Molecular chemisorption of N2 on IrO2(110).

We investigated adsorption of N2 on stoichiometric and O-rich IrO2(110) surfaces using temperature programmed desorption (TPD) experiments and density functional theory (DFT) calculations. TPD shows that N2 desorbs predominantly from the stoichiometric-IrO2(110) surface in a well-defined peak at 270 K for N2 coverages below about 0.5 ML and that a shoulder centered near 235 K develops in the N2 TPD traces as the coverage approaches saturation, indicating that adsorbed N2 molecules destabilize at high N2 coverages. Experiments of N2 adsorption onto O-rich IrO2(110) surfaces provide evidence that N2 adsorbs exclusively on the coordinatively unsaturated Ir atoms (Ircus) of the surface and that pre-adsorbed O-atoms ("on-top" oxygen) stabilize adsorbed N2 molecules, causing the main N2 TPD peak to shift toward higher temperature with increasing oxygen coverages. Consistent with prior results, our DFT calculations predict that an N2 molecule preferentially adsorbs into an upright configuration on an Ircus atom of the IrO2(110) surface and achieves a binding energy of about 100 kJ/mol. The computed binding energy agrees well with our experimental estimate of ∼90 kJ/mol for low N2 coverages on stoichiometric IrO2(110). The DFT calculations also quantitatively reproduce the observed stabilization of N2 by co-adsorption on-top O-atoms and predict the destabilization of N2 on IrO2(110) as the N2 adlayer becomes crowded at high coverages.

Commentary on R&D Trends Away from General Medicine/Cardiovascular Drugs: Can the FDA Help Reverse the Trend?

In the latter part of the 20th century, drug development in cardiovascular diseases (CVDs) was a paragon of "modern" therapeutics, bringing about a substantial number of effective, well-tolerated agents targeting some of the most prevalent diseases of the Western world. These drugs were often examples of rational drug development targeting specific pathophysiologic pathways previously elucidated through basic research (e.g., targeting of the renin-angiotensin system or the cholesterol synthesis pathway). The widespread adoption of these ground-breaking medications in practice and into medical guidelines undoubtedly played a role in the fall of morbidity and mortality from CVD in the United States in recent decades. For instance, the combined, age-adjusted rates of death due to heart disease and CVD fell in the United States from an aggregate of 329.6 per 100,000 in 1999 to 203.5 in 2014. Although lifestyle trends (e.g., decreased smoking prevalence) contributed to this decline, the impact of safe and effective medications for common CVD conditions cannot be dismissed. Yet, despite the drop in CVD morbidity and mortality, CVDs remain a leading cause of morbidity and mortality in the United States and, therefore, a large area of unmet medical need.

Should recent experiences with CVOTs for oral hypoglycemic drugs allow us to rethink the regulatory paradigm?

In response to a meta-analysis raising significant concerns over the cardiovascular safety of rosiglitazone, the US Food and Drug Administration (FDA) issued a draft guidance directing sponsors of novel diabetes drugs to address cardiovascular risk, including large outcomes trials. Regulatory experience supports that outcomes trials, absent a clear signal of risk, may add reassurance, but also have significant consequences. The FDA should finalize this guidance, taking into account the regulatory experience since 2008.

The role of academic medical centers in advancing regulatory science.

The US Food and Drug Administration (FDA) has oversight of an increasingly complex array of therapeutic and scientific advances, as well as an expanded mission that now includes enabling innovation. This complex mission necessitates access to and understanding of relevant scientific expertise in what is commonly called "regulatory science." Academic medical centers have much of this relevant expertise, and there is an increasing need and opportunity for the FDA to engage with them to shape the regulatory science agenda.

Material selection for acoustic radiators that are light and stiff.

The headmass is a key element in tonpilz transducer design. As an acoustic radiator, a successful headmass must be built from a material that is both light and stiff. To assess the suitability of ceramics for this application, the authors used the mechanical properties of candidate materials to perform a theoretical comparison based on the flexural behavior of square plates. Although not a comprehensive metric for identifying the best headmass materials, the headmass flexure may be usefully employed as a first-level selection criteria. A software routine based on thin plate and thick plate theory was created to evaluate the flexural behavior in candidate materials.

