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PubMed1976

Modern war surgery: operations in an evacuation hospital during the October 1973 Arab-Israeli war.

A forward evacuation hospital functioned in the southern front in October 1973 Israeli-Arab War as an intermediate unit in the Israeli casualty management logistics. Casualties were characterized by frequent multiple-system injuries and variable combinations of penetrating wounds, blunt trauma, burns, and inhalation injury, with an increased incidence of associated blunt trauma. As the result of the systems organization, the EH was able to provide the wounded with early intensive and definitive resuscitation therapy which permitted further evacuation of the casualties to the central hospitals in a better state of physiological stability. In the most critically wounded when there was imminent threat to survival, operations were performed at the EH as an integral part of the resuscitation process. Performance of operations in a forward evacuation hospital did not increase the number or severity of postoperative complications. Morbidity and mortality were related to the nature and magnitude of injury.

Egypt↗
PubMed1980

Nursing home levels of care: reimbursement of resident specific costs.

The companion paper on nursing home levels of care (Bishop, Plough and Willemain, 1980) recommended a "split-rate" approach to nursing home reimbursement that would distinguish between fixed and variable costs. This paper examines three alternative treatments of the variable cost component of the rate: a two-level system similar to the distinction between skilled and intermediate care facilities, an individualized ("patient-centered") system, and a system that assigns a single facility-specific rate that depends on the facility's case-mix ("case-mix reimbursement"). The aim is to better understand the theoretical strengths and weaknesses of these three approaches. The comparison of reimbursement alternatives is framed in terms of minimizing reimbursement error, meaning overpayment and underpayment. We develop a conceptual model of reimbursement error that stresses that the features of the reimbursement scheme are only some of the factors contributing to over- and underpayment. The conceptual model is translated into a computer program for quantitative comparison of the alternatives.

Medicaid↗
PubMed1999

Investigation of apparent diffusion coefficient and diffusion tensor anisotrophy in acute and chronic multiple sclerosis lesions.

BACKGROUND AND PURPOSE: The various stages of multiple sclerosis (MS) are characterized by de- and remyelination as well as by inflammation. Diffusion MR imaging is sensitive to tissue water motion, which might correspond to these pathologic processes. Our purpose was to demonstrate differences in apparent diffusion coefficient (ADC) and diffusion tensor anisotropy in acute and chronic MS plaques and in normal-appearing brain. METHODS: Twelve MS patients underwent conventional and full-tensor diffusion MR imaging with B = 1221 s/mm2. Derivation of trace ADC and calculation of anisotropic scalars, including eccentricity, relative anisotropy (RA), and fractional anisotropy (FA) was performed on a per-pixel basis. Regions of interest of plaques and normal structures were determined on coregistered maps. MS lesions were classified as acute, subacute, or chronic on the basis of their appearance on conventional images and in relation to clinical findings. RESULTS: Seven patients had acute plaques with a concentric arrangement of alternating high and low signal intensity on diffusion-weighted images. In nine acute lesions, plaque centers had high ADC with reduced anisotropy compared with rim, normal-appearing white matter (NAWM), and chronic lesions. The thin rim of diffusion-weighted hyperintensity surrounding the center showed variable ADC and anisotropic values, which were not statistically different from NAWM. Subacute and chronic MS lesions had intermediate ADC elevations/anisotropic reductions. Calculated FA pixel maps were superior to eccentricity or RA maps; however, quality was limited by signal-to-noise constraints. CONCLUSION: ADC and diffusion anisotropic scalars reflect biophysical changes in the underlying pathology of the demyelinating process.

Adolescent↗
PubMedDate not supplied

[Geographical distribution of hepatitis E virus genotypes].

Hepatitis E virus (HEV) is the major agent of acute hepatitis in developing countries where the infection occurs sporadically or in large waterborne epidemics. HEV, classified in the Caliciviridae, is not culturable. The detection of HEV RNA by RT-PCR in serum and stool samples is reliable during the 7 to 15 days following the onset of the disease. Restriction endonuclease analysis, cloning and sequencing of PCR products allow a phylogenetic analysis of HEV isolates. Although they belong to a single serotype, strains recovered from different geographical regions display a significant genetic heterogeneity. Sequencing data from ORF1 and ORF2 regions has led to the characterization of 3 distinct genotypes: genotype I gathering the Asian and African subgenotypes; genotype II gathering swine and human US strains; genotype III limited to the Mexico prototype. Novel variants are currently described from Africa (Nigeria), China and Europe (Greece and Italy). Each genotype appears to be related to a well defined geographical area. Nevertheless, a genetic variability is observed within endemic regions such as Asia or Africa. Nigerian endemic isolates especially could represent an intermediate stage in the evolutionary process towards genetic diversity. The animal reservoir, proved by the detection of HEV sequences by PCR among pigs in Nepal and in the USA, could help to resolve unanswered questions about the origin of HEV genotypes, their spread and evolution.

