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Background Some patients with autoimmune characteristics and idiopathic interstitial pneumonia, particularly usual interstitial pneumonia (UIP), do not fit neatly into the category of connective tissue disease-associated interstitial lung disease (CTD-ILD), idiopathic pulmonary fibrosis (IPF), or recently proposed yet to be validated criteria for interstitial pneumonia with autoimmune features (IPAF). Outcomes of these patients are unknown. Methods This was a retrospective single-center study. Analyses of variance compared differences in mean change in FVC and diffusion capacity (Dlco) over 1 year among 124 well-defined patients (20 patients with positive autoantibodies with or without symptoms of connective tissue disease [AI-ILD], 15 patients with IPAF, 36 patients with CTD-ILD, and 53 patients with IPF with negative CTD serologies [Lone-IPF]). Results Of the patients, 75% with AI-ILD, 33% with IPAF, and 33% with CTD-ILD had UIP. Initial FVC and Dlco were similarly moderately reduced across groups. Mean change in FVC over 12 months was as follows: −60 mL (IPAF), −110 mL (AI-ILD), −10 mL (CTD-ILD), and −90 mL (Lone-IPF) ( P = .52). Mean change in Dlco was as follows: 2.39 mL/mm Hg/min (IPAF), −1.15 mL/mm Hg/min (AI-ILD), −0.27 mL/mm Hg/min (CTD-ILD), and −1.05 mL/mm Hg/min (Lone-IPF) ( P P = .001). Conclusions No clinically significant differences in pulmonary function to distinguish between patients with AI-ILD, IPAF, CTD-ILD, and Lone-IPF were observed after 1 year. Longer periods of follow-up are needed to understand the outcomes of these patients. It is not yet clear whether AI-ILD is a distinct phenotype or a variant of the newly proposed entity IPAF.

Objectives The purpose of this study was to investigate changes in the use of transcatheter aortic valve replacement (TAVR) relative to surgical aortic valve replacement (SAVR) and to examine relative 1-year TAVR and SAVR outcomes in 2011 to 2012 in a population-based setting. Background TAVR has become a popular option for patients with severe aortic stenosis, particularly for higher-risk patients. Methods New York’s Cardiac Surgery Reporting System was used to identify TAVR and SAVR volumes and to propensity match TAVR and SAVR patients using numerous patient risk factors contained in the registry to compare 1-year mortality rates. Mortality rates were also compared for different levels of patient risk. Results The total number of aortic valve replacement patients increased from 2,291 in 2011 to 2,899 in 2012, an increase of 27%. The volume of SAVR patients increased by 7.1% from 1,994 to 2,135 and the volume of TAVR patients increased 157% from 297 to 764. The percentage of SAVR patients that were at higher risk (≥3% New York State [NYS] score, equivalent to a Society of Thoracic Surgeons score of about 8%) decreased from 27% to 23%, and the percentage of TAVR patients that were at higher risk decreased from 83% to 76%. There was no significant difference in 1-year mortality between TAVR and SAVR patients (15.6% vs. 13.1%; hazard ratio [HR]: 1.30 [95% confidence interval (CI): 0.89 to 1.92]). There were no differences among patients with NYS score Conclusions TAVR has assumed a much larger share of all aortic valve replacements for severe aortic stenosis, and the average level of pre-procedural risk has decreased substantially. There are no differences between 1-year mortality rates for TAVR and SAVR patients.

The identification of the cellular mechanisms responsible for the wide differences in species lifespan remains one of the major unsolved problems of the biology of aging. We measured the capacity of nuclear protein to recognize DNA double strand breaks (DSBs) and telomere length of skin fibroblasts derived from mammalian species that exhibit wide differences in longevity. Our results indicate DNA DSB recognition increases exponentially with longevity. Further, an analysis of the level of Ku80 protein in human, cow, and mouse suggests that Ku levels vary dramatically between species and these levels are strongly correlated with longevity. In contrast mean telomere length appears to decrease with increasing longevity of the species, although not significantly. These findings suggest that an enhanced ability to bind to DNA ends may be important for longevity. A number of possible roles for increased levels of Ku and DNA-PKcs are discussed.

