Ethyl Lithiodiazoacetate: Extremely Unstable Intermediate Handled Efficiently in Flow.

Ethyl diazoacetate (EDA) is one of the most prominent diazo reagents. It is frequently used in metal-carbene-type reactions. However, EDA can also be used as a nucleophile under base catalysis. Whilst the addition of EDA to aldehydes can be performed using organic bases, the addition of EDA to other carbonyl electrophiles requires the use of organometallics such as lithium diisopropylamide (LDA). The generated ethyl lithiodiazoacetate is highly reactive and decomposes rapidly, even at low temperatures. Herein, we report a continuous flow protocol that overcomes the problems associated with the instantaneous decomposition of ethyl lithiodiazoacetate. The addition of ethyl lithiodiazoacetate to ketones provides direct access to tertiary diazoalcohols in good yields.

Rapid Generation and Safe Use of Carbenes Enabled by a Novel Flow Protocol with In-line IR spectroscopy.

A powerful new continuous process for the formation and use of donor/acceptor-substituted carbenes is described. The safety profile of diazo group transfer on methyl phenylacetate was determined including kinetic studies in batch and in flow using in-line IR analysis. Batch work-up and liquid chromatography were circumvented by developing an optimized liquid/liquid flow separation method providing aryl diazoacetates in high purity. Fast screening of reaction conditions in flow with in-line IR analysis allowed rapid reaction optimization. Finally, a multistep process of diazo group transfer, extraction, separation and subsequent diazo decomposition combined with multiple X-H insertion reactions was established.

Synthesis, characterization, and antioxidant activity of Zn2+ and Cu2+ coordinated polyhydroxychalcone complexes.

ABSTRACT: Four new metal complexes [Cu(ISO)2], [Cu(BUT)2] and [Zn(ISO)2], [Zn(BUT)2] of the polyhydroxychalcones (isoliquiritigenin and butein) are synthesized, structurally characterized and their antioxidant activity is investigated. The formation of the complexes [Cu(ISO)2] and [Zn(ISO)2] is followed by Job's plot using NMR titration. The resulting compounds are characterized by mass spectrometry, IR spectroscopy, and elemental analysis. Studies on the radical scavenging activity are performed using DPPH as substrate. The results showed that the antioxidant activities of isoliquiritigenin and butein are enhanced after binding to copper or zinc.

Diazo compounds in continuous-flow technology.

Diazo compounds are very versatile reagents in organic chemistry and meet the challenge of selective assembly of structurally complex molecules. Their leaving group is dinitrogen; therefore, they are very clean and atom-efficient reagents. However, diazo compounds are potentially explosive and extremely difficult to handle on an industrial scale. In this review, it is discussed how continuous flow technology can help to make these powerful reagents accessible on large scale. Microstructured devices can improve heat transfer greatly and help with the handling of dangerous reagents safely. The in situ formation and subsequent consumption of diazo compounds are discussed along with advances in handling diazomethane and ethyl diazoacetate. The potential large-scale applications of a given methodology is emphasized.

Toxicity of indium-111 on the radiolabeled lymphocyte.

The radiolabeling of lymphocytes with 111In has resulted in detectable toxic changes in the cells. The mechanisms of toxicity for lymphocytes have been related to the label's radioactivity and to the chelator used to mediate the intracellular localization. These mechanisms were examined by assessing cellular function with mitogen-mediated blastogenesis after labeling lymphocytes with either the chelator (tropolone) alone, 111In complexed with tropolone, or cadmium (the decay product of 111In) complexed with tropolone. Successful lymphocyte labeling with 111In was shown to be dependent upon the concentration of the chelator (tropolone). Increasing concentrations of tropolone inhibited lymphocyte function to a variable degree. Further reduction in cellular function was detected after incorporation of a constant amount of 111In or 111In's decay product, cadmium. Lymphocyte function was decreased by these two labels in a parallel linear manner. This same toxic effect was seen after labeling with small constant amounts of tropolone and increasing quantities of 111In or cadmium. Thus, although both the required chelator and the radiobiologic exposure have a deleterious effect on the lymphocyte, significant lymphocyte toxicity appears to result from the metal-to-cell interaction as a result of the metal decay product (cadmium).

