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Biomedical subjects

J M Nicholson

Publications and source records attributed to J M Nicholson.

At least 19 recordsLinked to original sources
PubMed2004

Australian and New Zealand birth cohort studies: breadth, quality and contributions.

OBJECTIVE: To understand factors associated with successfully conducting longitudinal studies across early childhood by (i) describing the designs of Australian and New Zealand birth cohort studies; (ii) describing the breadth of variables studied; and (iii) identifying factors influencing study quality, productivity and contributions. METHODS: A systematic review was undertaken of 13 birth cohort studies. Data were collected from published papers and questionnaires administered to study investigators. RESULTS: These single cohort studies recruited children prior to their first birthday. Using an ecological model as an organizing framework, the studies were found to have contributed to knowledge about health and development in multiple domains and well beyond early childhood. Areas for increased focus included policy-relevant environmental factors such as child-care and rural/urban differences, and the influence of fathers, family factors, peers, social competence, and genetic factors. Investigators' responses indicated desires for an increased depth of data collection and stronger sampling designs. Data quality was enhanced by maintaining skilled staff and reduced by inadequate data for tracking study participants. Productivity ranged from 1 to 760 publications per study (median = 14.0). The most productive studies were those that had started before 1990, had representative samples, ongoing funding, and larger research teams. Policy impacts have included changed infant sleeping practices, reduced environmental lead emissions and regulated swimming pool safety standards. CONCLUSIONS: A suite of coordinated and nested studies could meet sampling needs and facilitate depth of inquiry. Stable, long-term funding is required to staff and maintain well-designed longitudinal studies that can address priority research areas and contribute to the development of health and social policy.

Australia↗
PubMed2003

Structure of the histone-core octamer in KCl/phosphate crystals at 2.15 A resolution.

The structure of the native chicken histone octamer, crystallized in 2 M KCl, 1.35 M potassium phosphate pH 6.9, has been refined at 2.15 A resolution to a final R factor of 21.4% and an R(free) of 25.2%. Unique crystal-packing interactions between histone-core octamers are strong and one of them (area 4000 A(2)) involves two chloride ions and direct interactions between six acidic amino-acid residues on one octamer and the equivalent number of basic residues on the next. These interactions are on the structured part of the octamer (not involving tails). Five phosphate ions, 23 chloride ions and 437 water molecules have been identified in the structure. The phosphate and some chloride ions bind to basic amino-acid residues that interact with DNA in the nucleosome. The binding of most of the anions and the packing interactions are unique to these crystals. In other respects, and including the positions of four chloride ions, the octamer structure is very close to that of octamers in nucleosome-core particle crystals, particularly with respect to 'docking' sequences of the histone H2As and H4s. These sequences together with the H2B-H4 four-helix bundles stabilize the histone structure in the nucleosome and prevent the dissociation of the (H2A-H2B) dimers from the (H3-H4)(2) tetramer. Possible reasons why this happens at high salt in the absence of DNA are given.

Amino Acid Sequence↗
PubMed2000

Patient recall versus physician documentation in report of smoking cessation counselling performed in the inpatient setting.

OBJECTIVES: To determine rates of patient reported and physician documented counselling; to identify predictors of each report; and to identify the impact of each report on smoking cessation attempts after discharge from the hospital. DESIGN: Stickers on subjects' charts prompted physicians to give brief smoking cessation counselling to patients in the hospital. Patients reported counselling received and quit attempts in a phone interview conducted 7-18 days after discharge. Rates of counselling and correlations were calculated, and multivariate analysis identified predictors of patient report, physician documentation, and quit attempts. SETTING: Four hospitals in the Minneapolis/St Paul metropolitan area. SUBJECTS: 682 hospital patients who had smoked more than 100 cigarettes in their lifetime and had smoked in the last three months. RESULTS: 71.0% of patients reported counselling, and physicians documented counselling in the charts of 46.2% of patients (correlation = 0.15, kappa = 0.13). Patient report was predicted by specific hospital, belief that their hospitalisation was smoking related, diagnosis of a smoking related disease, and physician documentation of counselling. Physician documentation was predicted by female patient, specific hospital, longer hospital stay, and marginally predicted by smoking related disease. Quit attempts were predicted by patient report of counselling, but not physician documentation. CONCLUSIONS: Physicians document counselling in the hospital at a lower rate than patients report it, and the correlation between reports is very low, making an accurate assessment of true rates of counselling difficult. While it is important to increase physician documentation, it is even more important to increase patient recall, as this is the only report that predicts a quit attempt.

Adolescent↗
PubMed1999

Synthesis, characterization and anticonvulsant activity of enaminones. Part 6: Synthesis of substituted vinylic benzamides as potential anticonvulsants.

