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PubMed1997

Monitoring cholesterol crystallization from lithogenic model bile by time-lapse density gradient ultracentrifugation.

BACKGROUND/AIMS: Cholesterol crystallization in a dilute, bile salt-rich model bile is a multiphase process in which early filamentous crystals gradually transform to classical cholesterol monohydrate plates. The pertinence of similar transformations in more complex model systems or native bile is, however, unclear. The aim of the present study was to characterize and monitor cholesterol crystallization in a model bile of physiological relevance. METHODS: A supersaturated model bile was prepared with a lipid composition (18 mM cholesterol, 37 mM lecithin, 120 mM taurocholate) that was derived from analyzing 10 gallbladder biles from cholesterol gallstone patients. Cholesterol crystallization was followed by light and electron microscopy, and sequential density gradient analysis of cholesterol-containing precipitates. RESULTS: During cholesterol crystallization a reproducible sequence of events was recorded. First (T<18 h), cholesterol-rich vesicular and multilamellar structures (density 1.005-1.015 g/ml) were observed. Later, (T>60 h) filamentous, helical, tubular (density 1.015-1.04 g/ml) and plate-like (density 1.04-1.06 g/ml) cholesterol crystals appeared. The concentration of crystals increased gradually, while bilayer structures became desaturated with cholesterol and disappeared, and early crystal forms were replaced by plates. Eventually (T>25 days) only classical plate-like cholesterol monohydrate crystals were present. Exposure of cholesterol-containing precipitates to micellar (100 mM) deoxycholate dissolved the bilayer structures but not the crystals. CONCLUSIONS: These data demonstrate that cholesterol crystallization in a physiologically relevant model bile is a multiphase process consisting of a sequence of transitions from vesicular and multilamellar structures to early crystal forms and to classical plate-like cholesterol monohydrate crystals. These transitions are associated with increasing density and decreasing phospholipid content of cholesterol precipitates. We suggest that time-lapse density gradient ultracentrifugation is a useful method for investigating and quantitating the process of cholesterol crystallization and factors that influence this process in bile.

Animals↗
PubMed2001

Culture and the restoration of self among former American Indian drinkers.

This paper explores the social and cultural context of remission from alcohol problems in an urban American Indian community. Using the discourse of interviews conducted with 48 self-defined problem drinkers, 13 of whom had abstained from alcohol for at least a year prior to the interview, it explores the ways in which alcohol problems have been understood and dealt with by these Indian men and women. Drawing on the ethnographic literature on AA and culturally specific healing practices, the analysis centers on how new understandings of the self are articulated in sobriety and the ways in which this discourse draws on the themes of cultural restoration that are widely articulated in Indian communities. The paper closes with a consideration of how this inquiry with a community sample forces us to broaden models of self transformation that are derived from work in more circumscribed institutional contexts and, in turn, how the testimony of these men and women forces us to take quite seriously the idea that cultural restoration can be crucially involved as Indian people and communities grapple with problems with alcohol.

Alcoholics Anonymous↗
PubMed2003

Prostate-specific antigen as an estimator of prostate volume in the management of patients with symptomatic benign prostatic hyperplasia.