McCune-Albright syndrome: the patterns of scintigraphic abnormalities.

This study of 22 patients with the McCune-Albright syndrome examined the scintigraphic distribution of fibrous dysplasia. The most frequently affected areas were the base of the skull (82% of patients), mandible (50%), facial bones (45%), femora (59%), and legs (64%). The least frequently affected areas included the hands (none), wrists (none), ankles (none), feet (5%), sacrum (5%), and vertebrae (9%). The distribution varied somewhat from idiopathic fibrous dysplasia but generally agreed with the distributions reported in radiographic studies of patients with the McCune-Albright Syndrome. The serum alkaline phosphatase was not an accurate predictor of the extent of fibrous dysplasia.

Direct determination of the attenuation coefficient for radionuclide volume measurements.

Correcting for the attenuation of photons between the cardiac chambers and chest surface is crucial for accurate nongeometric ventricular volume determinations from equilibrium radionuclide angiograms. Previous techniques have assumed that the attenuation coefficient of water for 99mTc (0.15/cm) should be used for this correction. In this study, this assumption was tested directly by measuring attenuation of the activity of a radioactive source within the right and left cardiac chambers. The balloon of a flow-directed catheter, filled with 99mTc, was used as a source and its depth within the body was measured with biplane fluoroscopy. In ten patients, a total of 36 measurements of attenuation were made. With linear regression analysis, the overall calculated attenuation coefficient, mu, was 0.12/cm (standard error of slope = 0.01, R = 0.93). Although the mean value of mu varied from 0.08 to 0.13 for four different intracardiac locations these differences were not significant. These direct measurements indicate that the attenuation of photons in the heart is not equivalent to that of water and suggest that an attenuation coefficient of 0.12/cm should be used in analyzing ventricular activity.

Dynamic process captured on a single image: an approach to screening for abnormal superior vena caval flow.

A strategy for displaying and archiving dynamic quantitative data from scintigraphic imaging is described and applied to diagnosing obstructed thoracic veins. A prospective series of 25 patients with concurrent radiographic contrast and tracer venograms along with 49 controls showed a 33% sensitivity, comparable to previously published data. The use of first harmonic Fourier analysis enhanced the screening value of the test by identifying all abnormals. Moreover, this format captured the dynamic physiologic data on a single photograph. This technique is readily available to nearly any nuclear imaging laboratory equipped with a gamma camera and a computer.

A realistic dynamic cardiac phantom for evaluating radionuclide ventriculography: description and initial studies with the left ventricular chamber.

A phantom was devised to validate scintigraphically determined left ventricular ejection fractions (LVEFs) and cardiac chamber volumes in the following simulated cardiac situations: normal contraction, moderately impaired left ventricular contraction, severely impaired left ventricular contraction, mitral regurgitation, and cardiomyopathy. The phantom, assembled from anatomically realistic cardiac chambers, simulated contraction and expansion using individual chamber pumps coordinated by a microcomputer. Scintigraphic studies were performed by sequential imaging of [99mTc]pertechnetate introduced into each chamber. The images were analyzed like conventional clinical studies, using both automatic and manual techniques. Scintigraphic techniques correlated with chamber volumes that were determined by weight to yield the following regression formulae: LVEF (by automatic method 1) = 1.08 x LVEF (by weight) -5.11; LVEF (by automatic method 2) = 1.00 x LVEF (by weight) -3.15; and LVEF (by manual method) = 1.04 x LVEF (by weight) -5.08 ml (Correlation coefficients greater than 0.98). The absolute left ventricular volumes (LVVs), determined by scintigraphy, correlated well with LVVs determined by weight. These correlations were performed with separations between the center of the left ventricle and the collimator varying from 5 cm to 9 cm. The regression formulae for 5, 7, and 9 cm distances were: LVV (by counts) = 0.99 x LVV (by weight) + 0.13, LVV (by counts) = 1.04 x LVV (by weight) + 9.08, LVV (by counts) = 0.88 x LVV (by weight) + 15.25, respectively. At 9 cm, slight volumetric underestimation occurred, as predicted from the work of Fearnow et al., possibly because of oversubtraction of background. Thus, this phantom provides a useful tool for validating scintigraphic cardiac blood-pool studies simulating a wide range of clinically relevant situations.