Increased silver activity for direct propylene epoxidation via subnanometer size effects.

Production of the industrial chemical propylene oxide is energy-intensive and environmentally unfriendly. Catalysts based on bulk silver surfaces with direct propylene epoxidation by molecular oxygen have not resolved these problems because of substantial formation of carbon dioxide. We found that unpromoted, size-selected Ag3 clusters and approximately 3.5-nanometer Ag nanoparticles on alumina supports can catalyze this reaction with only a negligible amount of carbon dioxide formation and with high activity at low temperatures. Density functional calculations show that, relative to extended silver surfaces, oxidized silver trimers are more active and selective for epoxidation because of the open-shell nature of their electronic structure. The results suggest that new architectures based on ultrasmall silver particles may provide highly efficient catalysts for propylene epoxidation.

Regulatory considerations for determining postmarketing study commitments.

Postmarketing Study Commitments (PMCs) are, most commonly, agreements made by pharmaceutical companies at the time of an FDA approval to perform a study or studies to elucidate further characteristics of the drug under consideration. The role of PMCs in drug regulation has come under considerable scrutiny in recent years, particularly as discussions of drug safety have intensified. Although these agreed-upon PMCs are described in FDA regulations, such PMCs are not sought by FDA with every approval, and completion of the agreed-upon studies is not a requirement for the drug's sponsor (there are required PMCs under certain regulatory provisions and these are discussed below). Requests by FDA at the time of regulatory approval for studies under PMCs have been a common practice for many years. When made, PMCs are described in the approval letters and are therefore publicly available. Concerns over whether PMCs were being duly performed, reported, and reviewed by FDA were addressed in the FDA Modernization Act of 1997, which required more detailed reporting by manufactures on their progress in meeting the PMCs and required FDA to report certain information publicly.

Hemodialysis followed by continuous hemofiltration for treatment of lithium intoxication in children.

Hemodialysis is the usual recommended treatment for severe lithium intoxication; however, rebound of lithium levels may require repeated hemodialysis treatments. We proposed that the addition of continuous hemofiltration after hemodialysis would prevent rebound by providing ongoing clearance of lithium. We report two pediatric patients with lithium intoxication treated by hemodialysis followed by continuous venovenous hemofiltration with dialysis (CVVHD). Both patients were symptomatic at presentation and had initial lithium levels more than three times the usual therapeutic range. Hemodialysis followed by CVVHD resulted in rapid resolution of symptoms, followed by continuous clearance of lithium without requiring repeated hemodialysis sessions. Both patients had return of normal mental status during CVVHD treatment, and neither patient experienced complications of hemodialysis or CVVHD. Total duration of treatment with hemodialysis followed by CVVHD was 34.5 hours for the first patient and 26 hours for the second patient. We conclude that hemodialysis followed by CVVHD is a safe and effective approach to the management of lithium intoxication in children.

Internal Transcribed Spacer Sequence-Based Phylogeny and Polymerase Chain Reaction-Restriction Fragment Length Polymorphism Differentiation of Tilletia walkeri and T. indica.

ABSTRACT A polymerase chain reaction-restriction fragment length polymorphism assay to distinguish Tilleita walkeri, a rye grass bunt fungus that occurs in the southeastern United States and Oregon, from T. indica, the Karnal bunt fungus, is described. The internal transcribed spacer (ITS) region of the ribosomal DNA repeat unit was amplified and sequenced for isolates of T. indica, T. walkeri, T. horrida, and a number of other taxa in the genus Tilletia. A unique restriction digest site in the ITS1 region of T. walkeri was identified that distinguishes it from the other taxa in the genus. Phylogenetic analysis of the taxa based on ITS sequence data revealed a close relationship between T. indica and T. walkeri, but more distant relationships between these two species and other morphologically similar taxa.

Recognition of oriT for DNA processing at termination of a round of conjugal transfer.