OBJECTIVES: To assess the ability of serum prostate specific antigen (PSA) to estimate prostate volume (PV) to aid in the management of patients with benign prostatic hyperplasia (BPH). METHODS: From 1989 to 2002, data were collected from 2264 patients complaining of lower urinary tract symptoms (LUTS) who visited the Department of Urology of the University Medical Centre Nijmegen, The Netherlands. Baseline PV and serum PSA was determined using standard techniques. All patients who had a baseline PV < or =200 ml, as well as a baseline serum PSA 0-10 ng/ml, were included. Patients with a history of prostate surgery, prostate cancer and conditions other than BPH at baseline were excluded. A log-transformed linear regression model was used to estimate PV. Receiver-operating characteristic (ROC) curves were constructed to evaluate the ability of serum PSA to estimate threshold PVs in men with BPH, and to select the optimal serum PSA cut-off values. RESULTS: The analyses included 1859 patients with a mean age of 63.5 years, mean baseline PV 43.9 ml, and mean baseline PSA value 3.1 ng/ml. PV as well as serum PSA increases with age. Linear regression analyses showed that PV and serum PSA have an age-dependent log-linear relationship, where 42% of the variance of PV can be explained by PSA and age. ROC's area under the curves (AUC) reveal that PSA has a good predictive value for assessing 'prostate enlargement', with AUC around 82% in the overall age groups irrespective of the PV cut-off values. Optimal serum PSA cut-off values for the overall study population irrespective of age are 2.0 ng/ml to detect PV >30 ml and 2.5 ng/ml to detect PV >40 ml. CONCLUSIONS: This study suggests that serum PSA can estimate prostate enlargement sufficiently accurately to be useful for therapeutic, especially medical, management. It is well accepted that the outcome of pharmacotherapy for BPH depends on baseline PV. Therefore, in the absence of reliable direct measurement of PV, serum PSA determination may be used to optimise patient management.

Adult↗
PubMed1999

Choosing the calibration model in assay validation.

Data transformations and weighting schemes are normally used to obtain the best-fit of standard curves in bioanalysis and the calibration model is usually selected during prevalidation. In the present study, a comparison has been made between unweighted and weighted (1/x, 1/x2, and 1/square root of x) regression models with or without an intercept in achieving the best-fit for the standard curve of CDRI compound 81/470, a new anthelmintic agent, in cow milk. Validation samples in milk at the LLOQ, medium, and high concentrations were also analysed by each of the calibration models. An unweighted regression equation with an intercept overestimated the concentrations at the LLOQ. An unweighted equation without intercept and weighted equations with or without an intercept significantly minimized the bias at the LLOQ without distorting the results at higher concentrations. Hence, an unweighted equation for a straight line passing through the origin was found to be the best model for a standard curve of 81/470 in milk. Similar results were obtained for 81/470 and UMF-078 in serum and plasma, respectively. Bioanalysts should routinely test these models to obtain the best fit model for their calibration curves as part of their assay validation not during prevalidation.

Animals↗
PubMed1997

Cortical control of reaching movements.

Recent studies provide further support for the hypothesis that spatial representations of limb position, target locations, and potential motor actions are expressed in the neuronal activity in parietal cortex. In contrast, precentral cortical activity more strongly expresses processes involved in the selection and execution of motor actions. As a general conceptual framework, these processes may be interpreted in terms of such formalisms as sensorimotor transformations and 'internal models'.

Animals↗
PubMed2000

The mechanisms of radical formation in L-alpha-alanine

Modeling of radical transformations in L-alpha-alanine after irradiation was performed for isolated radicals and for clusters. Special attention was devoted to the explanation of the experimental results concerning selective proton transfer and behavior of cation-radicals because a unique interpretation of the corresponding experiments is very difficult. Both semi-empirical and ab initio methods were used depending on the size of system under investigation. The results obtained show the usefulness of the computer simulation for processes in rather complex materials used in dosimetry.

Journal Article↗
PubMed2003

DNA alterations during multi-step development of human hepatocellular carcinomas revealed by laser capture microdissection.

In order to clarify early molecular events involved in liver carcinogenesis, we analyzed 53 liver-cirrhosis nodules (LCNs) from five patients and 13 micro-hepatocellular carcinoma (HCC) nodules from one patient and looked for alterations of microsatellites in genomic DNA after carefully preparing the tissue samples by laser-capture microdissection (LCM). Allelotyping was done with 20 markers corresponding to anonymous microsatellites and 13 corresponding to tumor suppressor genes (TSGs) that had shown significant alterations in HCCs. We detected both loss of heterozygosity (LOH) and microsatellite shifts (MS). Overall, 24 of 53 (47%) of LCNs showed LOH with any of the informative markers used in the study, reflecting that proportion of LCNs with clonal growth. The fractional allelic loss (FAL) index, an indication of total genomic complexity, was not significantly different between LCN and micro-HCC nodules, but their profiles of alteration were different. These profiles were classified into three groups: (1) LCN profile-allelic loss at chromosomal arms 1q and 14q, TBP and BRCA1; (2) HCC profile-LOH at 4q, 6q, 7q, 17p, NF1, IGFIIr and p53 in micro-HCC nodules; these changes in early lesions were identical to those seen in mature HCCs; (3) Common profile-LOH at NF1 and 6q, including IGFIIr, common to both LCN and HCC. No LCN showed LOH at p53 and Rb, loci that are generally altered in HCCs. However, 12 intra-tumoral nodules examined had lost p53 in all informative cases, although the loss of Rb was a late event. These results suggest that early genomic profiles confined to LCNs, and additional profiles that can be observed when liver tissue undergoes malignant transformation, support a model of multi-step development of HCC.

