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.

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.

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.

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.

Heterogeneous response to X-ray and ultraviolet light irradiations of cultured skin fibroblasts in two families with Gardner's Syndrome.

A heterogeneous response to X-ray and far UV (254 nm) light irradiations was found in cultured skin fibroblast lines from 2 separate families with Gardner's syndrome. When compared to 2 normal control cultures and cultures from 2 patients with nonfamilial colon cancer, cultures from 4 clinically affected members of family 1 showed increased sensitivity to the lethal effects of both X-ray and UV light irradiations. These cells also showed a delayed pattern of X-ray potentially lethal damage repair (PLDR) and absent UV PLDR. In contrast, cultures from 3 members of family 2 (2 of whom were clinically affected) showed a normal response of survival and PLDR to both X-ray and UV light irradiations. Thus increased sensitivity of cultured skin fibroblasts to X-ray and UV light irradiations was not a consistent in vitro finding in patients with Gardner's syndrome. However, in families with Gardner's syndrome who demonstrate in vitro radiosensitivity, additional studies are needed to assess the usefulness of these techniques in detecting affected individuals prior to the development of colon carcinoma and other manifestations.

Unidirectional replication of the P-group plasmid RK2.

The mode of replication of the broad host-range plasmid RK2 has been determined from examination of molecular replicative forms cleaved with the restriction endonucleases EcoRI and Hind III. Replication is unidirectional, and proceeds from a unique origin. The location of the origin and other evidence suggests that genes involved in plasmid maintenance are not tightly clustered.

Unidirectional transfer of broad host-range plasmid R1162 during conjugative mobilization. Evidence for genetically distinct events at oriT.

A segment of R1162 DNA containing genes for conjugative mobilization (Mob) and the origin of transfer (oriT) was integrated into the Escherichia coli chromosome. Bacterial genes were transferred in a polar fashion during conjugative mobilization of the integrated segment by a self-transmissible plasmid vector. The direction of transfer, together with the properties of mutated derivatives of oriT, indicate that initial cleavage of oriT, and subsequent religation after transfer, entail different mechanisms that can be distinguished genetically.

Deletion of sites for initiation of DNA synthesis in the origin of broad host-range plasmid R1162.

The origin of replication of the broad host-range plasmid R1162 contains two, oppositely facing initiation sites for DNA synthesis. Either of these sites can be deleted from an R1162 plasmid derivative. However, the resulting plasmids are unstable, maintained at a lower copy-number in the cell, and form dimers and other recombinants that are required for propagation of the plasmid. In vitro, a derivative lacking one initiation site is deficient in synthesis of the strand normally initiated from that site. The properties of the intact origin are restored if it contains two oppositely facing sites; one initiation site may substitute for the other, and each site need not be in its original orientation. Overall, the results suggest that synthesis of each strand of R1162 DNA is initiated at a single site, and that there is no efficient system for initiation of lagging strand synthesis during transit of the replication forks.

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.

A 38 base-pair segment of DNA is required in cis for conjugative mobilization of broad host-range plasmid R1162.

oriT, the region required in cis for conjugative mobilization of broad host-range plasmid R1162, has been localized to a 38 base-pair segment of DNA. The oriT DNA is also required for conjugation-dependent recombination. Point mutations at the HinPI cleavage site within oriT affect both mobilization and recombination, and the crossover location has been mapped to this site. An inverted repeat ten base-pairs from the recombination site is also involved in mobilization and recombination, and may be a recognition site for proteins involved in cleavage of the oriT DNA. The properties of conjugation-dependent recombination suggest that mobilization entails the formation of a linear intermediate that is transferred with both a unique origin and polarity.

Copy number of the broad host-range plasmid R1162 is determined by the amounts of essential plasmid-encoded proteins.

DNA of the broad host-range plasmid R1162 contains a 1700 base-pair segment essential for plasmid maintenance. This region, RepI, consists of two cotranscribed genes encoding polypeptides with molecular weights of 29,000 and 31,000. Fusion of RepI to the strong tac promoter results in greatly increased amounts of at least one of these polypeptides. In trans, this construction has two other properties: it can raise the copy number of R1162, and it can protect this plasmid from loss due to incompatibility. Both effects require intact RepI genes. These properties of the RepI region, along with those of an origin-linked region described earlier, are discussed with respect to current models for control of plasmid copy number.

