High Precision Detection of Change in Intermediate Range Order of Amorphous Zirconia-Doped Tantala Thin Films Due to Annealing.

Understanding the local atomic order in amorphous thin film coatings and how it relates to macroscopic performance factors, such as mechanical loss, provides an important path towards enabling the accelerated discovery and development of improved coatings. High precision x-ray scattering measurements of thin films of amorphous zirconia-doped tantala (ZrO_{2}-Ta_{2}O_{5}) show systematic changes in intermediate range order (IRO) as a function of postdeposition heat treatment (annealing). Atomic modeling captures and explains these changes, and shows that the material has building blocks of metal-centered polyhedra and the effect of annealing is to alter the connections between the polyhedra. The observed changes in IRO are associated with a shift in the ratio of corner-sharing to edge-sharing polyhedra. These changes correlate with changes in mechanical loss upon annealing, and suggest that the mechanical loss can be reduced by developing a material with a designed ratio of corner-sharing to edge-sharing polyhedra.

Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto.

Background: In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and methods: Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). Results: A significantly better DFS (hazard ratio 0.56, 95% CI 0.34-0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26-5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46-9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17-1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23-1.04, P = 0.059). Conclusions: The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.

Emergency oxygenator change-out after massive fat embolism.

We present a case with an unusually high transmembrane pressure gradient over the oxygenator during initiation of extracorporeal membrane oxygenation (ECMO). This necessitated an immediate emergency oxygenator exchange. A detailed inspection revealed a large lipid formation in the oxygenator. We hypothesize that this lipid was dislodged during the cannulation process.

Mining the human genome using microarrays of open reading frames.

To test the hypothesis that the human genome project will uncover many genes not previously discovered by sequencing of expressed sequence tags (ESTs), we designed and produced a set of microarrays using probes based on open reading frames (ORFs) in 350 Mb of finished and draft human sequence. Our approach aims to identify all genes directly from genomic sequence by querying gene expression. We analysed genomic sequence with a suite of ORF prediction programs, selected approximately one ORF per gene, amplified the ORFs from genomic DNA and arrayed the amplicons onto treated glass slides. Of the first 10,000 arrayed ORFs, 31% are completely novel and 29% are similar, but not identical, to sequences in public databases. Approximately one-half of these are expressed in the tissues we queried by microarray. Subsequent verification by other techniques confirmed expression of several of the novel genes. Expressed sequence tags (ESTs) have yielded vast amounts of data, but our results indicate that many genes in the human genome will only be found by genomic sequencing.

A modular lymphographic magnetic resonance imaging contrast agent: contrast enhancement with DNA transfection potential.

A gadolinium-chelated liposomal contrast agent has been prepared, and magnetic resonance imaging (MRI) efficacy has been examined by indirect magnetic resonance lymphography. A lipidic N,N'-dimethylethylenediamine derivative (4) containing a 10,12-diyne-diacyl domain was treated with DTPA anhydride followed by GdCl3 complexation. The complex was confirmed using MALDI spectrometry. An equimolar mixture of the Gd-chelate lipid and a commercially available diyne-PE was formulated as a liposome suspension and irradiated with UV light prior to imaging experiments. Subcutaneous injection of the liposomal gadolinium agent and subsequent MRI of rabbit axillary and popliteal lymph nodes revealed significant contrast enhancement up to 4 h postinjection. To explore the possibility of imaging a DNA transfection event, the gadolinium contrast mixture was formulated with the cationic transfection lipid DOTAP and complexed with the reporter gene encoding luciferase. DNA transfection studies on the NIH3T3 cell line confirmed the transfection activity of the dual-purpose contrast agent and exemplified the potential toward development of an imaging and DNA delivery vehicle.

The complexation of protonated peptides with saccharides in the gas phase decreases the rates of hydrogen/deuterium exchange reactions.

Gas-phase noncovalently bound complexes are probed by hydrogen/deuterium exchange. The complexes, composed of a protonated amino acid and a monosaccharide, are investigated to observe the effects of complexation on the rates of exchange. Rate constants are determined and compared for complexed and uncomplexed amino acids. The overall rate constant, which corresponds to exchange of a specific number of hydrogens, is deconvoluted to yield site-specific rate constants. Complexation of amino acids with saccharides significantly decreases the rate constants of the exchange. Results of molecular orbital calculations are provided to explain the decrease in the rates.

Applications of gene arrays in environmental toxicology: fingerprints of gene regulation associated with cadmium chloride, benzo(a)pyrene, and trichloroethylene.

