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Biomedical subjects

A Greer

Publications and source records attributed to A Greer.

At least 19 recordsLinked to original sources
PubMed2001

On the origin of cytotoxicity of the natural product varacin. A novel example of a pentathiepin reaction that provides evidence for a triatomic sulfur intermediate.

A density functional theoretical study is presented, which implicates a novel S(3)-cleavage in the decomposition of a pentathiepin. This study predicts an interconversion between a pentathiepin and an open-chain polysulfur ion intermediate from which a key determinant in the chemistry then follows. Expulsion of diatomic sulfur, S(2), is unlikely from the unimolecular collapse of the open-chain polysulfur ion. Instead, S(3) can dissociate due to an unusually long and weak sulfur-sulfur (S4-S5) bond. A mechanistic picture now emerges which predicts that the novel S-S cleavage reaction and the unanticipated S(3) fragmentation are a result of delocalization of the negative charge within the remaining carbon-sulfur fragment. The computed results presented here reveal a new aspect to the chemistry of pentathiepins, that of S(3) unit transfer, which is proposed to have significance in the mechanism of cytotoxicity of the natural product varacin, 1.

Antineoplastic Agents↗
PubMed2001

Electrophilic oxidant produced in the photodeoxygenation of 1,2-benzodiphenylene sulfoxide.

We report that the photodeoxygenation of 1,2-benzodiphenylene sulfoxide, 1, generates an intermediate capable of oxidizing the solvent benzene to phenol. The reactivity of the intermediate was probed with various substrates (2-methylbutane, chloride ion, and para-substituted aryl sulfides). The intermediate produced in the sulfoxide photodeoxygenation displays an electrophilic oxidation chemistry. Our data on 1 contrast with the behavior of hydroxyl radical but resemble the chemistry observed for gas-phase atomic oxygen [O((3)P)] and for solution-phase photodeoxygenations of dibenzothiophene sulfoxide, 3, and pyridine N-oxide, 5. Correlations are made between the ionization potential of the acceptor molecules and the logarithm of the relative rate constants in order to advance the idea that the oxidizing agent of the title reaction may be solution-phase O((3)P).

Journal Article↗
PubMed2001

Thromboprophylaxis following caesarean section--a comparison of the antithrombotic properties of three low molecular weight heparins--dalteparin, enoxaparin and tinzaparin.

Pharmacological thromboprophylaxis is increasingly being used after caesarean section to prevent venous thromboembolism. Although a variety of low molecular weight heparins (LMWH) have been used no comparative study exists on their effects on the haemostatic system in this situation. Furthermore, their antithrombotic effect may be mediated through effects other than their inhibitory effect on activated factor X. We compared the plasma anti-factor Xa activity, plasma concentration of tissue factor pathway inhibitor (TFPI) and the reduction in plasma thrombin-antithrombin (TAT) complex concentration in 30 women randomised to receive either dalteparin 5,000 IU anti-Xa once daily (n = 10), enoxaparin 4,000 IU anti-Xa once daily (n = 10) or tinzaparin 50 IU/kg anti-Xa (average dose 3,650 anti-Xa units) once daily (n = 10) following caesarean section. Sampling occurred at 0, 1, 3, 6, 12 and 24 h relative to time of dosing. All preparations produced an increase in mean anti-Xa assay (p < 0.0001), a reduction in mean TAT (p < 0.05) and an increase in mean TFPI concentration (p <0.05). Analysis of variance (ANOVA) revealed a significant difference between the LMWHs in terms of mean anti-factor Xa activity (p < 0.005) and reduction in plasma TAT concentration (p < 0.005). Post hoc analysis indicated that the anti-Xa values of the groups receiving enoxaparin and dalteparin were significantly higher than those of the group receiving tinzaparin (p < 0.05), but not significantly different from each other. Post hoc analysis of the reduction in plasma TAT concentration showed the reduction to be significantly less in the group receiving enoxaparin compared to the dalteparin and tinzaparin groups (p < 0.05), which did not differ significantly from each other. There was no significant difference between treatment groups with regard to plasma concentration of TFPI. These findings demonstrate that LMWHs differ in their effects on haemostatic parameters including thrombin generation as assessed by TAT. The increase in TFPI may be an additional mediator of LMWH's antithrombotic effects. Although these findings demonstrate that LMWHs differ in their haemostatic effects, this does not necessarily infer a clinical difference between these agents.

