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Biomedical subjects

J King

Publications and source records attributed to J King.

At least 91 records · Page 5Linked to original sources
PubMed2000

Beta-helix core packing within the triple-stranded oligomerization domain of the P22 tailspike.

A right-handed parallel beta-helix of 400 residues in 13 tightly packed coils is a major motif of the chains forming the trimeric P22 tailspike adhesin. The beta-helix domains of three identical subunits are side-by-side in the trimer and make predominantly hydrophilic inter-subunit contacts (Steinbacher S et al., 1994, Science 265:383-386). After the 13th coil the three individual beta-helices terminate and the chains wrap around each other to form three interdigitated beta-sheets organized into the walls of a triangular prism. The beta-strands then separate and form antiparallel beta-sheets, but still defining a triangular prism in which each side is a beta-sheet from a different subunit (Seckler R, 1998, J Struct Biol 122:216-222). The subunit interfaces are buried in the triangular core of the prism, which is densely packed with hydrophobic side chains from the three beta-sheets. Examination of this structure reveals that its packed core maintains the same pattern of interior packing found in the left-handed beta-helix, a single-chain structure. This packing is maintained in both the interdigitated parallel region of the prism and the following antiparallel sheet section. This oligomerization motif for the tailspike beta-helices presumably contributes to the very high thermal and detergent stability that is a property of the native tailspike adhesin.

Adhesins, Bacterial↗
PubMed2000

Minimax D-optimal designs for the logistic model.

We propose an algorithm for constructing minimax D-optimal designs for the logistic model when only the ranges of the values for both parameters are assumed known. Properties of these designs are studied and compared with optimal Bayesian designs and Sitter's (1992, Biometrics, 48, 1145-1155) minimax D-optimal kk-designs. Examples of minimax D-optimal designs are presented for the logistic and power logistic models, including a dose-response design for rheumatoid arthritis patients.

Algorithms↗
PubMed2000

Sleep-related c-Fos protein expression in the preoptic hypothalamus: effects of ambient warming.

Preoptic area (POA) neuronal activity promotes sleep, but the localization of critical sleep-active neurons is not completely known. Thermal stimulation of the POA also facilitates sleep. This study used the c-Fos protein immunostaining method to localize POA sleep-active neurons at control (22 degrees C) and mildly elevated (31.5 degrees C) ambient temperatures. At 22 degrees C, after sleep, but not after waking, we found increased numbers of c-Fos immunoreactive neurons (IRNs) in both rostral and caudal parts of the median preoptic nucleus (MnPN) and in the ventrolateral preoptic area (VLPO). In animals sleeping at 31.5 degrees C, significantly more Fos IRNs were found in the rostral MnPN compared with animals sleeping at 22 degrees C. In VLPO, Fos IRN counts were no longer increased over waking levels after sleep at the elevated ambient temperature. Sleep-associated Fos IRNs were also found diffusely in the POA, but counts were lower than those made after waking. This study supports a hypothesis that the MnPN, as well as the VLPO, is part of the POA sleep-facilitating system and that the rostral MnPN may facilitate sleep, particularly at elevated ambient temperatures.

Animals↗
PubMed2000

The educational needs of part time clinical facilitators.

Clinical facilitators play an important role in the clinical practicum component of an undergraduate nursing programme. Part time teachers are often employed in this role, however very little has been written about the needs of these facilitators. An exploratory study design incorporating focus group interviews and questionnaires was used to identify the needs of clinical facilitators at a large Australian university. This study showed that they are committed nurses who often feel inadequate in a role they feel lacks support and identity. The findings of the study have implications for the preparation of clinical facilitators.

Attitude of Health Personnel↗
PubMed2000

Ligament reconstruction tendon interposition arthroplasty for basal joint arthritis: simplifying flexor carpi radialis tendon passage through the thumb metacarpal.