Conjugal transfer of plasmid DNA is terminated when the transferred strand, linearized at the 38 base-pair origin of transfer (oriT), is recircularized. For the plasmid R1162, it is the protein MobA, covalently linked to the linear strand, that rejoins the ends by a reversible transesterification reaction. We have identified from those oligonucleotides with a partially degenerate oriT base sequence, subpopulations bound by MobA that undergo transesterification, and support efficient termination of conjugal transfer. Two domains of oriT, a ten base-pair inverted repeat and an adjacent TAA, are required for tight binding by the protein, whereas the location of the dinucleotide YG determines the site of strand cleavage. The results indicate that capture of MobA by oriT, and subsequent processing of the DNA for termination, are determined by different sequence motifs within this locus.

Nonpulmonary organ failure and outcome in children treated with high-frequency oscillatory ventilation.

PURPOSE: The purpose of this study was to quantitate the contribution of nonpulmonary organ failure to mortality of patients treated with high-frequency oscillatory ventilation (HFOV) and to determine which gas-exchange differences are associated with improvement on HFOV. MATERIALS AND METHODS: Charts of all patients treated with HFOV in our pediatric intensive care unit from January 1992 until January 1997 were retrospectively reviewed. RESULTS: Sixty-six patients were treated and 21 patients improved during HFOV (group 1); 45 patients did not improve (group 2). Seventeen patients (26%) had isolated respiratory failure and their mortality was 12%. Percentages of patients with 2, and 3 or more organ failure were 45%, 29%, and their mortality was significantly higher, 67% and 95%, respectively. Patients with primary respiratory failure demonstrated a significantly greater risk of improvement on HFOV (RR ratio of 2.5, 95% CI 1.5 to 4.2). There was a significantly greater proportion of patients with primary cardiac failure who did not improve on HFOV compared with all other patients. Oxygenation index significantly improved over the first 72 hours for both groups, but then significantly worsened over the next 48 hours in group 2 but not in group 1. CONCLUSION: Patients with nonpulmonary organ failure were significantly less likely to improve on HFOV and had a significantly higher mortality than patients with isolated respiratory failure. Children who do not improve on HFOV appear to reach a plateau in oxygenation indices after 3 days of HFOV.

Methanol poisoning.

AIMS: This study examines clinical experience with methanol poisoning during a one-year period. METHODS: All admissions with the diagnosis of suspected methanol toxicity were analysed and the current guidelines for the management of this problem were reviewed. RESULTS: Twenty-four subjects were identified. Most had a history of chronic use of methylated spirits. Four died before admission to hospital and the other 20 patients had 26 admissions to hospital and form the basis for this report. Four patients died in the Intensive Care Unit. In total 11 patients were admitted to the Intensive Care Unit. Seven patients received haemodialysis. There was no correlation between the methanol level and the outcome. The strongest predictor of death or a poor outcome was a blood pH < 7.0. Some patients, in spite of potentially lethal methanol levels of up to 160 mmol/L, did not develop signs of toxicity. CONCLUSIONS: The overall mortality was high and ethanol was given to most of the patients for up to several days. Some patients did not show any toxicity and some of those were not given ethanol. It is recommended that chronic meths drinkers, who are not acidaemic and are generally well, do not require ethanol treatment. Only the complete removal of methanol from methylated spirits will reduce the morbidity of this condition.

Cymbal array: a broad band sound projector.

A prototype 3 x 3 planar cymbal transducer array was built and tested. The array has a radiating area of 5.5 cm x 5.5 cm and a thickness of less than 8 mm. The measured transmitting voltage response was above 134 dB re 1 microPa/V @ 1 m and flat over the frequency range of 16 and 100 kHz. Array interaction was analyzed using an equivalent circuit model. The array interaction leads to variations in radiation resistance and velocity of the transducers in the array according to their surroundings in the array. The effect is enhanced overall efficiency and a flat response.

A United States regulator's perspective on the ongoing chlorofluorocarbon transition.