Reverse redistribution of thallium-201 detected by SPECT imaging after dipyridamole in angina pectoris.

Reverse redistribution refers to a thallium-201 perfusion defect that develops or becomes more evident on delayed imaging compared with the initial image immediately after stress. To determine the diagnostic importance of reverse redistribution after intravenous dipyridamole, thallium-201 single photon emission computed tomography and quantitative coronary arteriography were performed in 90 men with angina pectoris. Of the 250 myocardial segments analyzed, reverse redistribution was present in 17 (7%). Minimal coronary cross-sectional area in proximal vessel segments was less than or equal to 2.0 mm2 more often in regions with transient perfusion abnormalities than in regions with reverse redistribution (66 vs 29%, p less than 0.05). Compared with regions exhibiting transient perfusion abnormalities, regions with reverse redistribution had larger proximal arterial diameters (1.9 +/- 1.1 vs 1.3 +/- 1.1 mm, p less than 0.001) and cross-sectional areas (3.9 +/- 3.1 vs 2.2 +/- 2.6 mm2, p less than 0.001). Coronary artery dimensions and relative stenosis severity did not differ between those regions with normal perfusion and those with reverse redistribution. Reverse redistribution detected by thallium-201 single photon emission computed tomographic imaging after dipyridamole is uncommon, appears to occur as frequently in normal subjects as in patients undergoing coronary arteriography and does not indicate the presence of severe coronary artery disease.

Comparison of dipyridamole-Doppler echocardiography to thallium-201 imaging and quantitative coronary arteriography in the assessment of coronary artery disease.

This study was undertaken to determine whether Doppler measurements of systolic aortic and diastolic mitral blood flow velocities could reliably detect the presence of reversible myocardial perfusion defects during intravenous dipyridamole-thallium-201 imaging. In addition, the ability of dipyridamole-Doppler echocardiography to predict the presence of significant coronary artery disease (CAD) was evaluated. Baseline and post-dipyridamole Doppler studies were performed in 10 normal control subjects and 23 patients with CAD. Aortic peak velocity and acceleration increased from baseline to post-dipyridamole in normal subjects by 0.07 +/- 0.07 m/s (p = 0.016) and 2.1 +/- 2.0 m/s2 (p = 0.009), respectively. The ratio of early to late peak transmitral velocities decreased slightly in normal subjects, by 0.18 +/- 0.72 (difference not significant), whereas the ratio of early to late transmitral velocity-time integrals increased by 0.07 +/- 0.93 (difference not significant). The response of aortic velocity and acceleration to intravenous dipyridamole was not significantly different between normal subjects, patients without reversible thallium-201 perfusion defects and patients with reversible thallium-201 perfusion defects. Furthermore, only 3 of 14 subjects with reversible thallium-201 perfusion defects had abnormal (greater than 2 standard deviations from the mean) responses of aortic velocity or acceleration to intravenous dipyridamole. No patient had an abnormal response of the early to late mitral peak velocity ratio. In addition, the response of Doppler aortic and mitral indexes to intravenous dipyridamole was not able to identify the presence of significant CAD as assessed by quantitative coronary arteriography.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of cardiovascular nuclear medicine in evaluating trauma and the postoperative patient.

In the patient with cardiac trauma, radionuclide imaging may provide important information about cardiac mechanical function, vascular anatomy and integrity, myocardial perfusion, and myocardial metabolism. Studies require only minimal patient cooperation, can be performed relatively rapidly and often at the bedside, and may be repeated at frequent intervals for serial evaluations. These studies provide valuable adjunctive knowledge when selected and interpreted with knowledge of the mechanism of injury, timing of the examination relative to the time of injury, and most likely differential diagnoses.

Hypoxia and cyanosis in alpha-1-antitrypsin deficiency. Cirrhosis as an unusual etiologic factor.

A patient with type PiZZ alpha-1-antitrypsin deficiency was found to have severe hypoxia despite normal pulmonary function testing and a normal chest radiograph. A nuclear medicine ventilation-perfusion study revealed a right-to-left shunt. Computed tomography showed minimal bleb formation, no diffuse changes, and hepatic changes of cirrhosis with portal hypertension. No nodular pulmonary masses or enlarged peripheral pulmonary vessels were found. The diagnosis of diffuse intrapulmonic arteriovenous shunts ("pulmonary spiders of cirrhosis") was suggested and then confirmed with a dynamic radionuclide flow study.