Toxicity testing of unknown chemicals currently uses a number of short-term bioassays. These tests are costly and time consuming, require large numbers of animals, and generally focus on a single end point. The recent development of DNA arrays provides a potential mechanism for increasing the efficiency of standard toxicity testing through genome-wide assessments of gene regulation. In this study, we used DNA arrays containing 148 genes for xenobiotic metabolizing enzymes, DNA repair enzymes, heat shock proteins, cytokines, and housekeeping genes to examine gene expression patterns in the liver in response to cadmium chloride, benzo(a)pyrene (BaP), and trichloroethylene (TCE). Dose-response studies were carried out in mice for each chemical; each produced a unique pattern of gene induction. As expected, CdCl2 markedly up-regulated metallothionine I and II (5- to 10,000-fold at the highest doses) and several of the heat shock/stress response proteins and early response genes. In contrast, administration of BaP up-regulated only Cyp1a1 and Cyp1a2 genes and produced no significant increases in any of the stress response genes or any of the DNA repair genes present on the array. Likewise, TCE-induced gene induction was highly selective; only Hsp 25 and 86 and Cyp2a were up-regulated at the highest dose tested. Microarray analysis with a highly focused set of genes is capable of discriminating between different classes of toxicants and has potential for differentiating highly noxious versus more subtle toxic agents. These data suggest that use of microarrays to evaluate the potential hazards of unknown chemicals or chemical mixtures must include multiple doses and time points to provide effective assessments of potential toxicity of these substances.

Prolapsed sigmoid intussusception per anus in an elderly man: a case report.

BACKGROUND: Intussusception in pediatrics is widely documented and well described. On the basis of the literature, however, adult intussusception is a rare entity with a prevalence of from 1% to 5%. The majority of adult patients with intussusception have an underlying pathology that needs to be identified by performing a proper physical examination and a wide array of investigations. CASE PRESENTATION: We present a case of a 66-year-old African man who presented to our emergency department with a mass protruding per anus with obstipation. During laparotomy, we found that the sigmoid colon had intussuscepted into the rectum and out from the anus. Other abdominal viscera were normal and without any obvious mesenteric lymphadenopathy. Sigmoid colectomy and spectacle colostomy were performed. Grossly, the excised bowel looked normal, but the histologic results showed features of necrosis and chronic inflammation. CONCLUSION: While 70% to 90% of cases of adult intussusception have an identifiable cause or lesion, most pediatric intussusceptions are idiopathic. The presentation in an adult described herein was of an uncommon idiopathic type with no identifiable cause found on the basis of the history, physical examination, or histological findings.

Detection of human viral RNA via a combined fluorescence and SERS molecular beacon assay.

A dual-mode molecular beacon on a multiplexed substrate has been developed and applied to the measurement of unlabeled human viral RNA. The detection system is based on a combined surface-enhanced Raman scattering (SERS) and fluorescent molecular beacon assay that is assembled on Nanobarcodes™ particles. In this assay, a molecular beacon probe terminated with a fluorescent Raman label dye is conjugated to the metallic Nanobarcodes™ particles. The molecular beacon probe is a single-stranded oligonucleotide that has been designed with a hairpin structure that holds the dye at 3'-end close to the particle surface when the probe is attached through a 5'-thiol group. In this configuration, the SERS spectrum of the label was obtained and its fluorescence quenched because the dye is in very close proximity to a noble metal surface with nanoscale features (Nanobarcodes™ particles). The SERS signal decreased and the fluorescence signal increased when target viral RNA was captured by this molecular beacon probe. In addition, a hepatitis C virus reverse transcriptase-polymerase chain reaction (HCV RT-PCR) product was detected using this dual-mode beacon. The development of a multiplexed, label-free assay system with the reassurance offered by detection of two distinctly separate signals offers significant benefits for rapid molecular diagnostics.

The role of submacular surgery in the treatment of choroidal neovascular membranes.

The growth of choroidal neovascular membranes (CNVM) beneath the macula can cause significant disturbances of central vision. Conditions such as age-related macular degeneration (AMD) and presumed ocular histoplasmosis syndrome (POHS) are the most common etiologies. The Macular Photocoagulation Study group presented data that clearly showed laser photocoagulation to be beneficial in the treatment of CNVM. Poor visual results and a high rate of recurrence have prompted clinicians to seek out alternative treatments. Experiences with CNVM removal utilizing submacular surgical techniques have shown that central visual function may be restored or preserved in POHS, multifocal choroiditis and idiopathic causes. The Submacular Surgery Trials were designed to investigate whether submacular surgery is more effective in retaining central acuity in patients with subfoveal CNVM, than observation alone. The goal of this paper is to review the role of submacular surgery in the treatment of subfoveal choroidal neovascular membranes.

Adult onset foveomacular vitelliform dystrophy: a case report.