Background: Few recent studies have compared the outcomes of coronary artery bypass graft (CABG) surgery with percutaneous coronary interventions (PCIs) in patients with isolated (single ve...

ObjectivesThis study sought to determine the utilization and outcomes for radial access for percutaneous coronary intervention (PCI) for ST-segment elevation acute myocardial infarction (STEMI) in common practice.BackgroundRadial access for PCI has been studied considerably, but mostly in clinical trials.MethodsAll patients undergoing PCI for STEMI in 2009 to 2010 in New York were studied to determine the frequency and the patient-level predictors of radial access. Differences in in-hospital/30-day mortality between radial and femoral access were also studied.ResultsRadial access increased from 4.9% in the first quarter of 2009 to 11.9% in the last quarter of 2010. Significant independent predictors were higher body surface area, non-Hispanic ethnicity, Caucasian race, stable hemodynamic state, ejection fraction

article i nfo Background: Appropriate use criteria (AUC) for diagnostic catheterization (DC) developed by the American Col- lege of Cardiology Foundation (ACCF) and other professional societies were recently published. These criteria have yet to be examined thoroughly using existing DC databases. Methods and results: New York State's Cardiac Diagnostic Catheterization Database was used to identify patients undergoing DC "for suspected coronary artery disease (CAD)" in 01/2010-06/2011 who underwent noninvasive stress testing. Patients rated for appropriateness using symptomsand stress test results were examined to deter- mine the percentage with obstructive CAD and to explore the benefit of adding Global Risk Score (GRS) to the AUC. Of the 4432 patients who could be rated, 1530 (34.5%) had obstructive CAD, which varied from 22% for pa- tients rated inappropriate to 47% for patients rated appropriate. Of all patients with low riskstress test results/no symptoms, all of whom were rated "inappropriate" for DC, only 8% of those patients with low GRS had obstruc- tive CAD, whereas 44% of the patients with high GRS had obstructive CAD. Conclusions: Global Risk Score improved the ability of symptoms and stress test results to identify obstructive CAD in patients with "suspected CAD" with prior stress tests, and it might be helpful to add GRS to the DC AUC for those patients. These findings should be regarded as hypothesis generating unless/until they can be con- firmed by other data bases.

Experimental operation of three fluidized bed processors is compared with CFD simulation results. The capacities of the fluidized bed processors represent two orders of magnitude scale-up. Qualitative fluidization patterns as well as quantitative data are compared with simulated processor operation. The numerical method and simulation approach were found to successfully predict the flow behavior of several different sizes of fluidized beds based solely on material properties, processor loading, inlet air flow rate and fluidized bed process geometry.

Objectives The purpose of this study was to determine appropriateness of percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery performed in New York for patients without acute coronary syndrome (ACS) or previous CABG surgery. Background The American College of Cardiology Foundation (ACCF) and 6 other societies recently published joint appropriateness criteria for coronary revascularization. Methods Data from patients who underwent CABG surgery and PCI without acute coronary syndrome or previous CABG surgery in New York in 2009 and 2010 were used to assess appropriateness and to examine the variation across hospitals in inappropriateness ratings. Results Of the 8,168 patients undergoing CABG surgery in New York without ACS/prior CABG who could be rated, 90.0% were appropriate for revascularization, 1.1% were inappropriate, and 8.6% were uncertain. Of the 33,970 PCI patients eligible for rating, 28% lacked sufficient information to be rated. Of the patients who could be rated, 36.1% were appropriate, 14.3% were inappropriate, and 49.6% were uncertain. A total of 91% of the patients undergoing PCI who were classified as inappropriate had 1- or 2-vessel disease without proximal left anterior descending artery disease and had no or minimal anti-ischemic medical therapy. Conclusions For patients without ACS/prior CABG, only 1% of patients undergoing CABG surgery who could be rated were found to be inappropriate for the procedure according to the ACCF appropriateness criteria, but 14% of the PCI patients who could be rated were found to be inappropriate, and 28% lacked enough noninvasive test information to be rated.

