Noise-optimized virtual monoenergetic reconstructions of dual-energy CT angiographies improve assessability of the lower leg arterial segments in peripheral arterial occlusive disease.

INTRODUCTION: The aim of this study was to evaluate the influence of a noise optimized virtual monoenergetic reconstruction algorithm (VMI+) on the image quality and assessability of dual energy (DE) computed tomography angiography (CTA) of the lower extremity runoff. METHODS: A total of 118 lower extremity runoff CTA performed on a 3rd generation DE-CT scanner in 109 patients (54 females; 75.6 ± 9.5 years) were included in this retrospective study. Axial image stacks were reconstructed with a standard 120 kV setting and VMI+ of different keV levels. Objective image quality criteria (contrast attenuation, signal-to-noise [SNR] and contrast-to-noise ratio [CNR]) were measured. Two radiologists evaluated subjective image quality regarding intraluminal attenuation and image noise using a 5-point Likert scale. Diagnostic accuracy for significant stenosis (>75%) and vessel occlusion was assessed for 120 kV and 50 keV VMI+ images rated by two radiologists. In all patients, a digital subtraction angiography (DSA) rated by on board-certified radiologist served as the standard of reference. RESULTS: Intraluminal attenuation was highest in 40/50 keV VMI+ while SNR were similar to 120 kV images. In subjective assessment, intraluminal contrast of 50 keV images was deemed superior compared to 120 kV despite higher image noise. Sensitivity, specificity, and accuracy for detection of a vessel occlusion were similar in 50 keV VMI+ compared to 120 kV (70%/92%/84%; 70%/91%/83%; p < 0.001) but 13 of 118 (11%) lower leg runoffs were only assessable with 50 keV VMI+. CONCLUSION: VMI+ reconstructions improve assessability of DE-CTA by increased luminal attenuation with consistent image noise, also allowing the evaluation of lower leg arterial segments inassessable with standard reconstructions. IMPLICATIONS FOR PRACTICE: Providing higher intraluminal attenuation and similar image noise compared with conventional reconstructions, 50 keV VMI+ may be appropriate for routine evaluation of DE-CTA.

Biomarkers of exposure and potential harm in adult smokers of 3-7 mg tar yield (Federal Trade Commission) cigarettes and in adult non-smokers.

The paper reports levels of 24-h urine nicotine and five of its major metabolites (expressed as nicotine-equivalents) and blood carboxyhaemoglobin as biomarkers of exposure to particulate- and gas-phase cigarette smoke, respectively, from an exploratory pilot study of adult smokers of 3.0-6.9 mg tar delivery (Federal Trade Commission (FTC) method) cigarettes. On multiple occasions over 6 weeks, blood high-sensitivity C-reactive protein (hs-CRP), fibrinogen, HDL- and LDL-cholesterol, and 24-h urine 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) and 11-dehydro-thromboxane B2 (11-dehydro-TxB2) were also evaluated as biomarkers of potential harm. All the biomarkers examined, except for LDL-cholesterol, discriminated with high sensitivity and specificity between adult smokers and non-smokers overall. Except for HDL-cholesterol, all biomarker medians were greater in adult smokers than in non-smokers: urine nicotine-equivalents 64.514 versus < 0.034 nmol mg-1 creatinine (p<0.001), carboxyhaemoglobin 4.0 versus 0.4% saturation (p<0.001), hs-CRP 0.27 versus 0.12 mg dl-1 (p=0.05), fibrinogen 292 versus 248 mg dl-1 (p<0.001), HDL-cholesterol 46 versus 53 mg dl-1 (p=0.003), LDL-cholesterol 119 versus 109 mg dl-1 (p=0.18), urine 8-epi-PGF2alpha 1935 versus 1034 pg mg-1 creatinine (p<0.001) and urine 11-dehydro-TxB2 973 versus 710 pg mg-1 creatinine (p<0.001). All the biomarkers of exposure and most of the biomarkers of potential harm showed no time of sampling (by visit week) effect.

Mechanisms involved in A/J mouse lung tumorigenesis induced by inhalation of an environmental tobacco smoke surrogate.