Africa↗
PubMed1999

Egocentric localization: visually directed alignment to projected head landmarks in binocular and monocular observers.

PURPOSE: To determine the accuracy and precision with which humans align moving, non-moving, point-like and linear stimuli to three head landmarks projected to a frontal plane. Monocularly enucleated and binocularly normal subjects, performing monocularly, were tested. METHODS: Experimental tasks consisted of aligning the stimulus, a luminescent target, using a remote steering wheel control, to three projected landmarks; the nose, and the outside edge of each ear. Experiments were performed with a fixed [static] linear stimulus and a small dynamic stimulus, and then with a fixed stimulus at both a very close and an intermediate distance. RESULTS: The data from the monocular enucleated observers showed better accuracy in some conditions but their variable errors were larger than those of the controls. CONCLUSIONS: We propose that, for the alignments of the enucleated monocular subjects, a) the increase in accuracy is consistent with a shift of the egocenter in the direction of the remaining eye, and b) the decrease in precision may be due to the fact that the egocenter does not correspond to the mid-sagittal or median plane. This disparity would require adjustments to be learned in order to perform tasks involving visually directed alignments to the self.

Adolescent↗
PubMed2006

Mib-1 proliferation index is an independent predictor of lymph node metastasis in invasive breast cancer: a prospective study on 675 patients.

In order to evaluate the potential risk factors for lymph node metastasis in invasive breast cancer patients submitted to axillary dissection, 675 patients who received surgery between January 1995 and December 2002 were included in a prospective study. In all cases, MIB-1 proliferation index was investigated by immunohistochemistry. Lymph node involvement was found in 248 out of 675 patients. Univariate analysis showed that peritumoral lymphovascular invasion, pT stage, tumor multiplicity, MIB-1 proliferation index >10%, oestrogen receptor status, histological type, tumor grade and progesterone receptor status were related to a higher incidence of lymph node metastasis, with various levels of statistical significance. Multivariate analysis identified lymphovascular invasion [relative risk (RR, 7.69; p<0.001), pT stage (RR, 3.08; p<0.001), tumor multiplicity (RR, 3.89; p<0.001), and MIB-1 proliferation index (RR, 1.66; p=0.019)] as independent predictive variables. The impact of MIB-1 positivity on the incidence of lymph node metastasis was particularly evident in intermediate risk groups (pT1c, pT2 without lymphovascular invasion), as well as in grade-2 tumors. In conclusion, the MIB-1 proliferation index could provide additional information about the risk of lymph node metastasis in invasive breast cancer, and may be useful to identify grade-2 tumors with a more aggressive clinical behaviour.

Biomarkers, Tumor↗
PubMed1996

Noise reduction in PET attenuation correction by maximum likelihood histogram sharpening of attenuation images.

UNLABELLED: A new method for PET transmission data processing was developed and found to reduce transmission noise in 18F-FDG cardiac emission images. This method is based on a model that describes the measured attenuation image histogram as some unknown true underlying histogram, blurred by noise. METHODS: Emission data from an elliptical phantom (cardiac insert) and three humans were reconstructed using transmission data of varying duration with varying levels of smoothing. Biases and noise levels (cardiac sector analysis) were evaluated for the phantom (simulated replicates) and human emission images. RESULTS: The estimated attenuation histograms typically displayed three distinct peaks corresponding to air, lung and soft tissue without a priori assumptions of the underlying mu values. This method effectively sharpened the histogram peaks and performed well for the phantom and human data. For intermediate transmission noise levels, biases in the phantom sector values were <4%. The human sector results were more variable but consistent with the phantom results. Noise reduction (approximately 30%) was demonstrated across all smooth levels for the phantom data. CONCLUSION: This histogram sharpening method introduces only small bias in the cardiac sector values while achieving an increase in effective transmission scan time of 50-100%. Alternatively, histogram sharpening permits less transmission data smoothing without increased noise.

Algorithms↗
PubMed1997

Diagnostic value of SCC, CEA and CYFRA 21.1 in lung cancer: a Bayesian analysis.