A comparison of enaminones from various unsubstituted and p-substituted benzamides to the analogous benzylamines has been undertaken with the aim of elucidating the essential structural parameters necessary for anticonvulsant activity. Initial studies on methyl 4-N-(benzylamino)-6-methyl-2-oxocyclohex-3-en-1-oate, 3a, 3-N-(benzylamino)cyclohex-2-en-1-one, 3p, and 5,5-dimethyl-3-N-(benzylamino)-cyclohex-2-en-1-one, 3r indicated that benzylamines possessed significant anti-maximal electroshock seizure (MES) activity. Evaluation of the analogous benzamides revealed significant differences in anticonvulsant activity, these differences were most probably related to the differences in their three-dimensional structures.

Animals↗
PubMed1999

Purification of histone core octamers and 2.15 A X-ray analysis of crystals in KCl/phosphate.

Intact histone octamers, produced by a new method quickly and in bulk, were crystallized in KCl/phosphate, and the X-ray data were analysed to 2.15 A, confirming a P65 space group. This environment preserves the high-resolution structure of the octamers and will be useful for studying them with other functionally important molecules. The octamers form into left-handed superhelices hexagonally spaced by 158.65 A, having a pitch of 102.57 A with six octamers per turn. A dipotassium tetraiodo mercurate derivative had good phasing power and should prove valuable in refining the structure after molecular-replacement analysis with lower resolution coordinates; the heavy atom was isomorphously placed at a unique site between the two H3-cysteine residues in the octamer.

Crystallization↗
PubMed1999

Effects on later adjustment of living in a stepfamily during childhood and adolescence.

This paper examines the effects of living in a stepfamily during childhood and adolescence on a range of psychosocial outcomes at age 18 years. Data collected during an 18-year longitudinal study were used to examine a sample of 907 children with respect to: exposure to living in a stepfamily during the period from age 6 to 16 years; measures of psychosocial outcomes including mental health, antisocial behaviour, substance use, restricted life opportunities, and sexual risk-taking at age 18 years; and measures of prospectively collected confounding factors. The analyses revealed that children exposed to living in a stepfamily for the first time between ages 6-16 years had elevated risks of a range of psychosocial outcomes at 18 years. These included elevated risks of: (1) juvenile offending; (2) nicotine dependence; (3) abuse or dependence on illicit substances; (4) leaving school without qualifications; (5) early onset of sexual activity; and (6) multiple sexual partners. However, these risks were reduced substantially when psychosocial outcomes were adjusted for the confounding effects of antecedent factors such as: family socioeconomic characteristics: family history of instability, adversity, and conflict; mother's age, religiosity, and smoking; child gender; and preexisting child conduct and attentional problems. After adjustment, the odds ratios between exposure to a stepfamily and adolescent outcomes were nonsignificant. Additional analysis revealed that there were no significant differences in outcomes for boys and girls exposed to stepfamilies. It was concluded that although young people exposed to living in a stepfamily had increased risks of poor psychosocial outcomes, much of this association appeared to be spurious, and arose from confounding social, contextual, and individual factors that were present prior to the formation of the stepfamily.

Adaptation, Psychological↗
PubMed1998

Synthesis, characterization, and anticonvulsant activity of enaminones. Part 5: investigations on 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothizin-4[10H]-one derivatives.

A new series of anticonvulsant 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-on es is herein reported. 2-Aminothiophenols underwent cyclocondensation with 4-carboalkoxy-5-methylcyclohexane-1,3-diones in refluxing dimethylsulfoxide (DMSO) to yield 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-on es, 4ak. In the case of the carbo-tert-butoxy derivatives (4c and 4k) prolonged reaction times led to the isolation of the respective 3-unsubstituted-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-ones (41 and 4m) instead. Significant anticonvulsant activity was displayed by these analogues, most particularly 4k, which was active at 30 mg/kg intraperitoneally (ip) in mice in the maximal electroshock seizure (MES) evaluation, with no toxicity noted at dosages up to 300 mg/kg. Oral (p.o.) rat evaluation of 4k in the MES evaluation provided an ED50 of 17.60 mg/kg, with no toxicity noted at dosages up to 500 mg/kg, providing a protective index (PI = TD50/ED50) > 28.40. These compounds represent the first reported series of phenothiazines which possess anticonvulsant activity.

Animals↗
PubMed1996

New crystals of the histone core octamer diffract to higher resolution, 2.65 A.

A new crystal form of the histone octamer, crystallized in 1.6 M KCl, 1.6 M phosphate, diffracts to appreciably better than 2.6 A resolution. The crystals have space group P6(1) or P6(5) and lattice parameters a = b = 158.29, c = 103.27 A, alpha = beta = 90, gamma = 120 degrees, with one molecule per asymmetric unit. The new crystals promise to yield more detail of the histone basic domains and a higher resolution structure for the histone octamer.

Journal Article↗
PubMed1995

Microenzymatic fluorescence assay for serum cholesterol.