We developed an engineering model for predicting the active pharmaceutical ingredient (API) content uniformity (CU) for a drug product in which the active is coated onto a core. The model is based on a two-zone mechanistic description of the spray coating process in a perforated coating pan. The relative standard deviation (RSD) of the API CU of the coated tablets was found to be inversely proportional to the square root of the total number of cycles between the spray zone and drying zone that the tablets undergo. The total number of cycles is a function of the number of tablets in the drying zone, the spray zone width, the tablet velocity, the tablet number density, and the total coating time. The sensitivity of the RSD to various critical coating process parameters, such as pan speed, pan load, spray zone width, as well as tablet size and shape was evaluated. Consequently, the critical coating process parameters needed to achieve the desired API CU were determined. Several active film coating experiments at 50, 200, and 400 kg using various pan coaters demonstrated that good correlation between the model predictions and the experimental results for the API CU was achieved.

Objectives The purpose of this study was to examine the differences in in-hospital and longer-term mortality for ST-segment elevation myocardial infarction (STEMI) patients with multivessel disease as a function of whether they underwent single-vessel (culprit vessel) percutaneous coronary interventions (PCIs) or multivessel PCI. Background The optimal treatment of patients with STEMI and multivessel disease is of continuing interest in the era of drug-eluting stents. Methods STEMI patients with multivessel disease undergoing PCIs in New York between January 1, 2003, and June 30, 2006, were subdivided into those who underwent culprit vessel PCI and those who underwent multivessel PCI during the index procedure, during the index admission, or staged within 60 days of the index admission. Patients were propensity-matched and mortality rates were calculated at 12, 24, and 42 months. Results A total of 3,521 patients (87.5%) underwent culprit vessel PCI during the index procedure. A total of 259 of them underwent staged PCI during the index admission and 538 patients underwent staged PCI within 60 days of the index procedure. For patients without hemodynamic compromise, culprit vessel PCI during the index procedure was associated with lower in-hospital mortality than multivessel PCI during the index procedure (0.9% vs. 2.4%, p = 0.04). Patients undergoing staged multivessel PCI within 60 days after the index procedure had a significantly lower 12-month mortality rate than patients undergoing culprit vessel PCI only (1.3% vs. 3.3%, p = 0.04). Conclusions Our findings support the American College of Cardiology/American Heart Association (ACC/AHA) recommendation that culprit vessel PCI be used for STEMI patients with multivessel disease at the time of the index PCI when patients are not hemodynamically compromised. However, staged PCI within 60 days after the index procedure, including during the index admission, is associated with risk-adjusted mortality rates that are comparable with the rate for culprit vessel PCI alone.

Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the oxidative pentose phosphate cycle, regulates the NADPH/NADP(+) ratio in eukaryotic cells. G6PD deficiency is one of the most common mutations in humans and is known to cause health problems for hundreds of millions worldwide. Although it is known that decreased G6PD functionality can result in increased susceptibility to oxidative stress, the molecular targets of this stress are not known. Using a Chinese hamster ovary G6PD-null mutant, we previously demonstrated that exposure to a thiol-specific oxidant, hydroxyethyldisulfide, caused enhanced radiation sensitivity and an inability to repair DNA double strand breaks. We now demonstrate a molecular mechanism for these observations: the direct inhibition of DNA end binding activity of the Ku heterodimer, a DNA repair protein, by oxidation of its cysteine residues. Inhibition of Ku DNA end binding was found to be reversible by treatment of the nuclear extract with dithiothreitol, suggesting that the homeostatic regulation of reduced cysteine residues in Ku is a critical function of G6PD and the oxidative pentose cycle. In summary, we have discovered a new layer of DNA damage repair, that of the functional maintenance of repair proteins themselves. In view of the rapidly escalating number of roles ascribed to Ku, these results may have widespread ramifications.