Lung tumors have been reproducibly induced in A/J mice exposed to a surrogate for experimental environmental tobacco smoke (ETSS) in a 5-mo inhalation period followed by 4 mo without further exposure. In order to increase our mechanistic understanding of this model, male mice were whole-body exposed for 6 h/d, 5 d/wk to ETSS with a particulate matter concentration of 100 mg/m(3). Food restriction regimens were included to model or exceed the ETSS-related impairment of body weight development. Half of the mice were pretreated with a single ip injection of urethane to study the effect of the above treatments on lung tumor development induced by this substance. At 5 mo, the tumor response was statistically the same for all groups of non-pretreated mice; however, the expected urethane-induced lung tumorigenesis was significantly inhibited by approximately 25% by ETSS and food restriction. This inhibition was accompanied by a threefold increase in blood corticosterone as a common stress marker for both ETSS and food restriction. At 9 mo, in mice not pretreated, the lung tumor incidence and multiplicity were significantly increased by twofold in the ETSS group; in the urethane-treated groups, the same high tumor multiplicity was reached regardless of previous treatment. The predominant tumor type in all groups was bronchiolo-alveolar adenoma. There was no induction of a specific K-ras mutation pattern by ETSS exposure. These data suggest a stress-induced inhibition of lung tumorigenesis in this model, explaining the need for the posttreatment period.

Toxicological evaluation of an electrically heated cigarette. Part 4: Subchronic inhalation toxicology.

The biological activity of mainstream smoke from an electrically heated cigarette (EHC) with controlled combustion and from the University of Kentucky Reference Cigarette 1R4F was determined in Sprague Dawley rats exposed nose-only for 90 days, 6 h a day, 7 days per week. For an equivalent response comparison between the two cigarette types, two doses were chosen for the EHC where the anticipated results were in the dynamic range of the 1R4F dose-response curve (four concentrations) for most end points. The number of cigarettes smoked per m(3) of diluted smoke resulted in total particulate matter concentrations of 40 and 90 microg l (-1) for the EHC and 40-170 microg l (-1) for the 1R4F. Biomonitoring indicated achievement of target doses. Mainstream smoke yields were lower for the EHC, with the exception of formaldehyde. No smoke-related mortality, remarkable in-life observations or abnormal gross pathological findings were observed. Smoke- and dose-related clinical pathology and organ weight changes included: increases in segmented neutrophils, some liver parameters and lung and adrenal weight relative to body weight; and decreases in lymphocytes, glucose concentration and spleen weight. Smoke-related histopathological findings in the respiratory tract included epithelial cell hyperplasia, squamous metaplasia, atrophy and accumulation of pigmented alveolar macrophages; they were mostly dose-dependent, more pronounced in the upper than lower respiratory tract and completely or partially reversed by 6 weeks post-inhalation. Qualitatively, the biological effects seen for the EHC and the 1R4F were comparable and similar to those observed in other mainstream smoke inhalation studies. Quantitatively, the biological activity of the EHC mainstream smoke was, on average, 65% lower than that of the 1R4F mainstream smoke on an equal cigarette basis and equivalent activity on an equal TPM basis.

Enzymatic synthesis of N-acetyllactosamine in aqueous-organic reaction media.

Beta-galactosidase from Bacillus circulans was used for the biocatalytic transfer of D-galactose (D-Gal) from o-nitrophenyl-beta-D-galactoside (ONPG) to the O-4 position of 2-acetamido-2-deoxy-D-glucopyranose (D-GlcNAc) forming the disaccharide N-acetyllactosamine (LacNAc, beta-D-Gal-(1 --> 4)-D-GlcNAc). In order to investigate the potential of this biocatalytic synthesis, first the optimal reactant ratio in an aqueous buffer system was determined. On the basis of these standard conditions we then performed reactions in aqueous-organic media applying organic cosolvents of different structure and polarity in various amounts. In this way we received in some cases appreciably better results than without organic cosolvent. The highest obtainable disaccharide yield was 50% in a mixture of 20% (v/v) cyclohexane/80% buffer versus 35% in buffer solution alone.

Are PhAcOZ and Nsc suitable N alpha-protecting groups for protease-catalysed peptide synthesis?