The aim of this study was to evaluate the diagnostic value of three tumour markers, squamous cell carcinoma (SCC) antigen, carcinoembryonic antigen (CEA) and CYFRA 21.1, in lung cancer using a Bayesian analysis to obtain the predictive values for different pretest probabilities or prevalences. A cross-sectional study included 94 patients with lung cancer, 40 with benign lung disease, and 40 healthy controls. SCC antigen and CEA were measured in blood samples by microparticle enzyme immunoassay (MEIA), and CYFRA by enzyme-linked immunosorbent assay (ELISA). The results of tumour marker determinations were expressed as percentiles, and showed significantly higher levels in the cancer group than in the two control groups. Taking the 95th percentile of benign lung diseases as the cut-off point (specificity 95%), the following sensitivities were found: SCC 41%, CEA 31% and CYFRA 79%. After a Bayesian analysis, the best results for the three tumour markers were found in prevalences of 30-40%. The highest incremental gain was obtained by CYFRA (at prevalence of 36%, positive and negative predictive value approximately 90%). The three tumour markers were included in a stepwise regression analysis to predict lung cancer, and CYFRA was the only selected variable. We conclude that CYFRA 21.1 may be a useful marker in lung cancer when there is an intermediate pretest probability of disease.

Adenocarcinoma↗
PubMed1997

Regression of severe atherosclerotic plaque in patients with mild elevation of LDL cholesterol.

BACKGROUND: Intensive risk factor reduction in patients with dyslipidemias and coronary atherosclerosis has been shown to result in alterations in coronary artery morphology and reduced clinical events. However, the impact of such interventions in populations with relatively normal levels of low-density lipoproteins (LDL) is unclear. METHODS: To test the hypothesis that intensive risk factor reduction results in angiographic regression in patients with only mildly elevated levels of LDL, 14 patients with angiographically proven coronary atherosclerosis were entered into the University of California Davis Coronary Artery Disease Regression Program and intensively treated with pharmacologic and nonpharmacologic interventions for 2 years. Quantitative angiography was performed prior to and after 2 years of therapy to determine changes in coronary artery diameter. RESULTS: As a result of this program, dietary fat intake was reduced by 58% and LDL fell from 120 +/- 7 mg/dL to 104 +/- 6 mg/dL (p = 0.05). The average diameter of the measured arterial locations (including all 53 stenoses and 292 nondiscrete regions) on study entry was 2.74 +/- 0.05 mm. After 24 months, there was a net increase in arterial diameter (regression) of +0.05 +/- 0.04 mm to 2.81 +/- 0.05 mm (p = 0.01). While there was no significant change in the average diameter of discrete stenoses, all 8 lesions > or = 50% initial diameter narrowing regressed, with a mean diameter change of + 0.2 mm. Conversely, only 1 of 8 mild lesions < or = 20% regressed, while 4 progressed. Intermediate lesions (20% to 50%, n = 37) had balanced progression and regression. CONCLUSIONS: When examined as a continuous variable, there was a significant linear correlation between initial lesion severity (% stenosis) and the extent of regression (mm). Therefore, risk factor reduction (dietary therapy, exercise, psycho-social counseling, and lipid lowering therapy) in patients with only mild dyslipidemia results in angiographic regression of more severe lesions (> 50% initial stenosis), but does not prevent progression of mild lesions (< 20%). These findings demonstrate that intensive risk factor reduction in patients with only mild elevation of lipids beneficially influences the morphology of the most severe lesions.

Adult↗
PubMed1995

Intermediate forms of glycoconjugates are present in the envelope of herpes simplex virions during their transport along the exocytic pathway.

In cells infected with herpes simplex virus 1, intracellular virions in transit along the exocytic pathway carry glycoconjugates that react, in fracture-label technique, with helix pomatia lectin. This lectin is specific for unsubstituted N-acetylgalactosamine, an intermediate sugar added in O-linkage to ser/thr residues in cis-Golgi and then substituted with galactose and sialic acid in the trans-Golgi. Virions in the perinuclear space do not react with helix pomatia lectin. In intracellular transport vesicles and vacules, close to the Golgi complex, virions are positively labeled by helix pomatia lectin and variably labeled by wheat germ agglutinin, a lectin specific for fully mature glycoconjugates. Extracellular virions react only with wheat germ agglutinin. The detection of glycoconjugates at intermediate steps of maturation, coupled with previous results that virions in the perinuclear space carry high mannose oligosaccharides (Torrisi et al., J. Virol. 66, 554-561, 1992), favor the view that maturation of herpes simplex virion envelope proceeds in a stepwise manner along the exocytic pathway. Should transit of virions involve a deenvelopment of enveloped virions followed by reenvelopment of naked nucleocapsids, our results rule out reenvelopment at trans- or post-Golgi compartments and could be consistent with reenvelopment occurring earlier in the exocytic pathway, most likely at the cis-Golgi.