During the ligament reconstruction tendon interposition arthroplasty for basal joint arthritis, the flexor carpi radialis tendon is passed through the base of the thumb and out an exit hole on its dorsum. When the entire width of the tendon is harvested, this aspect of the procedure can be difficult. Tapering the width of the proximal tendon and using a Carroll tendon retriever simplify the procedure and eliminate the need for enlarging the transosseous hole in the thumb metacarpal.

Arthroplasty↗
PubMed2000

Effect of marimastat on serum tumour markers in patients with colorectal cancer.

BACKGROUND: Matrix metalloproteinases (MMPs) are a family of enzymes that break down extra cellular matrix proteins during tissue formation. Tumours have been shown to over-express certain matrix metalloproteinases relative to normal tissue. Matrix metalloproteinases are associated with the disruption of tissue architecture in the growth of tumours and they are also important in the development of metastases. Pre-clinical studies have shown that inhibitors of matrix metalloproteinases (MMPIs) can restrict malignant growth and block the process of tumour neovascularisation. Marimastat is a synthetic MMPI which has been investigated in clinical studies of patients with advanced cancers. OBJECTIVE: The aim of this open study is to describe the change in serum CEA in eight patients with advanced colorectal metastatic disease treated with Marimastat. RESULTS: The mean percentage change in serum CEA level of the patients before commencing Marimastat treatment was 35.6 (SD 25.7) with a mean percentage change in serum CEA of 6.8 (SD 18.3) during the first month of treatment. The average percentage change in serum CEA after one month of treatment with Marimastat was 20 percent. CONCLUSIONS: Although the study sample is small, there is a significant difference in serum CEA change prior to and post commencement of marimastat treatment. It is important to note that the observation period was short for most patients due to their advanced disease.

Adult↗
PubMed1999

Adenosinergic modulation of rat basal forebrain neurons during sleep and waking: neuronal recording with microdialysis.

1. The cholinergic system of the basal forebrain (BF) is hypothesized to play an important role in behavioural and electrocortical arousal. Adenosine has been proposed as a sleep-promoting substance that induces sleep by inhibiting cholinergic neurons of the BF and brainstem. However, adenosinergic influences on the activity of BF neurons in naturally awake and sleeping animals have not been demonstrated. 2. We recorded the sleep-wake discharge profile of BF neurons and simultaneously assessed adenosinergic influences on wake- and sleep-related activity of these neurons by delivering adenosinergic agents adjacent to the recorded neurons with a microdialysis probe. Discharge rates of BF neurons were recorded through two to three sleep-wake episodes during baseline (artificial cerebrospinal fluid perfusion), and after delivering an adenosine transport inhibitor (s-(p-nitrobenzyl)-6-thioinosine; NBTI), or exogenous adenosine, or a selective adenosine A1 receptor antagonist (8-cyclopentyl-1, 3-dimethylxanthine; CPDX). 3. NBTI and adenosine decreased the discharge rate of BF neurons during both waking and non-rapid eye movement (NREM) sleep. In contrast, CPDX increased the discharge rate of BF neurons during both waking and NREM sleep. These results suggest that in naturally awake and sleeping animals, adenosine exerts tonic inhibitory influences on BF neurons, supporting the hypothesized role of adenosine in sleep regulation. 4. However, in the presence of exogenous adenosine, NBTI or CPDX, BF neurons retained their wake- and sleep-related discharge patterns, i.e. still exhibited changes in discharge rate during transitions between waking and NREM sleep. This suggests that other neurotransmitters/neuromodulators also contribute to the sleep-wake discharge modulation of BF neurons.

Adenosine↗
PubMed1999

Teaching and assessing ethics and law in the dental curriculum.

The General Dental Council's recommendations on dental education places a new emphasis on the importance of ethics and law in the dental curriculum, stating that students should have an awareness of moral and ethical responsibilities involved in the provision of care to individual patients and to populations. The duties of care to protect a patient's life and health at all times, to respect their autonomy to make informed choices about what happens to them, and to do this fairly and without prejudice, are widely accepted as the fundamental ethical principles governing all health care. The specifics of these duties of care are detailed in Maintaining Standards: guidance to dentists on professional and personal conduct, published by the GDC.