BACKGROUND: Pattern dystrophies of the retinal pigment epithelium, an arrangement of a pattern of dots, lines, or branches, are infrequent fundus abnormalities. Adult onset foveomacular vitelliform dystrophy (AOFVD) is considered a subtype of pattern dystrophy. Onset occurs during middle age, with an accumulation of yellow-gray macular deposits in the deeper retinal layers. Typically electro-oculograms are mildly subnormal or normal. Genetic studies suggest an autosomal dominant inheritance with variable penetrance. CASE REPORT: A case of a 56-year-old Hispanic women with a 1-month onset of "wavy moving vision" in both eyes is presented. Previous ocular and family history were unremarkable. Ophthalmoscopic examination revealed yellow circumscribed subretinal lesions of one-third to one-half disk diameter in the foveal centers of both eyes. Fluorescein angiography revealed a circumscribed area of mottled hyperfluorescence surrounding a central hypofluorescent spot. The patient was diagnosed with AOFVD. Examination of the patient's children revealed retinal pigment epithelial disturbances in the two oldest daughters, consistent with pattern dystrophies. CONCLUSION: Our investigation supports an autosomal dominant inheritance pattern, as seen on pedigree. The presence of different pattern dystrophies within the same family suggests a common etiologic continuum.

Differential binding of tioconazole enantiomers to hydroxypropyl-beta-cyclodextrin studied by capillary electrophoresis.

Capillary electrophoresis has been used to determine binding constants of tioconazole enantiomers with hydroxypropyl-beta-cyclodextrin (HP-beta-CD), after correcting for changes in mobility with increasing viscosity. The predicted and observed values of enantiomeric mobility difference were found to be maximum at a concentration of HP-beta-CD equal to the reciprocal of the average binding constant.

Capillary electrophoresis with chiral selectors: optimization of separation and determination of thermodynamic parameters for binding of tioconazole enantiomers to cyclodextrins.

A systematic approach is outlined for optimization of enantiomeric separations in free solution capillary electrophoresis using chiral mobile-phase additives. Maximum electrophoretic mobility difference between the enantiomers occurs when the concentration of free selector is equal to the reciprocal of the average binding constant. General equations and data analysis methods are presented to relate mobilities to equilibrium constants in simple and competitive binding equilibria and used to determine thermodynamic parameters for host-guest complexation of tioconazole enantiomers with a range of cyclodextrin selectors. Selectivities are found to be in the reverse order of binding constants in the series dimethyl-beta-cyclodextrin (K1 = 6.9 x 10(3) M-1, alpha = 1.10) to hydroxypropyl-beta-cyclodextrin (K1 = 0.72 x 10(3) M-1, alpha = 1.29). For beta-cyclodextrin (K1 = 1.32 x 10(3)M-1, alpha = 1.20), delta H zero provides the dominant contribution to binding but delta delta H zero and T delta delta S zero terms give comparable contributions to the selectivity. Addition of alcohol does not affect the selectivity, but allows displacement of the optimum separation conditions to higher cyclodextrin concentration through either competitive binding (with cyclohexanol) or preferential solvation of reactants (with methanol).

Alkaline degradation of oligosaccharides coupled with matrix-assisted laser desorption/ionization Fourier transform mass spectrometry: a method for sequencing oligosaccharides.

A new technique for determining sequence and linkage information of underivatized oligosaccharides is developed using alkaline degradation and matrix-assisted laser desorption/ionization Fourier transform mass spectrometry (MALDI-FTMS). Alkaline degradation (also known as the "peeling" reaction) is a chemical degradation technique that only cleaves the glycosidic bond at the reducing end by beta-elimination to yield a new reducing end. The reaction products are sampled directly with minimal cleanup and monitored by MALDI-FTMS to elucidate the oligosaccharide sequence. Linkage information is provided by cross-ring cleavage fragmentation of the new reducing ends, created by either MALDI source fragmentation or sustained off-resonance irradiation collision-induced dissociation. This method is illustrated by the successful sequence and linkage determination of neutral, branched, fucosylated, and sialylated oligosaccharides. Experiments on differently linked disaccharides are also performed to determine the specificity of the cross-ring cleavage reactions. The power of this technique is enhanced by the Fourier transform mass analyzer, which provides high-resolution, exact mass, and facile tandem mass spectrometry experiments of MALDI-produced ions.

Collision-induced dissociation of branched oligosaccharide ions with analysis and calculation of relative dissociation thresholds.

Collision-induced dissociation (CID) is used in an external source Fourier transform mass spectrometer (FTMS) equipped with matrix-assisted laser desorption/ionization (MALDI) to study a number of complex, branched oligosaccharides. The relative dissociation thresholds for various oligosaccharide fragmentation pathways have been calculated in terms of kinetic and center-of-mass frame energy. For two isomers of difucosyllacto-N-hexaose, the loss of the fucose sugar is always the lowest energy fragment observed and occurs at the same energy for both isomers when the oligosaccharide is coordinated to a sodium ion. When the oligosaccharide is complexed to cesium, the threshold for the removal of the fucose moiety increases, indicating that the cesium is involved in a coordination complex that stabilizes the sugar. MS/ MS/MS is performed on a sugar, mannose core, which does not readily fragment during MALDI. In all the sugars examined, CID produces additional structural information relative to MALDI/FTMS.