studied. Results indicate that the mass stability of filters is uniform, but the mass stability of the cassette material may dramatically affect the results of the measurement. Cassettes constructed from plastic exhibited drastic shifts in mass depending on the environmental conditions of their storage. Under room humidity, the plastic cassettes absorbed 1 to 2 mg of water over several days. When these cassettes were placed in a desiccator, they lost mass consistently but did not approach a stable mass. Studies repeated with cassettes made of stainless steel showed negligible mass variability. Based on this study, the use of stainless steel cassettes is recommended for gravimetric determinations of aerosol exposure, although field blanks may in some cases be used for correction of data from plastic cassettes. This study shows the need to evaluate the mass stability of the cassette material of any sampling device where an internal cassette is weighed together with the filter.