An enzymatic assay using fluorometric detection for cholesterol determination in serum is described. Results were compared to a conventional enzymatic colorimetric procedure and to the definitive method, which is based on isotope dilution mass spectrometry. Fluorescence detection enhances sensitivity over current colorimetric methods by approximately two orders of magnitude, and the assay response is linear over three orders of magnitude of cholesterol concentration. The reaction is performed in a single step and can be performed with small sample (1 microliter) and reaction (200 microliters) volumes. The fluorescence intensity is stable after a 30-min sample incubation at room temperature. The sensitivity of this fluorescence assay makes it possible to measure subnanomoles of cholesterol, allowing accurate measurement of total cholesterol in 1 microliter of serum or less. This level of sensitivity will also allow measurement of cholesterol in various isolated lipoprotein fractions.

Cholesterol↗
PubMed1994

Cyclization reactions leading to beta-hydroxyketo esters.

The purpose of the research was to synthesize beta-diketo esters and to evaluate them for anticonvulsant activity. The reaction of methyl vinyl ketone with dimethyl malonate in the presence of potassium carbonate gave an uncyclized product that underwent a Claisen condensation to yield methyl 2-hydroxy-4-oxocyclohex-2-en-1-oate (5a). Similarly, other cyclized beta-hydroxyketo esters were prepared, and their spectrometric data confirmed that the enol tautomers were preferred to the beta-diketo tautomers. The synthetic work clarified the reaction pathway for the Michael addition of malonate esters to enones. Of the intermediates and products tested for anticonvulsant activity, dimethyl 2,2-bis-(3-oxobutyl)malonate (9a) was found to possess anticonvulsant property. However, it is emphasized that the beta-hydroxyketo esters could be useful intermediates in the synthesis of enaminone anticonvulsants.

Animals↗
PubMed1994

Synthesis, reactions, and preliminary evaluations of enaminone esters.

The objective of this work was to design enaminone esters that would possess potential medicinal properties. The reaction between beta-hydroxyketo esters and primary or secondary amines yielded secondary or tertiary enaminone esters, respectively. The UV spectra of the enaminone esters were determined in acidic, alkaline, and neutral media; the spectra have a hypsochromic shift in acidic media in comparison with neutral media. The enaminone esters provided nucleophilic and electrophilic sites for a variety of reactions. Thus, the enaminone esters were converted into enaminone amides and O-alkylation products exclusively. Although the enaminone esters were generally resistant to reduction by metal hydrides, one unhindered enaminone ester was reduced to an alcohol with sodium borohydride. Another enaminone ester reacted with guanidine to give the corresponding quinazolinone. Due to the variety of nucleophilic and electrophilic sites in the enaminone system, enaminone esters possess a great potential as reaction intermediates and medicinal compounds. Preliminary evaluations of the enaminone esters revealed a histaminergic effect, uterine relaxant properties, and anticonvulsant activity.

Animals↗
PubMed1994

Synthesis and evaluation of amino analogues of valproic acid.

Valproic acid, an antiepileptic drug, is extensively metabolized in humans. Two putative metabolites, 2-n-propyl-3-aminopentanoic acid (3-aminovalproic acid, 3-amino-VPA; 2a) and 2-n-propyl-4-aminopentanoic acid (4-amino-valproic acid, 4-amino-VPA; 4a), which may result from the transamination of the respective keto acids 1a and 3a may explain the unusual extended seizure protection elicited by valproic acid. The title compounds were synthesized as their diasteriomeric ethyl esters 2b and 4b and submitted for anticonvulsant evaluation by the Antiepileptic Drug Development Program of the National Institute of Neurological and Communicative Disorders and Stroke. The results verified our hypothesis, as 4b was active in the subcutaneous pentylenetetrazol (scMet) evaluation at 30 mg/kg. Both compounds were highly toxic at 300 mg/kg.

Animals↗
PubMed1993

Synthesis and anticonvulsant activity of enaminones. 2. Further structure-activity correlations.

This report continues the in-depth evaluation of methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate , 1 (ADD 196022), and methyl 4-(benzylamino)-6-methyl-2-oxocyclohex-3-en-1-oate, 2, two potent anticonvulsant enaminones. These compounds were evaluated employing the amygdala kindling model. Neither 1 nor 2 was active against amygdala kindled seizures, further supporting the corneal kindled model as a definitive tool for antielectroshock seizure evaluation as previously reported. Additional intraperitoneal (ip) data on 1 revealed toxicity at 24 h at 100 mg/kg. Several active analogs have been prepared with the view to minimizing toxicity. In a special ip rat screen developed by the Antiepileptic Drug Development (ADD) Program, these newer analogs were evaluated for protection against maximal electroshock seizures (MES) at 10 mg/kg and neurotoxicity at 100 mg/kg. From this screen, several compounds were shown to be safer alternatives, the most notable was methyl 4-[(p-bromophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate, 13. Compound 13 had an ip ED50 of 4 mg/kg in the rat and a TD50 of 269 mg/kg, providing a protective index (TD50/ED50) of > 67. By variation in the ring size, additional aromatic substitutions and the synthesis of acyclic analogs, these newer compounds provide a more definitive insight into the structure-activity correlation. CLOGP evaluation and molecular modeling studies are also provided to further elaborate the molecular characteristics of potential anticonvulsant enaminones.

Animals↗