Protecting groups are necessary chemical tools in peptide synthesis. In protease-catalysed peptide synthesis they exert influence both on enzyme-substrate binding and on solubility. In this study, we have investigated the usability of various PhAcOZ- and Nsc-protected amino acids for protease-catalysed peptide synthesis. PhAcOZ-protected peptides were obtained in high yields using papain and thermolysin. In contrast to this, Nsc, as a base-labile alpha-amino protecting group, is not suitable for biocatalytic synthesis under the conditions employed.

Evaluation of the potential effects of ingredients added to cigarettes. Part 4: subchronic inhalation toxicity.

Mainstream smoke from blended research cigarettes with (test) and without (control) the addition of ingredients to the tobacco was assayed for inhalation toxicity. In total, 333 ingredients commonly used in cigarette manufacturing were assigned to three different groups. Each group of ingredients was introduced at a low and a high level to the test cigarettes. Male and female Sprague-Dawley rats were exposed nose-only either to fresh air (sham) or diluted mainstream smoke from the test, the control, or the Reference Cigarette 1R4F at a concentration of 150 microg total particulate matter/l for 90 days, 6h/day, 7 days/week. A 42-day post-inhalation period was included to evaluate reversibility of possible findings. There were no remarkable differences in in-life observations or gross pathology between test and control groups. An increase in activity of liver enzymes, known to be due to the high smoke dose, revealed no toxicologically relevant differences between the test and control groups. No toxicological differences were seen between the test and control groups for smoke-related hematological changes, such as a decrease in total leukocyte count. The basic smoke-related histopathological effects, which were more pronounced in the upper respiratory tract than in the lower respiratory tract, were hyperplasia and squamous metaplasia of the respiratory epithelium, squamous metaplasia and atrophy of the olfactory epithelium, and accumulation of pigmented alveolar macrophages. There were no relevant qualitative or quantitative differences in findings in the respiratory tract of the rats exposed to the smoke from the control and test cigarettes. The data indicate that the addition of these 333 commonly used ingredients, added to cigarettes in three groups, did not increase the inhalation toxicity of the smoke, even at the exaggerated levels used.

Language/culture/mind/brain. Progress at the margins between disciplines.

At the forefront of research on language are new data demonstrating infants' strategies in the early acquisition of language. The data show that infants perceptually "map" critical aspects of ambient language in the first year of life before they can speak. Statistical and abstract properties of speech are picked up through exposure to ambient language. Moreover, linguistic experience alters infants' perception of speech, warping perception in a way that enhances native-language speech processing. Infants' strategies are unexpected and unpredicted by historical views. At the same time, research in three additional disciplines is contributing to our understanding of language and its acquisition by children. Cultural anthropologists are demonstrating the universality of adult speech behavior when addressing infants and children across cultures, and this is creating a new view of the role adult speakers play in bringing about language in the child. Neuroscientists, using the techniques of modern brain imaging, are revealing the temporal and structural aspects of language processing by the brain and suggesting new views of the critical period for language. Computer scientists, modeling the computational aspects of childrens' language acquisition, are meeting success using biologically inspired neural networks. Although a consilient view cannot yet be offered, the cross-disciplinary interaction now seen among scientists pursuing one of humans' greatest achievements, language, is quite promising.

Stability of several LHRH antagonists against proteolytic enzymes and identification of degradation products by mass spectrometry.

In this study stabilities of several LHRH antagonists against proteolytic enzymes are compared. For the enzymatic tests 15 proteases which differ in both substrate specificity and pH optimum were selected. The cyclic and two linear antagonists proved to be extraordinarily stable against the enzymes used over an incubation time of 50 h. Some degradation products were identified by high-performance liquid chromatography combined with mass spectrometry.

A new view of language acquisition.

At the forefront of debates on language are new data demonstrating infants' early acquisition of information about their native language. The data show that infants perceptually "map" critical aspects of ambient language in the first year of life before they can speak. Statistical properties of speech are picked up through exposure to ambient language. Moreover, linguistic experience alters infants' perception of speech, warping perception in the service of language. Infants' strategies are unexpected and unpredicted by historical views. A new theoretical position has emerged, and six postulates of this position are described.