Journal Article↗
PubMed2001

Phentolamine suppresses the increase in arteriolar vasomotion frequency due to systemic hypoxia in hamster skeletal muscle microcirculation.

Systemic hypoxia (8%, 11% and 15% oxygen gas mixture inspiration) has been shown to increase the frequency of arteriolar rhythmic diameter changes in hamster skeletal muscle microcirculation. The effects of phentolamine on vasomotion frequency during systemic hypoxia were studied in Syrian hamsters implanted with a plastic chamber in the dorsum skin. Phentolamine (50 microg/100 g body wt.) was injected intravenously before the 20-min exposure to 11% oxygen gas mixture. The microvessels were studied with a fluorescent microscopy technique, using fluorescein isothiocyanate bound to dextran (mol. wt. 150,000) as a tracer. Vessel diameters were measured with a shearing method. Fourier transform and autoregressive modeling were used to assess the time variant features of diameter changes. Under baseline conditions, the arterioles were characterized by rhythmic diameter changes with fundamental frequency related to vessel size. The terminal branchings were dominated by order 3 vessel activity (frequency: 0.08-0.16 Hz) spreading downstream to all daughter arterioles. Systemic hypoxia caused an increase in vasomotion frequency of order 3 arterioles up to 0.3-0.5 Hz (average: 0.40 +/- 0.06 Hz) and a significant decrease in mean diameter (-28 +/- 5%). Phentolamine completely suppressed the rhythmic changes in diameter of order 3 arterioles that dilated significantly (+ 30 +/- 4%). Therefore, the effects of systemic hypoxia on arteriolar vasomotion appear to be triggered by an increase in sympathetic nervous discharge that induces a rise in frequency up to 0.3-0.5 Hz.

Animals↗
PubMed1987

Determination of the depth of bromine atoms in bilayers formed from bromolipid probes.

X-ray diffraction analysis has been performed on a series of 1-palmitoyl-2-dibromostearoyl-phosphatidylcholines (BRPCs) with bromine atoms at the 6, 7-, the 11, 12-, or the 15, 16-positions on the sn-2 acyl chains. The diffraction patterns indicate that, when hydrated, each of these lipids forms liquid-crystalline bilayers at 20 degrees C. For each lipid, electron density profiles and continuous Fourier transforms were calculated by the use of swelling experiments. In the electron profiles, high-density peaks, due to the bromine atoms, are observed. The separation between these bromine peaks in the profile decreases as the bromine atoms are moved toward the terminal methyl of the acyl chain. For the 6, 7- and 11, 12-bromolipids, experimental Fourier transforms can be approximated by the sum of the transform of 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) and the transform of two symmetrically placed peaks of electron density (the bromines). For the case of the 15, 16-bromolipids, a better fit is obtained for the transforms of a model bilayer where the thickness of the methylene chain region of the bilayer is 3 A greater than that of POPC. Our analysis indicates the following: for each of these bromolipids, the bromines are well localized in the bilayer; the distance of the bromines from the head-group-hydrocarbon boundary are 3.5, 8.0, and 14 A, for 6, 7-, 11, 12-, and 15, 16-BRPC, respectively; the bilayer thickness and perturbation to bilayer hydrocarbon chain packing caused by the bromine atoms depend on the position of the bromines on the hydrocarbon chain.