We used Glucose 6 phosphate dehydrogenase (G6PD) minus cells (89 cells) and G6PD containing cells (K1) to understand the mechanisms of bioreduction of disulfide and the redox regulation of protein and non protein thiols in mammalian cells. The 89 cells reduce hydroxyethyldisulfide (HEDS) to mercaptoethanol (ME) at a slower rate than K1 cells. HEDS reduction results in loss of nonprotein thiols (NPSH) and a decrease in protein thiols (PSH) in 89 cells. The effects are less dramatic with K1 cells. However, the loss of NPSH and PSH in K1 cells are increased in the absence of glucose. Glutathione-depletion with L-BSO partially blocks HEDS reduction in K1 and 89 cells. Treatment with the vicinal thiol reagent phenyl arsenic oxide (PAO) blocks reduction of HEDS in both cells. Surprisingly, dehydroepiandrosterone (DHEA), a known inhibitor of G6PD, inhibits the growth and blocks the reduction of HEDS both in 89 and K1 cells suggesting that its mechanism for inhibition of growth is not G6PD related.

XRCC4 was identified via a complementation cloning method that employed an ionizing radiation (IR)-sensitive hamster cell line. By gene-targeted mutation, we show that XRCC4 deficiency in primary murine cells causes growth defects, premature senescence, IR sensitivity, and inability to support V(D)J recombination. In mice, XRCC4 deficiency causes late embryonic lethality accompanied by defective lymphogenesis and defective neurogenesis manifested by extensive apoptotic death of newly generated postmitotic neuronal cells. We find similar neuronal developmental defects in embryos that lack DNA ligase IV, an XRCC4-associated protein. Our findings demonstrate that differentiating lymphocytes and neurons strictly require the XRCC4 and DNA ligase IV end-joining proteins and point to the general stage of neuronal development in which these proteins are necessary.

Many studies have shown that drug-eluting stents (DESs) are associated with better outcomes for patients receiving coronary stents, and earlier studies showed disparities in use by race and payer. It is of interest to know whether these differences persist in an era of higher use of DESs and to examine DES use differences across providers.New York State's percutaneous coronary intervention registry was used to identify significant predictors of DES vs bare-metal stent use among patients receiving stents, including race, ethnicity, sex, payer, and numerous patient clinical risk factors in 2011-2012. Variations in DES use across hospitals and operators were also examined.African Americans (adjusted odds ratio [AOR], 0.70; 95% confidence interval [CI], 0.66-0.75) and Hispanics (AOR, 0.80; 95% CI, 0.74-0.85) were less likely to receive DESs than their counterparts. Patients with private insurance were more likely to receive DESs than patients in all other payer categories. More than one third of the 60 hospitals in the study had significantly lower adjusted use of DESs than the mean rate of 83%. For these hospitals, adjusted rates ranged from 52%-80%, and 5 of these hospitals had adjusted rates70%. Twenty-five percent of the total variation in the use of DESs was related to differences across hospitals that were unrelated to patient characteristics.Disparities by race, ethnicity, and insurance status persist in the use of DESs among patients receiving coronary stents. There are also large differences in use among hospitals that are unrelated to patient clinical characteristics and demographics.

The interaction between free radicals derived from the catalytic decomposition of carbon tetrachloride and tyrosine (the N-acetyl tyrosine ethyl ester, ATEE) under anaerobic and aerobic conditions was studied. The structure of the reaction products formed was desciphered by the GLC/MS analysis of their trimethylsilyl derivatives. Under anaerobic conditions the formation of the following products was found: (1) an unsaturated derivative of the amino acid; (2) the trimethylsilyl derivative of N-acetyl chloro tyrosine ethyl ester; (3) a hydroxyl adduct of ATEE ; (4) an ATEE adduct having a chlorine and a CCl3 group in the molecule (it is suggested that CCl3 is attached to the benzyl carbon and the chlorine located in the benzene ring); (5) an ATEE adduct having only a CCl3 group tentatively assigned to be located on the benzyl carbon; and (6) and (7) were found to be two isomers of an ATEE having one CCl3 on the aromatic ring. Under aerobic conditions the following reaction products were identified: Two products which were similar to those numbered (1) and (2) and formed anaerobically; (8) and (11) two isomeric dichlorinated adducts of ATEE; (9) and (10) two isomeric dichlorinated monohydroxylated derivatives of ATEE. Concerning the potential relevance of these findings, we consider that if similar interactions to those here reported occurred during CCl4 poisoning, the activity of enzymes having tyrosine in their active center might result in impairment. Further, enzymes operating on tyrosine moieties in proteins might be perturbed in their action if tyrosine groups were attacked by the free radicals arising from catalytic decomposition of CCl4 evidenced here.