Adult↗
PubMed1999

In vitro unfolding/refolding of wild type phage P22 scaffolding protein reveals capsid-binding domain.

The scaffolding proteins of double-stranded DNA viruses are required for the polymerization of capsid subunits into properly sized closed shells but are absent from the mature virions. Phage P22 scaffolding subunits are elongated 33-kDa molecules that copolymerize with coat subunits into icosahedral precursor shells and subsequently exit from the precursor shell through channels in the procapsid lattice to participate in further rounds of polymerization and dissociation. Purified scaffolding subunits could be refolded in vitro after denaturation by high temperature or guanidine hydrochloride solutions. The lack of coincidence of fluorescence and circular dichroism signals indicated the presence of at least one partially folded intermediate, suggesting that the protein consisted of multiple domains. Proteolytic fragments containing the C terminus were competent for copolymerization with capsid subunits into procapsid shells in vitro, whereas the N terminus was not needed for this function. Proteolysis of partially denatured scaffolding subunits indicated that it was the capsid-binding C-terminal domain that unfolded at low temperatures and guanidinium concentrations. The minimal stability of the coat-binding domain may reflect its role in the conformational switching needed for icosahedral shell assembly.

Binding Sites↗
PubMed1999

Folding and stability of mutant scaffolding proteins defective in P22 capsid assembly.

Bacteriophage P22 scaffolding subunits are elongated molecules that interact through their C termini with coat subunits to direct icosahedral capsid assembly. The soluble state of the subunit exhibits a partially folded intermediate during equilibrium unfolding experiments, whose C-terminal domain is unfolded (Greene, B., and King, J. (1999) J. Biol. Chem. 274, 16135-16140). Four mutant scaffolding proteins exhibiting temperature-sensitive defects in different stages of particle assembly were purified. The purified mutant proteins adopted a similar conformation to wild type, but all were destabilized with respect to wild type. Analysis of the thermal melting transitions showed that the mutants S242F and Y214W further destabilized the C-terminal domain, whereas substitutions near the N terminus either destabilized a different domain or affected interactions between domains. Two mutant proteins carried an additional cysteine residue, which formed disulfide cross-links but did not affect the denaturation transition. These mutants differed both from temperature-sensitive folding mutants found in other P22 structural proteins and from the thermolabile temperature-sensitive mutants described for T4 lysozyme. The results suggest that the defects in these mutants are due to destabilization of domains affecting the weak subunit-subunit interactions important in the assembly and function of the virus precursor shell.

Bacteriophage P22↗
PubMed1999

Randomized trial of preoperative cimetidine in patients with colorectal carcinoma with quantitative assessment of tumor-associated lymphocytes.

BACKGROUND: Previous studies have suggested that cimetidine, a histamine-2 receptor antagonist with immunostimulatory effects, may improve survival in patients with colorectal carcinoma. This effect may be apparent by an increase in the number of peritumoral lymphocytes. A prospective, double blind, randomized, placebo-controlled trial of a short course of preoperative treatment with cimetidine in patients with colorectal carcinoma was performed to assess the effect of cimetidine on survival and on the number of peritumoral lymphocytes. METHODS: One hundred and twenty-five patients who were scheduled to undergo elective colon or rectal excision for carcinoma were randomized to receive either placebo or cimetidine preoperatively for 5 days. In addition to standard histopathology, immunohistochemistry and computer video image analysis were used to assess the number of peritumoral lymphocytes in an objective manner. Interim survival analysis according to the Kaplan-Meier method was performed. RESULTS: A trend toward a survival advantage in the group of patients receiving cimetidine (800 mg twice daily) compared with the placebo group was observed (P = 0.20, log rank test) that was most marked in patients with replication error negative tumors (P = 0.04). Similarly, in these two groups there was a trend toward an increase in the number of patients with a conspicuous lymphocytic infiltration (P = 0.10, chi-square test). However, there was no difference in the number of peritumoral lymphocytes as measured by image analysis. CONCLUSIONS: Based on the results of the current study, a short course of preoperative treatment with cimetidine does appear to have an effect on patient survival; however, the exact mechanism is unknown. The failure of this study to demonstrate a clear increase in the local lymphocyte response does not exclude an immunologic mechanism of action.