Bromine↗
PubMed2005

Chiral organometallic triangles with Rh-Rh bonds. 2. Compounds prepared from enantiopure cis-Rh2(C6H4PPh2)2(OAc)2(HOAc)2 and their catalytic potentials.

Enantiomers of the orthometalated dirhodium compound cis-Rh2(C6H4PPh2)2(OAc)2(HOAc)2 (R-1 and S-1) were prepared from carboxylate exchange reactions of the resolved diasteroisomers of cis-Rh2(C6H4PPh2)2(protos)2(H2O)2 (protos = N-4-methylphenylsulfonyl-l-proline anion) and acetic acid. These compounds react with excess Me3OBF4 in CH3CN, producing the enantiomers of [cis-Rh2(C6H4PPh2)2(CH3CN)6](BF4)2 (R-2 and S-2) which have six labile and replaceable CH3CN ligands in equatorial and axial positions. Reactions of R-2 and S-2 with tetraethylammonium salts of the linear dicarboxylic acids, terephthalic acid (HO2CC6H4CO2H), oxalic acid (HO2CCO2H), and 4,4'-diphenyl-dicarboxylic acid (HO2CC6H4C6H4CO2H) afford the enantiopure triangular supramolecules [cis-Rh2(C6H4PPh2)2(O2CC6H4CO2)(py)2]3, RRR-3 and SSS-3, Rh6(cis-C6H4PPh2)6(O2CCO2)3(py)5(CH2Cl2), RRR-4 and SSS-4, and Rh6(cis-C6H4PPh2)6(O2CC6H4C6H4CO2)3(py)4(CH2Cl2)2, RRR-5 and SSS-5, respectively. The absolute structures of each of the enantiomers of 1, 3, 4, and 5 were determined by X-ray diffraction analyses. The enantiomers of 3, 4, and 5 were found to be enantiomorphically isostructural, whereas R-1 and S-1 crystallized in different space groups. In 4 and 5, CH2Cl2 molecules coordinate to rhodium atoms in the axial positions. The 1H and 31P[1H] NMR spectra of all compounds are reported. The triangular compounds are redox-active, and their electrochemistry is also discussed. An assay of the catalytic activity/selectivity performance of the triangles for typical metal carbene transformation, using the model intermolecular cyclopropanation of styrene with ethyl diazoacetate in both homogeneous and heterogeneous phases, show that these chiral triangles are very active and have remarkable selectivity when compared with simple Rh2 paddle-wheel catalysts with chiral amidate ligands.

Journal Article↗
PubMed2002

The first general enantioselective catalytic Diels-Alder reaction with simple alpha,beta-unsaturated ketones.

The first general approach to enantioselective catalysis of the Diels-Alder reaction with simple ketone dienophiles has been accomplished. The use of iminium catalysis has enabled enantioselective access to a fundamental Diels-Alder reaction variant that has previously been unavailable using chiral Lewis acid catalysis. A new chiral amine catalyst has been developed that allows a variety of monodentate cyclic and acyclic ketones to successfully participate in enantioselective [4 + 2] cycloadditions. A wide spectrum of cyclic and acyclic diene substrates can also be accommodated in this new organocatalytic transformation. A computational model is provided that is in accord with the sense of enantioinduction observed for all reactions conducted during the course of this study.

Journal Article↗
PubMed2004

Discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of c-Src.

Deregulated activity of the nonreceptor tyrosine kinase c-Src is believed to result in signal transduction, cytoskeletal and adhesion changes, ultimately promoting a tumor-invasive phenotype. We report here the discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of the c-Src enzyme. Special attention was directed toward finding inhibitors selective against KDR tyrosine kinase in order to ensure that the in vivo profile of a specific Src inhibitor could be determined. The 4-aminobenzodioxole quinazoline series gave compounds with excellent potency and selectivity. The most interesting compounds were evaluated in vivo and displayed good pharmacokinetics following oral dosing. Compounds such as the aminobenzodioxoles were shown to be potent inhibitors of tumor growth in a c-Src-transformed 3T3 xenograft model in vivo, resulting in more than 90% growth inhibition at doses as low as 6 mg/kg po once daily. Src tyrosine kinase inhibitors such as these may provide a novel therapeutic modality for targeting cancer invasion and metastasis.