The prevention of youth violence. The rationale for and characteristics of four evaluation projects.

In response to the magnitude of violence in the United States, a number of violence-prevention programs have been implemented throughout the country. However, relatively few have been rigorously evaluated for effectiveness. To encourage development and evaluation of violence-prevention interventions that focus on young children and their families, the Centers for Disease Control and Prevention (CDC) provided funding to four projects in 1996. This paper briefly describes the rationale for funding these projects, which is based on our understanding of the development of aggressive and violent behavior and on the literature regarding promising approaches to prevent problem behavior in this age group. We provide an overview of the four specific projects funded by the CDC as well as a short discussion of some of the many challenges encountered during their implementation.

Intraventricular immunotoxin therapy for leptomeningeal neoplasia.

OBJECTIVE: The goals of this clinical trial of intraventricular 454A12-rRA therapy were to identify dose-limiting toxicities, to evaluate the pharmacokinetics of single-dose intraventricular 454A12-rRA, and to detect antitumor activity. METHODS: We performed a pilot study of intraventricular therapy with the immunotoxin 454A12-rRA in eight patients with leptomeningeal spread of systemic neoplasia. The immunotoxin 454A12-rRA is a conjugate of a monoclonal antibody against the human transferrin receptor and recombinant ricin A chain, the enzymatically active subunit of the protein toxin ricin. Patients were treated with single doses of 454A12-rRA ranging from 1.2 to 1200 micrograms. RESULTS: The early phase half-life of 454A12-rRA in ventricular cerebrospinal fluid (CSF) averaged 44 +/- 21 minutes, and the late phase half-life averaged 237 +/- 86 minutes. The clearance of the immunotoxin was faster than the clearance of coinjected technetium-99m-diethylenetriamine penta-acetic acid, averaging approximately 2.4-fold greater. No 454A12-rRA degradation was detected by Western blot analysis of ventricular CSF for a period of 24 hours, and bioactivity was retained in CSF paralleling the concentration of immunotoxin. No acute or chronic drug toxicity was identified in patients who received less than or equal to 38 micrograms of 454A12-rRA by intraventricular injection. Doses more than or equal to 120 micrograms caused a CSF inflammatory response that was associated with transient headache, vomiting, and altered mental status. This acute syndrome was responsive to steroids and CSF drainage. No systemic toxicity was detected. In four of the eight patients, a greater than 50% reduction of tumor cell counts in the lumbar CSF occurred within 5 to 7 days after the intraventricular dose of 454A12-rRA; however, no patient had their CSF cleared of tumor, and clinical or magnetic resonance imaging evidence of tumor progression was demonstrated in seven of the eight patients after treatment. CONCLUSION: Tumoricidal concentrations of the immunotoxin 454A12-rRA can be attained safely in the CSF of patients with leptomeningeal tumor spread.

Students who carry weapons to high school: comparison with other weapon-carriers.

PURPOSE: To determine if those who have recently carried a weapon on school grounds differ from those who carry weapons elsewhere. We hypothesized that involvement in other problem behaviors and exposure to school crime and violence would be associated with risk for weapon carrying on school grounds. METHODS: The data for this study were from the 1995 Youth Risk Behavior Survey of 10,904 high school students. Logistic regression analysis was used to examine risk for weapon carrying on school grounds. RESULTS: Among the students who carried a weapon, 48% carried a weapon on school grounds. Female gender, lower parental education levels, substance use on school grounds, involvement in physical fights, exposure to school crime and violence, frequency of weapon-carrying, and gun carrying distinguished students who carried weapons on school grounds from those who carried weapons off school grounds. CONCLUSIONS: The results suggest that weapon-carrying on school grounds is associated with individual and school-related characteristics. Efforts to reduce weapon-carrying on school grounds might focus on reduction of students' actual and perceived vulnerability to victimization, as well as by helping students understand that other problem behaviors increase their risk for violence.

Homeless youth and their exposure to and involvement in violence while living on the streets.