Perceptual magnet and phoneme boundary effects in speech perception: do they arise from a common mechanism?

The question of whether sensitivity peaks at vowel boundaries (i.e., phoneme boundary effects) and sensitivity minima near excellent category exemplars (i.e., perceptual magnet effects) stem from the same stage of perceptual processing was examined in two experiments. In Experiment 1, participants gave phoneme identification and goodness ratings for 13 synthesized English /i/ and /e/ vowels. In Experiment 2, participants discriminated pairs of these vowels. Either the listeners discriminated the entire range of stimuli within each block of trials, or the range within each block was restricted to a single stimulus pair. In addition, listeners discriminated either one-step or two-step intervals along the stimulus series. The results demonstrated that sensitivity peaks at vowel boundaries were more influenced by stimulus range than were perceptual magnet effects; peaks in sensitivity near the /i/-/e/ boundary were reduced with restricted stimulus ranges and one-step intervals, but minima in discrimination near the best exemplars of /i/ were present in all conditions.

Accuracy of methemoglobin measurements: comparison of six different commercial devices and one manual method.

OBJECTIVE: During nitric oxide inhalation, methemoglobinemia needs to be monitored. We compared six commercially available instruments and one manual method for methemoglobin measurements. In addition, we studied whether and to what degree methylene blue interferes with methemoglobin measurements. DESIGN: In vitro methodologic study. SETTING: Research laboratory in a university hospital. PATIENTS: Five healthy volunteers from whom red blood cells were obtained. INTERVENTIONS: Methemoglobinemia was generated in a red blood cell suspension by nitric oxide; methemoglobin was measured with six commercial instruments and one manual photometric method to calculate variation coefficients and to determine the differences between the devices. Methemoglobin was measured with and without the addition of methylene blue with two instruments. Measurements were performed immediately after the addition of methylene blue. MEASUREMENTS AND MAIN RESULTS: All six commercially available instruments had variation coefficients of <0.1 at methemoglobin concentrations of 5%, whereas the manual photometric method did not reach a variation coefficient of <0.1 at 8% of methemoglobin. Apart from two devices that measured slightly but significantly higher methemoglobin levels, all instruments measured similar values of methemoglobin when the same samples were determined simultaneously. Higher concentrations of methylene blue (10, 40, 100 microM) reduced substantially the apparent concentrations of methemoglobin. Interference by methylene blue was most pronounced at low methemoglobin levels. CONCLUSIONS: With some limitations, all commercial instruments that were tested performed adequately for the monitoring of methemoglobinemia. Methylene blue interferes with the methemoglobin measurements in a dose-dependent manner.

Birdsong and human speech: common themes and mechanisms.

Human speech and birdsong have numerous parallels. Both humans and songbirds learn their complex vocalizations early in life, exhibiting a strong dependence on hearing the adults they will imitate, as well as themselves as they practice, and a waning of this dependence as they mature. Innate predispositions for perceiving and learning the correct sounds exist in both groups, although more evidence of innate descriptions of species-specific signals exists in songbirds, where numerous species of vocal learners have been compared. Humans also share with songbirds an early phase of learning that is primarily perceptual, which then serves to guide later vocal production. Both humans and songbirds have evolved a complex hierarchy of specialized forebrain areas in which motor and auditory centers interact closely, and which control the lower vocal motor areas also found in nonlearners. In both these vocal learners, however, how auditory feedback of self is processed in these brain areas is surprisingly unclear. Finally, humans and songbirds have similar critical periods for vocal learning, with a much greater ability to learn early in life. In both groups, the capacity for late vocal learning may be decreased by the act of learning itself, as well as by biological factors such as the hormones of puberty. Although some features of birdsong and speech are clearly not analogous, such as the capacity of language for meaning, abstraction, and flexible associations, there are striking similarities in how sensory experience is internalized and used to shape vocal outputs, and how learning is enhanced during a critical period of development. Similar neural mechanisms may therefore be involved.

Preparation and use of tethered ligands as biomaterials and tools for cell biology.