Adolescent↗
PubMed2000

Reaction of singlet oxygen with trans-4-propenylanisole. Formation Of

We report the effects of added acid in the reaction of singlet oxygen with trans-4-propenylanisole (1). We provide evidence that solvent acidity modifies the behavior of the transient intermediates. Relative to reactions in aprotic solvent, enhanced dioxetane concentrations are observed in MeOH and in nonprotic solvents with acid. We suggest a new mechanism that invokes a proton transfer from MeOH and benzoic acid to perepoxide (2) and zwitterion (3) intermediates.

Journal Article↗
PubMed2000

Attractive through-space S-O interaction in the DNA-cleaving antitumor antibiotic leinamycin.

We describe here a study on the intramolecular nonbonded 1, 5-sulfur-oxygen (S-O) interaction in the antitumor antibiotic leinamycin 1. The results from density-functional theoretical and semiempirical calculations on leinamycin 1 and model systems 2-5 provide evidence for the 1,5-S-O nonbonded interaction. Our results are used to explain previous experimental data on the X-ray structure of leinamycin 1 (Hirayama, N.; Matsuzawa, E. S. Chem. Lett. 1993, 1957). The amide oxygen (O5) alters the thiosulfinate ester conformation and stabilizes the 1,2-dithiolan-3-one 1-oxide heterocycle. The attractive interaction induces S1 of leinamycin to adopt a distorted trigonal bipyramidal geometry. The magnitude of this stabilizing interaction is approximately 6 kcal/mol.

Antibiotics, Antineoplastic↗
PubMed2000

An adjacent thioester provides apical-directed stabilization to 3-isothiazolidinone 1-oxide heterocycles.

The structural and energetic features of the attractive intramolecular through-space S-X interaction [X being oxygen (O) or sulfur (S)] of thioester containing 3-isothiazolidinone 1-oxide heterocycles are described. Density functional theoretical and semiempirical calculations are used to explain the previous X-ray data on 3-isothiazolidinone 1-oxides 5 and 6 [Kanda, Y., Ashizawa, T. , Kakita, S., Takahashi, Y., Kono, M., Yoshida, M., Saitoh, Y., and Okabe, M. (1999) J. Med. Chem. 42, 1330-1332] and implicate a mechanism where the adjacent thioester participates in an apical-directed stabilization of the sulfur heterocycle. A key factor that distinguishes the S-O interaction from the S-S interaction is the stronger through-space interaction of the former, which is a consequence of the greater electronegativity of apical O compared to apical S. Reaction field theory reveals that the conversion of the S-O interaction to the S-S interaction is more facile compared to gas phase computations, which suggest a reduced importance of the 1,5-S-X interactions in solution. The conversion of the S-O interaction to the S-S interaction gives an isothiazolidinone oxide that places the reacting sulfurs in proximity with an orientation presumably suitable for bond formation and access to the dithiolanone oxide surface. Factors that influence the through-space S-X interactions may represent important issues in identifying target 3-isothiazolidinone 1-oxide prodrugs capable of rearranging to 1,2-dithiolan-3-one 1-oxide drugs.

Antibiotics, Antineoplastic↗
PubMed1996

Redesigning secondary structure to invert coenzyme specificity in isopropylmalate dehydrogenase.

Rational engineering of enzymes involves introducing key amino acids guided by a knowledge of protein structure to effect a desirable change in function. To date, all successful attempts to change specificity have been limited to substituting individual amino acids within a protein fold. However, the infant field of protein engineering will only reach maturity when changes in function can be generated by rationally engineering secondary structures. Guided by x-ray crystal structures and molecular modeling, site-directed mutagenesis has been used to systematically invert the coenzyme specificity of Thermus thermophilus isopropylmalate dehydrogenase from a 100-fold preference for NAD to a 1000-fold preference for NADP. The engineered mutant, which is twice as active as wild type, contains four amino acid substitutions and an alpha-helix and loop that replaces the original beta-turn. These results demonstrate that rational engineering of secondary structures to produce enzymes with novel properties is feasible.

3-Isopropylmalate Dehydrogenase↗
PubMed1996

A national survey of hospital -and community-based approaches to pretrial mental health evaluations.

To document the scope of recent trends in performing pretrial mental health evaluations, telephone interviews were conducted with 157 authorities in 50 states and the District of Columbia. These authorities included forensic mental health program directors and forensic clinical professionals. In all states, evaluations were made on an outpatient basis to some extent, and 45 states used inpatient evaluations. However, only ten states relied primarily on inpatient pretrial evaluations, generally in facilities with statewide catchment areas. A total of 32 states relied primarily on outpatient evaluations, generally conducted by providers with regional or local catchment areas.

Ambulatory Care↗
PubMed1995

A highly active decarboxylating dehydrogenase with rationally inverted coenzyme specificity.