3T3 Cells↗
PubMed2000

The expression of the myogenic regulatory factors in denervated and normal muscles of different phenotypes.

The nerve is known to play a pivotal role in the diversification of muscle fibre types postnatally. Reducing neuronal activity in a slow muscle such as the soleus by denervation, switches on genes associated with a fast muscle phenotype. On the other hand, denervating a fast muscle such as the extensor digitorum longus (EDL) induces the conversion of fast fibres to a 'slower' contractile phenotype. The myogenic regulatory factors (MRFs) are proposed as the regulators of muscle phenotype as MyoD and myogenin have been shown to differentially accumulate in fast and slow muscle upon the induction of fibre type transformation. The denervation model has been used in the present study to induce changes in MRF expression in the muscles of the lower hindlimb which have distinct phenotypic characteristics. The level of MRF expression in pairs of denervated and innervated soleus, EDL, tibialis anterior (TA), plantaris and gastrocnemius muscles has been determined by Northern analysis and compared. The present study has shown that each muscle responds differently to denervation with respect to the increases in MRF expression. Fast muscles responded very quickly to denervation by increasing the level of MRF transcripts while slow muscles did not show significant increases in expression after 48 h denervation. The innervated EDL (fast) and soleus (slow) muscle differed with respect to the level of MRF-4 expressed, MRF-4 being expressed at higher levels in the slow muscle compared to the fast, suggesting that MRF-4 is important in the maintenance of a slow muscle phenotype. Moreover, MRF-4 and myogenin show the greatest fold increases in expression in the fast muscles examined. MyoD and Myf 5 show less dramatic increase in expression in response to denervation but exhibit the greatest fold increases in the fast muscles compared to slow.

Animals↗
PubMed2002

Psychosocial rehabilitation in a public psychiatric hospital.

Patients with chronic mental illnesses have complex treatment needs that often pose significant challenges to mental health professionals. This paper describes the implementation of a psychosocial rehabilitation program to meet the treatment needs of patients in a public psychiatric hospital providing long-term care. A core group of professional staff adopted psychosocial rehabilitation principles in order to transform a custodial model of care to a highly interactive educational and skills building program. A model of service delivery was established to address patients' skill deficits and barriers to returning to the community. This article describes the major steps and challenges faced in overcoming obstacles and implementing a psychosocial philosophy of treatment in an inpatient setting. It suggests that it is possible for the public hospital to reinvent itself into an environment that can stimulate recovery and hope.

Deinstitutionalization↗
PubMed1983

Perception of growth from changes in body proportions.

Three experiments examine the perception of age level from computer-generated line drawings of a human body, a Martian, a robot, and a flower that were mathematically transformed using a model of human growth developed by P.B. Medawar. The results suggest that observers' age level judgments are related by a power function to the size of the head relative to the rest of the body but that the exponents of these functions vary systematically across the different body forms. These results are discussed in relation to other research on biological event perception.

Growth↗
PubMed2006

Cross-sectional relations of serum aldosterone and urine sodium excretion to urinary albumin excretion in a community-based sample.