The immobilization of biomolecules to various supports has been an important research area for many years. Molecules such as heparin (1,2), as well as various enzymes (3,4), antibodies (5,6), and adhesion ligands (7), have been bound to such supports as silicon or glass, agarose gels, polyethylene oxide (PEO) gels, poly(vinyl alcohol) (PVA) gels, and polymer surfaces. These studies have had important applications in the creation of antithrombogenic surfaces for blood contact, affinity chromatography, and tissue growth and regeneration.

Prospective randomized multicenter clinical trial on the use of interferon -2a plus acitretin versus interferon -2a plus PUVA in patients with cutaneous T-cell lymphoma stages I and II.

Cutaneous T-cell lymphoma (CTCL) constitutes a malignant proliferative disease involving mostly CD4(+) T cells arising in the skin. Because of the lack of curative treatment options, interferons (IFN) have been introduced into the therapy of CTCL. Although effective even in advanced disease, response rates were about 50% and the duration of response was short. To improve the results of interferon monotherapy, combinations of IFN with oral photochemotherapy (PUVA) or retinoids were investigated in nonrandomized trials showing higher response rates. We have therefore conducted this prospective randomized multicenter trial to compare these two combination therapies, ie, IFN plus PUVA and IFN plus acitretin. IFN -2a was administered at 9 MU three times weekly subcutaneously in both groups, with lower increasing doses during the first week. Photochemotherapy was applied after oral intake of 8-methoxypsoralen (0.6 mg/kg body weight) 5x weekly during the first 4 weeks, 3x weekly from weeks 5 through 23, and 2x weekly from weeks 24 through 48, with escalating doses beginning with 0.25 J/cm2. Twenty-five milligrams of acitretin was administered daily during the first week, and 50 mg was administered from weeks 2 through 48. Of 98 patients randomized in this study, 82 stage I and II patients were evaluable: 40 in the IFN+PUVA group and 42 in the IFN+acitretin group. With 70% complete remissions in the IFN+PUVA group, this treatment was significantly superior to the IFN+acitretin group with only 38.1% complete remissions. Time to response was significantly shorter in the IFN+PUVA group, with 18.6 weeks compared with 21.8 weeks in the IFN+acitretin group. Side effects were mostly mild to moderate and did not differ significantly in both treatment groups. However, there were more adverse events leading to study discontinuation in the IFN+acitretin group. Based on these findings, we conclude that IFN plus oral photochemotherapy is superior to IFN plus acitretin, inducing more complete remissions in patients with CTCL stages I and II.

Early versus late surfactant treatment in preterm infants of 27 to 32 weeks' gestational age: a multicenter controlled clinical trial.

OBJECTIVE: To investigate whether early (<1 hour after birth) surfactant administration would be superior to late treatment (2-6 hours after birth) in preterm infants. STUDY DESIGN: Randomized controlled multicenter clinical trial. PATIENTS AND METHODS: Prenatal randomization of all infants of 27 to 32 weeks' gestational age stratified by center after parental informed consent. Early treatment: 100 mg/kg body weight bovine surfactant (SF-RI1, Alveofact; Dr K. Thomae, Biberach, Germany) to infants requiring intubation after birth. Late treatment: identical dosage to infants requiring intubation up to 6 hours of age with the fraction of inspired oxygen >0.4 at 2 to 6 hours after birth. Primary endpoint: the time on mechanical ventilation. Main secondary endpoints: mortality, bronchopulmonary dysplasia, intraventricular hemorrhage >/=grade III, and periventricular leukomalacia. Sample size calculation: at least 280 infants to prove superiority of either approach (alpha = 0.05; beta = 0.90). RESULTS: Enrollment of 317 infants, 154 randomized to early surfactant treatment, 163 to late surfactant treatment. Study infants (all following data intent-to-treat groups: early versus late surfactant) were similar with respect to: gestational age, 29.5 +/- 1.6 weeks versus 29.7 +/- 1.6 weeks; birth weight, 1227 +/- 367 g versus 1269 +/- 334 g; and the rate of prenatal corticosteroids, 79.9% versus 72.8%. Duration of mechanical ventilation: 3 days (0-8) versus 2 days (0-6) (median, interquartile); further outcome variables: death or bronchopulmonary dysplasia (day 28) 25.9% versus 23.9%, mortality 3.2% versus 1.8%, intraventricular hemorrhage >/=grade III 6.5% versus 3.7%, and periventricular leukomalacia 5.2% versus 5.5% not differing statistically. CONCLUSION: In preterm infants with a high rate of prenatal glucocorticoids, early surfactant administration was not found to be superior to late treatment in terms of relevant outcome variables.