Double-strand DNA break repair is important in maintaining the genetic integrity of the genome. Using a mobility shift assay, we find that a protein, or complex of proteins, that is present in mammalian and yeast cells binds to the ends of double-strand DNA and renders the ends resistant to exonuclease digestion. Additionally, a mammalian DNA double-strand repair-deficient mutant, xrs, has no observable DNA end binding activity, while a revertant cell has wild-type activity. In addition, mobility supershift assays using monoclonal antibodies to the human Ku antigen (M(r) 70,000 subunit) reveal that one of the proteins of this end binding activity may be the Ku antigen or a protein with similar antigenic determinants. These observations suggest that this DNA end-binding protein may function in DNA repair.

Using a replica-plating procedure and a 32P-NAD+ permeable cell-screening assay, we have isolated a CHO mutant, PADR-9, which displays approximately 17% of the wild-type level of poly(ADP-ribose) polymerase activity. Biochemical analysis of the mutant using activity, Western, and Northern blot techniques indicate that relative to its parent cell, the mutant's enzyme activity, antibody recognition, and mRNA levels have been reduced to approximately the same extent. These results are consistent with a mutation in the PADR-9 cell which has resulted in a reduction in enzyme synthesis due to reduced mRNA synthesis and/or stability. Relative to wild-type CHO cells, the PADR-9 mutant has increased sensitivity to killing by DNA-alkylating agents but has normal gamma-ray sensitivity. Correlation between a decrease in poly(ADP-ribose) polymerase activity and an increased sensitivity to DNA-alkylating agents suggests that poly(ADP-ribose) synthesis may be important in the repair and/or induction of DNA damage produced by these agents.

Tung et al. ([1][1]) are to be congratulated for their insightful and meticulous analysis of the literature of randomized trials of implantable cardioverter-defibrillator (ICD) therapy. There are 2 additional points that deserve amplification and to be made regarding the use of ICDs in clinical

Fifty-four patients presenting with stenotic lesions in a major coronary artery visually estimated by diagnostic angiography to be greater than 90% but less than 100% were randomized to one of two angioplasty regimens, predilatation (group 1) or no predilatation (group 2). In group 1, the artery was initially dilated with a 2 mm balloon followed by a balloon that was considered by the operator to be the definitive size to fully dilate the target vessel. In group 2, the artery was dilated with a balloon deemed the definitive size to complete the angioplasty procedure. There were no statistical differences between groups with respect to age, sex, history of unstable angina, or prior acute myocardial infarction. There were also no significant differences in the angiographic characteristics of the coronary lesions including artery location, lesion length, concentric or eccentric morphology, tubular versus discrete stenosis, calcium in lesions, or lesions on a bend. Following angioplasty, luminal filling defects were present in 5% of the predilated group and in 9% of the nonpredilated group (p = NS). The incidence of luminal border haziness at the dilatation site did not differ between groups, seven (35%) in group 1 versus eight (24%) in group 2. Angiographic evidence of a linear dissection at the angioplasty site was also similar between groups, one (5%) in group 1 versus five (15%) in group 2. Occlusive complications were witnessed in 10% of the predilated group and 12% of the nonpredilated group (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic occlusion of saphenous vein aortocoronary bypass grafts is a common problem. Although percutaneous transluminal angioplasty of a saphenous vein with a stenotic lesion is feasible, angioplasty alone of a totally occluded vein graft yields uniformly poor results. Patients with such occlusion are often subjected to repeat aortocoronary bypass surgery. Experience with a new technique that allows angioplasty to be performed in a totally occluded saphenous vein bypass graft is reported. This technique utilizes infusion of prolonged low dose urokinase directly into the proximal portion of the occluded graft. Forty-six consecutive patients with 47 totally occluded grafts were studied. Patients had undergone end to side saphenous vein bypass grafting 1 to 13 (mean 7) years previously. All patients presented with new or worsening angina pectoris with ST-T changes or non-Q wave acute myocardial infarction and all had a totally occluded saphenous vein bypass graft. The new technique entailed the positioning of an angiographic catheter into the stub of the occluded graft and the advancement of an infusion wire into the graft. Patients were returned to the coronary care unit, where urokinase was delivered at a dose of 100,000 to 250,000 U/h. The total dose of urokinase ranged from 0.7 to 9.8 million U over 7.5 to 77 h (mean 31). After therapy, recanalization was seen in 37 (79%) of the 47 grafts. In 20 successfully treated patients, angiography was performed 1 to 24 (mean 11) months after treatment; 13 (65%) of these grafts were patent. It is concluded that direct, extended, low dose infusion of urokinase in a totally occluded saphenous vein bypass graft offers a promising alternative to repeat bypass surgery.