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.

Autoimmune hemolytic anemia and periodic pure red cell aplasia in systemic lupus erythematosus.

A patient with systemic lupus erythematosus and autoimmune hemolytic anemia complicated by periodic episodes of red cell hypoplasia is described. Using a plasma clot culture system a serum inhibitor of erythropoiesis was detected. In addition, heat eluates of the red cells of this patient were capable of impairing erythroid colony formation. The possibility that the autoantibodies of acquired autoimmune hemolytic anemia might influence the proliferation and/or maturation of erythroid progenitor cells is raised by these findings.

Central nervous system involvement at presentation in acute granulocytic leukemia. A prospective cytocentrifuge study.

We have undertaken a perspective study of the prevelance of the central nervous disease in acute granulocytic leukemia (AGL). Thirty-nine newly diagnosed patients with AGL underwent cytocentrifuge examination of cerebral spinal fluid. Seven of the 39 patients had blast cells in their cerebral spinal fluid. All seven of these patients had acute myelomonocytic leukemia (AMML). No patients with other variants of AGL demonstrated blast cells in their cerebral spinal fluid. Other high risk factors associated with meningeal infiltration were elevated serum lysozyme levels, high peripheral white blood cell count, low age, splemomegaly and the presence of infiltration in other organs. The admission rates for patients with meningeal leukemia were lower and the survival time was shorter than in both the 32 noninvolved patients and the noninvolved patients with AMML. We believe that a lumbar puncture is indicated in all patients with newly diagnosed AMML.

Association of monocytic leukemia in patients with extreme leukocytosis.

Fifteen of 73 newly diagnosed patients with acute myeloid leukemia (AML), admitted to Mount Sinai Hospital between July 1977 and October 1979, presented with leukocyte counts greater than 100,000/microliter. Eleven of these 15 patients with hyperleukocytosis had myelomonocytic (AMML-M4) or monocytic (AMOL-M5) leukemia compared to 15 of 58 patients with lower white cell counts (p < 0.001). Identification of type of leukemia, using the FAB classification, was based on morphology and special stains, including myeloperoxidase, Sudan black B, periodic acid-Schiff and nonspecific esterase with and without inhibition by fluoride. The proportion of patients with splenomegaly is higher in those with hyperleukocytosis (73 percent) than in those with lower white blood cell counts (p < 0.001) regardless of cell type. Leukemic infiltration of the skin, gums and central nervous system was seen exclusively in patients with AMML and AMOL. The serum lysozyme levels were significantly higher for all patients with AMML and AMOL regardless of the white blood cell count. The mean serum lysozyme for M-4, M-5 patients was 59.7 microgram/ml compared to 18.9 microgram/ml in patients with other cell types (p < 0.0001). Patients with a white blood cell count less than or equal to 100,000/microliter had a complete remission rate of 69 percent compared to 47 percent for patients with higher white blood cell counts.

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.

Egg shell nodal calcification in a patient with sinus histiocytosis with massive lymphadenopathy treated with interferon.

CT showed egg shell calcification in the cervical lymph nodes in a patient with sinus histiocytosis with massive lymphadenopathy treated for 1 year with interferon. CT scans before interferon treatment had shown no nodal calcification.

Psychometric modeling of consumer decisions in primary health care.

A psychometric technique, functional measurement, was used to measure the preferences of 77 persons for hypothetical health care providers identified by various levels of cost, travel time, and waiting time; responses were subjected to analysis of variance and graphic analysis to determine the functional relation by which respondents combined the three attributes in arriving at their preferences. Both modes of analysis suggested multiplicative decision models, but these yielded lower values of R2 than did linear models derived for comparison. Respondents were grouped by the proportion of response variance that was explained by each of the three attributes, and decision models were derived for each group. Discriminant analysis of socioeconomic characteristics of the respondents identified the variables that distinguished the groups and contributed to forming their preferences.

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.

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.