Reduction of NO-induced methemoglobinemia requires extremely high doses of ascorbic acid in vitro.

The objective of the present study was to investigate the treatment of nitric oxide (NO)-induced methemoglobinemia by ascorbate and its consequences on red blood cell (RBC) glutathione in vitro. RBC were obtained from five healthy volunteers. The following experiments were carried out: (1) After methemoglobin generation by NO, ascorbate was added (2) RBC were simultaneously exposed to NO and ascorbate (3) Methemoglobin was generated by NO, ascorbate was added and incubation with NO continued. (1) After discontinuation of NO, the mean half life for methemoglobin was reduced from 195 min (controls) to 60 min (10 mM ascorbate) in a dose-dependent manner. (2) Methemoglobin formation after 3 h of NO exposure was 2.7 +/- 0.3% in controls and 1.8 +/- 0.1% with 10 mM ascorbate (p < 0.01). (3) Further methemoglobin formation was inhibited only by 10 mM ascorbate (p < 0.001). NO incubation did not affect RBC glutathione (86.5 +/- 19.6 and 86.5 +/- 19.6 mg/l, respectively). Treatment with 10 mM ascorbate significantly decreased glutathione (p < 0.002). In vitro, NO-induced methemoglobin formation is significantly decreased only by a high (10 mM) ascorbate concentration. Glutathione, critical for ascorbate activity, is not influenced by NO.

Comparison of fresh and room-aged cigarette sidestream smoke in a subchronic inhalation study on rats.

Two experimental types of cigarette sidestream smoke (SS) were compared in a subchronic inhalation study on rats. Fresh SS (FSS) was generated continuously from the reference cigarette 2R1. Room-aged SS (RASS) was generated by aging FSS for 1.5 h in a room with noninert surfaces with materials typically found in residences or offices. Male Sprague-Dawley rats were head-only exposed to three dose levels of each SS type and to filtered, conditioned fresh air (sham-exposure) for 6 h/day, 7 days/week, for 90 days. Room-aging resulted in decreased concentrations of various SS components, e.g., total particulate matter (TPM) and nicotine, while other components, such as carbon monoxide (CO), were not affected. The CO concentrations were 6, 13, and 28 ppm for both SS types. TPM concentrations were between 0.6 and 8.7 micrograms/liter and thus up to 100-fold above the maximum of average concentrations of respiratory suspended particles reported for environmental tobacco smoke. Slight reserve cell hyperplasia in the anterior part of the nose as well as hyperplastic and metaplastic epithelial changes in the larynx were the only observed dose-dependent findings. The metabolism of benzo(a)-pyrene--as a proxy for polycyclic aromatic hydrocarbon metabolism--was induced in the nasal respiratory epithelium and in the lungs while no effect was seen in the nasal olfactory epithelium. The lowest-observed effect level was 6 ppm CO or 0.6 microgram TPM/liter. Most of the effects seen were less expressed in RASS-than in FSS-exposed rats when compared on the basis of the CO concentrations. When compared on the basis of TPM, these effects were equally pronounced for both SS types, suggesting a major role of particulate matter-associated compounds. All findings reverted to sham control levels following a 42-day postinhalation period.

Cross-language analysis of phonetic units in language addressed to infants.

In the early months of life, infants acquire information about the phonetic properties of their native language simply by listening to adults speak. The acoustic properties of phonetic units in language input to young infants in the United States, Russia, and Sweden were examined. In all three countries, mothers addressing their infants produced acoustically more extreme vowels than they did when addressing adults, resulting in a "stretching" of vowel space. The findings show that language input to infants provides exceptionally well-specified information about the linguistic units that form the building blocks for words.