The Food and Drug Administration (FDA) put in place a general ban on the use of chlorofluorocarbons for the products it regulates (medical devices, drugs, and foods) in 1978, exempting those products where chlorofluorocarbon use was determined to be essential for the public health. In the intervening years, as the international commitment to a full transition away from all chlorofluorocarbon use took shape under the Montreal Protocol, the FDA has worked with industry to facilitate the development and testing of alternative technologies and products for inhalation drug products. As these alternative products begin to move from testing through the approval process and into marketing, the FDA is working collaboratively with the Environmental Protection Agency, other governmental agencies, and nongovernmental stakeholders to develop a transition policy for the United States. The transition policy for metered dose inhalers must be one that achieves the dual aims of first protecting the patients who rely on these vital medical products, while also achieving the public health need of protecting the ozone layer. As a part of developing such a transition strategy, the FDA published an advance notice of proposed rulemaking (ANPRM) in March 1997. The ANPRM proposed mechanisms by which the FDA could determine when chlorofluorocarbon use in a drug product could no longer be considered essential. The ANPRM resulted in a large amount of valuable public debate and input. The FDA is now working to incorporate the knowledge gained from these public comments as it continues the rule-making process.

Stabilization of the relaxosome and stimulation of conjugal transfer are genetically distinct functions of the R1162 protein MobB.

MobB is a small protein encoded by the broad-host-range plasmid R1162 and required for efficient mobilization of its DNA during conjugation. The protein was shown previously to stabilize the relaxosome, the complex of plasmid DNA and mobilization proteins at the origin of transfer (oriT). We have generated in-frame mobB deletions that specifically inactivate the stabilizing effect of MobB while still allowing a high rate of transfer. Thus, MobB has two genetically distinct functions in transfer. The effect of another deletion, extending into mobA, indicates that both functions require a specific region of MobA protein that is distinct from the nicking-ligating domain. The mobB mutations that specifically affected stability also resulted in poor growth of cells, due to increased transcription from the promoters adjacent to oriT. The effects of the mutations could be suppressed not only by full-length MobB provided in trans, as expected, but also by additional copies of oriT, cloned in pBR322. In addition, in the presence of MobA both the full-length and truncated forms of MobB stimulated recombination between oriT-containing plasmids. We propose a model in which MobB regulates expression of plasmid genes by altering the stability of the relaxosome, in a manner that involves the coupling of plasmid molecules.

An audit of the assessment and management of adults admitted to Christchurch Hospital with community acquired pneumonia.

AIMS: To audit the management of adult patients admitted with community acquired pneumonia including the standards of clinical assessment, use of modified British Thoracic Society prognostic criteria and antibiotic therapy. METHODS: A prospective, 16 week, study of consecutive patients admitted to Christchurch Hospital with community acquired pneumonia. RESULTS: Ninety-six patients met the inclusion criteria. The median age was 70 years. A pathogen was identified in 28 (26%) patients. Forty two patients fulfilled the modified British Thoracic Society criteria for severe disease and all 9 deaths occurred in that subgroup. The management guidelines were followed without exception in only 15% of cases. Documentation of the prognostic criteria was often incomplete and therefore only 33% of those patients with severe disease were correctly identified. Seventy one percent of those with severe disease were treated with only one antibiotic and there was significant delay in administering the first dose in 44% of cases. A follow up chest radiograph was performed in 43 (51%) of those discharged. CONCLUSIONS: There was poor compliance with the management guidelines. There was a lack of awareness of the severity criteria leading to inadequate treatment in many cases. Further educational initiatives are indicated.

Acquisition of resistance genes by the IncQ plasmid R1162 is limited by its high copy number and lack of a partitioning mechanism.

R1162 is a representative member of the broad-host-range IncQ group of multicopy plasmids. Lower-copy-number derivatives of R1162 were constructed in vitro and shown to be unstable, indicating that partitioning of plasmid copies at cell division is due to random distribution and not to an active partitioning mechanism. However, the normal copy number of R1162 reduces cell fitness during growth in broth and favors the emergence of unstable, lower-copy-number variants. As a result, plasmid-borne antibiotic resistance genes active at a low copy number eventually result in plasmid loss during periods of no selection. We argue that the maintenance of R1162 in a population requires a gene that is selected only at high levels. This reduces the potential for acquiring genes from other R factors and could explain the limited variety of antibiotic resistance genes contained by naturally occurring IncQ plasmids.