Cell Line↗
PubMed1982

Morphological changes induced by sodium bromide in murine neuroblastoma cells in vitro.

Sodium bromide was applied in vitro to mouse neuroblastoma cells of different ages for short and long periods (2 h to 10 days). The changes observed light-and-electron microscopically were similar to those described earlier after GABA treatment. Coated vesicles proliferated and originated by pinching off from the Golgi complex and from the rough endoplasmic reticulum. Numerous coated vesicles were continuous with the plasma membrane, especially near zones in which electron-dense material aggregated at the inner aspect of the plasmalemma. Small invaginations, similar in ultrastructure to coated vesicles, were also formed. It is unclear whether the coated vesicles or the dense plasmalemma invaginations contribute to the "undercoating" by fusing with the adjacent electron-dense plasma membrane. There was a distinct increase in the number and area of specialized contacts (intermediate junctions and zonulae adhaerentes) between cells and their processes. A floccular or filamentous electron-dense substance varying in amount and appearance was occasionally seen between the contacting membranes. Varicosities of terminal swellings of cell processes contained vesicles of variable size, shape and density, and also profiles of the smooth endoplasmic reticulum. Under the influence of sodium bromide, similar to the effect of GABA, mitochondria appeared within the varicosities, and primitive contacts (intermediate junctions) were formed between the terminal swellings and potential postsynaptic elements, which were absent in controls. Additionally, dense-core vesicles proliferated and aggregated at the cell periphery. They were often arranged linearly below the plasma membranes of perikarya and processes, and surrounded by a highly electron-dense substance. The similarity of the present findings to those obtained after GABA treatment and their relation to synaptogenesis are discussed.

Animals↗
PubMed2000

Identification of severe coronary artery disease in patients with a single abnormal coronary territory on exercise thallium-201 imaging: the importance of clinical and exercise variables.

OBJECTIVES: The aim of this study was to determine which clinical, exercise and thallium variables can aid in the identification of three-vessel or left main coronary artery disease (3VLMD) in patients with one abnormal coronary territory (either a reversible or fixed defect) on exercise thallium testing and to test the prognostic value of these variables. BACKGROUND: Although the sensitivity of detection of coronary artery disease by thallium-201 imaging is high, the actual detection of 3VLMD by thallium tomographic images alone is not optimal. METHODS: A multivariate model for prediction of 3VLMD was developed from several clinical, exercise and thallium-201 variables in a training population of 264 patients who had one abnormal coronary artery territory on exercise thallium testing and had undergone coronary angiography. Using this model, patients were stratified into risk groups for prediction of 3VLMD. A separate validation cohort of 474 consecutive patients who were treated initially with medical therapy and who had one abnormal coronary territory were divided into identical risk groupings by the variables derived from the training population, and they were followed for a median of 7.0 years to evaluate the prognostic value of this model. RESULTS: The prevalence of 3VLMD was 26% in the training population despite one abnormal thallium coronary territory. Four clinical and exercise variables--diabetes, hypertension, magnitude of ST segment depression, and exercise rate-pressure product-were found to be independent predictors of 3VLMD. In the training population, the prevalence of 3VLMD in low-, intermediate- and high-risk groups was 15%, 22% and 51%, respectively. When the multivariate model was applied to the validation population, the eight-year overall survival rates in the low-, intermediate- and high-risk groups were 89%, 73% and 75%, respectively (p < 0.001). CONCLUSIONS: A substantial proportion of patients with one abnormal thallium coronary territory have 3VLMD with subsequent divergent outcomes based upon risk stratification by clinical and exercise variables. Consequently, the finding of only a single abnormal coronary territory by thallium-201 perfusion imaging does not necessarily confer a benign prognosis in the absence of consideration of nonimaging variables.

Coronary Angiography↗
PubMed2006

Isotopic criteria in the characterization of aromatic molecules. 1. Hydrogen affiliation in natural benzenoid/phenylpropanoid molecules.