Experimental models suggest that increased aldosterone and sodium intake are associated with renovascular damage and resultant proteinuria. We hypothesized that serum aldosterone and urinary sodium would be associated with urinary albumin excretion, an indicator of kidney damage. We evaluated 2700 participants (53% women, mean age 58 years) from the Framingham Offspring Study who attended a routine examination between 1995 and 1998, who were free of heart failure and renal failure, and underwent testing for serum aldosterone, spot urinary sodium, and urinary albumin excretion (urine albumin/creatinine ratio, UACR), the latter two indexed to urinary creatinine. Stepwise multivariable linear regression was used to evaluate the relations between UACR with urinary sodium index and serum aldosterone. In multivariable regression, log urinary sodium index was associated positively with log-UACR (P<0.0001). UACR levels in the fourth and fifth quintiles of urinary sodium index were 24% (95% confidence interval (CI) 3-49%), and twofold higher (95% CI 72-150%), respectively, relative to the lowest quintile (P-value for trend across quintiles <0.001). In multivariable models, log-transformed aldosterone was not related to log-UACR. The top quintile of serum aldosterone levels was associated with a 21% higher (95% 1-44%) UACR levels relative to the lowest quintile. Urinary albumin excretion was strongly and positively associated in a continuous fashion with urinary sodium excretion, whereas a weaker nonlinear positive relation with serum aldosterone was noted. Our cross-sectional observations raise the possibility that dietary salt intake may be associated with early renovascular damage.

Albuminuria↗
PubMed1998

BCR-ABL and constitutively active erythropoietin receptor (cEpoR) activate distinct mechanisms for growth factor-independence and inhibition of apoptosis in Ba/F3 cell line.

The interleukin-3 dependent murine Ba/F3 cell line has been widely used as an experimental model of cell transformation by BCR-ABL oncogenes as assessed by induction of growth-factor-independence and inhibition of apoptosis in vitro. The signaling pathways used by BCR-ABL oncogenes to exert these effects are unknown. To gain insights into this phenomenon, we have introduced the p190- and p210-encoding BCR-ABL oncogenes as well as the constitutively activated oncogenic murine erythropoietin receptor (cEpoR) into Ba/F3 and compared the behavior of individual clones in response to apoptotic stimuli. Both p210 and p190 BCR-ABL vectors induced IL-3-independent growth and the same result was obtained with the cEpo-R vector. Individual clones of Ba/F3 cells expressing BCR-ABL exhibited significant resistance to apoptosis induced by either etoposide, serum deprivation or growth-factor withdrawal. In contrast, Ba/F3 cells expressing the constitutively active cEpoR behaved like parental Ba/F3 cells undergoing apoptosis when similarly treated with etoposide or upon serum deprivation. Bc12 and Bax levels were similar in all BCR-ABL and cEpoR-transfected clones. However, in band-shift assays, nuclear extracts from growth-factor-independent Ba/F3 clones expressing cEpoR had no detectable STAT activity as opposed to the constitutive STAT activation detected in all Ba/F3 clones expressing p210 or p190 BCR-ABL. Our results indicate that although both constitutively activated cEpoR and BCR-ABL oncogenes induce growth-factor independence in Ba/F3 cells, only BCR-ABL is able to protect cells from etoposide and serum-deprivation-induced apoptosis and induce a strong constitutive activation of STAT factors, suggesting a role for these molecules in the anti-apoptotic activity of BCR-ABL.

Animals↗
PubMed2002

Telomere dysfunction and telomerase reactivation in human leukemia cell lines after telomerase inhibition by the expression of a dominant-negative hTERT mutant.

As activation of telomerase represents a key step in the malignant transformation process, experimental models to develop anti-telomerase drugs provide a rational basis for anticancer strategies. We analysed the short and long-term efficacy of a stably expressed dominant-negative mutant (DN) of the telomerase catalytic unit (hTERT) in UT-7 and U937 human leukemia cell lines by using an IRES-e-GFP retrovirus. As expected, telomerase inactivation resulted in drastic telomere shortening, cytogenetic instability and cell growth inhibition in all e-GFP positive DN clones after 15-35 days of culture. However, despite this initial response, 50% of e-GFP positive DN clones with short telomeres escaped from crisis after 35 days of culture and recovered a proliferation rate similar to the control cells. This rescue was associated with a telomerase reactivation inducing telomere lengthening. We identified two pathways, one involving the loss of the DN transgene expression and the other the transcriptional up-regulation of endogenous hTERT with persistence of the DN transgene expression. Although this second mechanism appears to be a very rare event (one clone), these findings suggest that genomic instability induced by short telomeres after telomerase inhibition might enhance the probability of activation or selection of telomere maintenance mechanisms dependent on hTERT transcription.

Cell Division↗