CHO-K1D cells electroporated in buffers containing [32P]NAD incorporated the label in a voltage-dependent manner. Electroporation with 650 V/cm at 1460 microF in Ham's F12 medium supplemented with 10 mM Hepes, pH 7.1, resulted in a greater than 20-fold increase in [32P]NAD uptake, while decreasing relative cellular survival by only 6%. Exposure of cells to gamma irradiation (20 Gy) prior to electroporation increased the steady-state level of poly(ADP-ribosylated) nuclear proteins two- to four-fold over that of unirradiated control cells. These data indicate that electrotransfer of [32P]NAD is a simple and rapid means of labeling the cellular NAD pool and should prove useful in the analysis of the relationship between poly(ADP-ribosylation) of nuclear proteins and DNA repair.

Eight molecules of antagonists of histamine at the H 2 -receptor were studied using the semiempirical AM1 method with geometry optimization. In all cases, it was found that the side chain is in an open conformation and that the N 3 -H tautomer is the predominant form in the tautomeric equilibrium for the neutral (pharmacologically active) form of the compounds. Relationships between the charge at the N 1 atom of the imidazole moiety, the N terminal atom of the side chain, the substituent group at position 4 in the imidazole ring and the mean charge of the ring were obtained.

The biological function of poly(ADP-ribose) polymerase in DNA repair, cell-cycle regulation and cellular differentiation has yet to be defined. Isolation of cells which are deficient in poly(ADP-ribose) synthesis would greatly facilitate the determination of the biological role of this enzyme. A method is described for isolating Chinese hamster ovary (CHO) cells deficient in the poly(ADP-ribose) polymerase activity by direct screening of colonies for enzyme activity. Colonies with decreased production of poly(ADP-ribose) are recovered from nylon replicas for further analysis. Using this method we have isolated a series of CHO cells which have 50% or less poly(ADP-ribose) polymerase activity. These mutants have normal generation times and are 20% more sensitive to the effects of DNA (m)ethylating agents than the parental cell. However, these mutants display normal sensitivity to γ-rays.

Repair or misrepair of DNA double-strand breaks (DSBs) is critical in determining cellular survival after γ-irradation. In this report, wer focus on the cellular and biochemical consequences of restriction enzyme induced DSBs in wild-type Chinese hamster ovary (CHP) cells and the DNA DSB repair-defective mutant XR-1. We find that XR-1 possess reduced cellular survival after the induction of restriction enzymes that produce either cohesive or blunt ends. XT-1's sensitivity to killing by restriction enzymes strongly mimics to its response to γ-rays. Using pulsed field electrophoresis, we find that for each enzyme, similar numbers of DNA DSBs are being intorduced in both cell lines. The simplest explanation for the increased sensitivity to restriction enzymes in the mutant is that the biochemical defect in XR-1 is not confined to the repair of ionizing radiation induced ends, but extends to DSBs that possess ligatable 3′-hydroxyl and 5′-phosphate ends as well.

We thank Dr. Matsoukis and colleages for their letter expressing an interest in our recent study [(1)][1]. Regarding the type of drug-eluting stents (DES) (first vs. second generation), 72% of the stents used in the propensity-matched DES/coronary artery bypass graft (CABG) pairs were second