The site-specific isotope ratios of several families of aromatic molecules are analyzed in terms of hydrogen affiliation and discriminating potential. Among the aromatic molecules produced by plants, many are biosynthesized by the shikimate pathway, but the terpenic pathway also forms some compounds with a benzenic ring. In compounds of the phenylpropanoid family, specific hydrogen connections are determined with cinnamic acid, a key intermediate in the formation of a large number of aromatic molecules. Then affiliations through the phenylalanine precursor, back to the parent d-erythrose 4-phosphate and phosphoenolpyruvate molecules and finally to glucose, are considered. Typical isotopic profiles of the benzenic ring in natural, as compared to non-natural, molecules are defined. The dispersion observed in the (D/H)i ratios of the lateral chains is illustrative of diverse mechanistic responses and the role of exchange phenomena. The isotopic patterns of aromatic molecules pertaining to the terpenic family are drastically different from those of the shikimate descendants, and they exhibit much less variability. They enable the stereochemical affiliation of individual hydrogen atoms to be traced back first to the parent atoms in the common intermediate, geranyl diphosphate, then to the glyceraldehyde 3-phosphate and pyruvate couple involved in the DOXP pathway, and ultimately to the glucose precursor. The results illustrate the aptitude of the site-specific isotope ratios not only to authenticate natural with respect to chemical molecules but also to characterize different metabolic pathways and to reveal differences associated with the nature of the plant precursor.

Benzene↗
PubMed2002

Development and assessment of the Osteoporosis Index of Risk (OSIRIS) to facilitate selection of women for bone densitometry.

A simple questionnaire would be useful to identify individuals most in need of bone mineral density (BMD) testing. We designed a new predictive model and risk assessment instrument based on an extensive review of the literature evaluating risk factors for osteoporosis, and tested its performance in a large cohort of postmenopausal women in whom BMD was measured by dual x-ray absorptiometry. In total, 1303 postmenopausal women from an outpatient osteoporosis clinic participated in this study. The Osteoporosis Index of Risk (OSIRIS) is based on four variables: age, body weight, current hormone replacement therapy use and history of previous low impact fracture. The sensitivity and specificity for an OSIRIS value of +1 were respectively 78.5% and 51.4%. The AUC under the ROC curve of OSIRIS was 0.71. Three categories were arbitrarily created using OSIRIS, with cutoff of +1 and -3. The low risk category (OSIRIS > +1) represented 41% of all women; only 7% of the women in this category had osteoporosis. The prevalence of osteoporosis was very high (66%) among the group at high risk (OSIRIS < -3 representing 15% of all women). The prevalence of osteoporosis was 39% in the intermediate risk group (-3 < OSIRIS < +1, 44% of all women). In conclusion, OSIRIS is a simple index based on four easy-to-collect variables from postmenopausal women, it shows a high degree of accuracy, and performed well for classifying the degree of risk of osteoporosis in western European women of Caucasian lineage. Based on this instrument it is possible to propose a strategy that would initiate treatment in women with very high risk, postpone BMD measurement in women with low risk and limit BMD measurement to women with intermediate risk of osteoporosis, this would spare more than 55% of the densitometry bill compared with a mass screening scenario.

Absorptiometry, Photon↗
PubMed1984

Short-term variability of the resting focus of accommodation.

Previous investigations have shown that, in dim illumination and empty visual fields, accommodation in most observers is for an intermediate distance referred to as the dark focus or resting focus of accommodation. Dynamic properties of the resting focus were examined in the present study with a high-speed infrared optometer. All subjects displayed fluctuations of accommodation in darkness that were primarily characterized by frequency components below 0.5 Hz. These fluctuations were substantially attenuated during cycloplegia or viewing a bright, high-contrast target. Both the mean resting-focus position and the magnitude of fluctuations varied from one subject to another and from day-to-day. A weak association was found between the mean a standard deviation of accommodation responses in the dark. The present findings suggest that the accommodation mechanism in most observers is somewhat unstable under degraded viewing conditions. In addition, the mean resting-focus value for a large sample of subjects was found to be lower for i.r. optometer measurements than for previous investigations employing a laser optometer.

Accommodation, Ocular↗
PubMed2002

[Effect of different observers on the interpretation of pulmonary perfusion scintigraphy].