PURPOSE: The purpose of this research were to explore homeless youths' histories of exposure to violence, perpetration of violence, and fear of violent victimization, and to examine the extent to which these constructs are associated with demographic variables. METHODS: A sample of 432 youth (between 13 and 23 years old) who were homeless or at imminent risk for homelessness were sampled from both service and street sites. The percentage of youth who reported exposure to each type of violence was calculated. Multiple regression analyses were used to examine differences in the risk of exposure to violence across gender, ethnicity, age, and length of time homeless. RESULTS: Respondents reported a high rate of exposure to violence. Female respondents reported levels of exposure to violence that were as high as those reported by males. Females were more likely to report having been sexually assaulted and fearing victimization, and tended to be less likely to report perpetrating violence. With a few exceptions, ethnic identity was not a significant predictor of exposure to violence or fear of victimization. Age tended to be inversely associated with risk of exposure to violence. Length of time homeless was not associated with fear of victimization. CONCLUSIONS: Homeless youth are at high risk for exposure to a variety of forms violence as both witnesses and victims. The overall rates of exposure to violence and patterns of association with demographic variables are significantly higher than those reported in national samples of adolescents.

The role of families and care givers as risk and protective factors in preventing youth violence.

This paper reviews research which discusses the risk and protective functions that families and other caregivers provide in influencing the development of aggressive behavior in youth. Currently, there is an emphasis on providing violence prevention programs in the school environment, typically with little parental or caregiver involvement. By enhancing the role of families and caregivers in youth violence prevention programs, we assert that an unique opportunity exists to both address specific risk factors for violence while enhancing the protective features of the family. Relatedly, the risk literature on youth violence indicates that the most influential risk factors (i.e., the family, community, and peers) have their principle impact on youth aggression outside the school. We suggest a shift in the focus of violence prevention programming that is more inclusive of families as both a risk and protective agent. In support of this position, relevant theory and reviews of exemplary family-involved programs are offered. Challenges to involving youth caregivers are identified and recommendations for overcoming those challenges suggested. Last, recommendations for future research and public policy in the prevention of youth violence are offered.

Prospective correlates of exclusive or combined adolescent use of cigarettes and smokeless tobacco: a replication-extension.

This one-year prospective study provides an extension of a previous cross-sectional investigation. The previous study found that the number of tobacco products used (i.e., smokeless tobacco, cigarettes), not type of tobacco product, was associated with higher scores on problem-prone variables. In the present study, a sample of 842 southern California seventh-grade adolescents who had not tried either cigarettes or smokeless tobacco were identified and surveyed one year later. Onset of tobacco use was examined as an outcome variable predicted by scores on four psychosocial and two alcohol use variables in seventh grade. Unlike the previous study, females were included in the current study, and the potential moderating effect of gender on the pattern of predictors was examined. Overall, these findings indicate that onset of cigarette smoking or use of both tobacco products is associated with alcohol use, risk taking, and low self-esteem. This study provides modest support for the previous investigation. In addition, two of the predictor variables were found to interact with gender. Risk-taking was found to have a stronger association with initiation of tobacco use for females than males. Susceptibility to social influence to use tobacco was found to be associated with initiation of tobacco use for males only.

Correlates of exclusive or combined use of cigarettes and smokeless tobacco among male adolescents.

Past studies which examined correlates of smokeless tobacco or cigarette use have investigated use of one tobacco product regardless of use of the other product. Thus, the etiology of exclusive use of the two tobacco products is not clear. The present study investigated the relationship of problem-prone-related variables to exclusive versus overlapping use of smokeless tobacco and cigarettes. Two samples of southern California male students (eighth-grade and high school) were divided into groups according to their tobacco use status: neither product, cigarettes only, smokeless tobacco only, or both tobacco products. Generally, triers and monthly users of both tobacco products reported a higher risk-taking preference, greater susceptibility to peer social influence to use tobacco products, and greater likelihood to have tried marijuana and alcohol than did subjects who were not users of either tobacco product. Adolescents who used either product, but not both, reported similar scores on most of the variables examined, which fell in between combined or nonuse categories. These results suggest that the number of tobacco products used, not the specific product, is associated with problem-prone attributes.