The isocitrate dehydrogenase of Escherichia coli, which lacks the Rossmann fold common to other dehydrogenases, displays a 7000-fold preference for NADP over NAD (calculated as the ratio of kcat/Km). Guided by x-ray crystal structures and molecular modeling, site-directed mutagenesis has been used to introduce six substitutions in the adenosine binding pocket that systematically shift coenzyme preference toward NAD. The engineered enzyme displays an 850-fold preference for NAD over NADP, which exceeds the 140-fold preference displayed by a homologous NAD-dependent enzyme. Of the six mutations introduced, only one is identical in all related NAD-dependent enzyme sequences--strict adherence to homology as a criterion for replacing these amino acids impairs function. Two additional mutations at remote sites improve performance further, resulting in a final mutant enzyme with kinetic characteristics and coenzyme preference comparable to naturally occurring homologous NAD-dependent enzymes.

Amino Acid Sequence↗
PubMed1995

Spelling and attention in early Alzheimer's disease: evidence for impairment of the graphemic buffer.

The present study was conducted to investigate the spelling ability of persons affected by mild Alzheimer's disease (AD). AD subjects produced more phonemically implausible (PI) spelling errors (e.g. enough-->enougigh) than normal subjects; in addition, AD subjects produced a higher percentage of PI spelling errors than normal AD subjects. We found that two clinical visual attention tests were better predictors of the number of PI spelling errors than a language measure. Moreover, we also found that AD subjects performed more poorly when they copied words that were viewed and removed from sight than when the same words were copied directly. In contrast, there was no significant difference in the performance of the normal elderly on direct and delayed copying tasks. AD subjects produced more errors when spelling long words than when spelling short words. Although the spelling performance of the normal elderly was also affected by the length of the words spelled, AD subjects showed a significantly greater drop in performance than normal subjects when the length of the words increased. The vocabulary of the short and long word lists did not differ in frequency of occurrence or imagability (i.e. abstractness). The results suggest that visual attention impairment and not language impairment accounts for the PI spelling errors of mild AD subjects. The results are discussed with reference to graphemic buffer deficits identified in case studies of stroke patients with dysgraphia.

Aged↗
PubMed1995

Screening prison inmates for mental disorder: an examination of the relationship between mental disorder and prison adjustment.

The rapidly expanding population of prison inmates has severely challenged the prison system's ability to effectively screen incoming inmates for mental disorders and mental health service needs. This study describes a comprehensive mental health screening of inmates at a maximum security prison, using a modified version of the Referral Decision Scale (RDS), a screening measure developed from the Diagnostic Interview Schedule. Modified items and adjusted cut-off scores were used in order to reduce the rate of false positives. Survey results indicate that this modified version of the RDS may be an effective screening measure for correctional settings. Subjects who were positive on the RDS were compared to negative subjects on a variety of offense and prison adjustment variables. Findings indicate that while subjects who were positive on the RDS experienced some initial adjustment problems within the prison, they were generally not found to be involved in an elevated rate of prison violence and were not more often remanded to disciplinary units than those subjects who were negative on the RDS.

Adaptation, Psychological↗
PubMed1993

Canadian immigration: an earlier perspective.

Some aspects of past immigration to Canada are examined. The author notes that "many young Canadians today believe that Canada has always been a multi-cultural and multi-ethnic country. This is true only in so far as it was formerly divided on fairly tight geographical lines between French and British-derived populations, with a small minority of American Indians and Inuit eskimoes. However, during the nineteenth century and first decades of this century it was regarded as comprising a nation of Caucasoids, or more precisely a nation of French and of British settlers, willingly accepting only immigrants from Northwestern Europe ethnically affiliated with those two main groups."

Americas↗
PubMed1990

A prospective, multicenter study of patients' refusal of antipsychotic medication.

Refusal of treatment with antipsychotic medication was studied prospectively in a sample of 1434 psychiatric patients admitted to four acute inpatient units in state-operated mental health facilities in Massachusetts during a 6-month period. Compared with a control group of patients who accepted prescribed antipsychotic treatment, the 103 patients who refused were older, of a higher social class, and less likely to have been prescribed antiparkinsonian medications. On admission, prior to refusal of medication, patients who refused were found to have significantly higher Brief Psychiatric Rating Scale scores than compliant patients and more negative attitudes regarding their hospitalization and past, present, and future treatment. Treatment refusal had negative effects on the hospital milieu and on the patient; refusers were more likely to require seclusion or restraint and had longer hospitalizations than treatment acceptors. Most refusal episodes ended with voluntary acceptance of treatment. In 23% of cases medications were discontinued. Only 18% of the sample reached formal, judicial review, and in every case that did, involuntary treatment was ordered. The policy implications of these findings are discussed.

Adult↗