AIM: The agreement in the interpretation of the scintigraphic images of pulmonary perfusion in the diagnosis of pulmonary tromboembolism (TEP) is not always the most adequate. The purpose of this study was to evaluate the degree of agreement by eight observers in the interpretation of these studies. MATERIAL AND METHODS: The study population consisted of 180 studies with clinically suspected pulmonary embolism referred to our department for scintigraphic perfusion imaging from April 98 to September 99. The patients received an intravenous injection of 111-148 MBq (3-4 mCi) of 99mTc-macroaggregated albumin whereas the images were obtained in the six routine projections. The observers consisted of five nuclear medicine physicians and three residents who independently reviewed the scintigrams (low, intermediate and high probability). In a second step, the physicians performed consensus interpretations. The Kappa statistics was used to evaluate the degree of agreement between individual observer interpretations beyond that expected by chance alone. RESULTS: The mean value SEM for Kappa index was 0.58 0.02, with maximum and minimum values of 0.76 and 0.27 respectively. The interobserver variability was greater than expected. Except in two observers scans in the interpretation of images in the low and high categories showed minor discrepancies, whereas scans in intermediate probability showed the most important interobserver variations. CONCLUSION: The study manifests the importance of a uniform criteria in lung scintigraphic interpretation.

Humans↗
PubMed2003

Cytologic findings of marginal zone lymphoma.

BACKGROUND: Low-grade lymphomas can be difficult to diagnose in cytology specimens, especially marginal zone B-cell lymphomas (MZLs). MZL is a low-grade lymphoma characterized by a heterogeneous lymphoid population, which can be difficult to distinguish from reactive processes in cytology specimens. METHODS: Fourteen cytology specimens of MZL from 11 patients with histologically confirmed MZL (n = 10) or flow cytometry (FC)-confirmed MZL (n = 1) were reviewed, including 13 fine-needle aspiration biopsy (FNAB) specimens (salivary gland, n = 6; lung, n = 3; lymph node, n = 2; breast, n = 1; and soft tissue, n = 1) and 1 pleural effusion specimen. Cytologic preparations included air-dried and alcohol-fixed direct smears, ThinPrep(R) slides, and cell blocks. FC studies were available in six specimens. RESULTS: All 13 FNAB specimens were composed predominantly of intermediate-sized lymphoid cells with interspersed small, round lymphocytes and transformed cells. The intermediate-sized cells displayed a moderate amount of cytoplasm, slight nuclear membrane irregularities, and inconspicuous-to-absent nucleoli. The pleural fluid contained mostly small-to-intermediate-sized, round lymphocytes. In 10 specimens, the intermediate-sized cells often showed plasmacytoid morphology, which were seen best in Diff-Quik (Mercedes Scientific Co., Inc., Sarasota, FL)-stained slides. Monocytoid cells (n = 6 specimens), plasma cells (n = 7), lymphohistiocytic aggregates (n = 11), and tingible body macrophages (n = 5) were variably identified. Lymphoepithelial lesions were not observed. Three specimens with FC studies showed a phenotype compatible with MZL, and three specimens were nondiagnostic. CONCLUSIONS: Cytologic features suggestive of MZL included abundant intermediate-sized lymphoid cells with mild atypia in a background of small lymphocytes and transformed cells, often with plasmacytoid morphology. Flow cytometry was beneficial only in selected MZL cytology specimens. Surgical correlation may be necessary to confirm the diagnosis.

Adult↗
PubMed1998

Key Intermediates in Combinatorial Chemistry: Access to Various Heterocycles from alpha,beta-Unsaturated Ketones on the Solid Phase.

The value of alpha,beta-unsaturated ketones as key intermediates for the combinatorial assembly of four different templates on the solid phase, namely pyrimidines, dihydropyrimidinones, pyridines, and pyrazoles, was explored with individual syntheses of variably substituted model compounds. Starting from aldehydes grafted on polystyrene support, the Wittig and the Claisen-Schmidt reaction conditions were adapted to efficiently prepare alpha,beta-unsaturated ketones on the solid phase. Further derivatization of the alpha,beta-unsaturated ketones to form pyrimidines succeeded with a number of amidines. In a feasibility study, the potential to obtain, in a modular fashion, other small heterocycles from the same intermediates was assessed. In this solid-phase approach alpha,beta-unsaturated carbonyl intermediates can act as a three-carbon component and a primary enamine is utilized to complement the system for pyridine ring formation. Instead, with N-methylurea a dihydropyrimidinone is obtained. As an alternative, substituted hydrazines are incorporated in one orientation, providing pyrazoles with defined regioisomerism. The study indicates that alpha,beta-unsaturated ketones grafted on the solid phase can take a pivotal role as branching points in a number of synthetic diversity schemes and, therefore, represent versatile intermediates for the efficient preparation of combinatorial small molecule libraries.

Journal Article↗