Adjuvants, Immunologic↗
PubMed1999

Resistance exercise and supraphysiologic androgen therapy in eugonadal men with HIV-related weight loss: a randomized controlled trial.

CONTEXT: Repletion of lean body mass (LBM) that patients lose in human immunodeficiency virus (HIV) infection has proved difficult. In healthy, HIV-seronegative men, synergy between progressive resistance exercise (PRE) and very high-dose testosterone therapy has been reported for gains in LBM and muscle strength. OBJECTIVE: To determine whether a moderately supraphysiologic androgen regimen, including an anabolic steroid, would improve LBM and strength gains of PRE in HIV-infected men with prior weight loss and whether protease inhibitor antiretroviral therapy prevents lean tissue anabolism. DESIGN: Double-blind, randomized, placebo-controlled trial; post hoc analysis for effect of HIV-protease inhibitor therapy conducted from January to October 1997. SETTING: Referral center in San Francisco, Calif. PATIENTS: Volunteer sample of 24 eugonadal men with HIV-associated weight loss (mean, 9% body weight loss), recruited from an AIDS clinic and by referral and by advertisement. INTERVENTION: For 8 weeks, all subjects received supervised PRE with physiologic intramuscular testosterone replacement (100 mg/wk) to suppress endogenous testosterone production. Randomization was between an anabolic steroid, oxandrolone, 20 mg/d, and placebo. MAIN OUTCOME MEASURES: Lean body mass, nitrogen balance (10-day metabolic ward measurements), body weight, muscle strength, and androgen status. RESULTS: Twenty-two subjects completed the study (1 1 per group). Both groups showed significant nitrogen retention and increases in LBM, weight, and strength. The mean (SD) gains were significantly greater in the oxandrolone group than in the placebo group (5.6 [2.1] vs 3.8 [1.8] g of nitrogen per day [P=.05]; 6.9 [1.7] vs 3.8 [2.9] kg of LBM [P=.005]; greater strength gains for various upper and lower body muscle groups by maximum weight lifted [P = .02-.05] and dynamometry [P = .01 -.05]). The mean (SD) high-density lipoprotein cholesterol level declined 0.25 (0.14) mmol/L (9.8 [5.4] mg/dL) significantly in the oxandrolone group (P < .001 compared with placebo). Results were similar whether or not patients were taking protease inhibitors. One subject in the oxandrolone group discontinued the study because of elevated liver function test results. CONCLUSIONS: A moderately supraphysiologic androgen regimen that included an anabolic steroid, oxandrolone, substantially increased the lean tissue accrual and strength gains from PRE, compared with physiologic testosterone replacement alone, in eugonadal men with HIV-associated weight loss. Protease inhibitors did not prevent lean tissue anabolism.

Adult↗
PubMed1999

Effects of nandrolone decanoate therapy in borderline hypogonadal men with HIV-associated weight loss.

Serum testosterone concentrations are frequently in the low-normal range (lowest quartile, <500 ng/dl) in men with AIDS-wasting syndrome (AWS) and in other chronic wasting disorders. The response of patients in this group to androgen treatment has not been determined, however. Eighteen men with AWS (mean +/- standard error [SE]: 87% +/- 1% usual body weight; CD4 count 90 +/- 24) and borderline low serum testosterone concentrations (382 +/- 33 ng/dl) completed a 21-day placebo-controlled inpatient metabolic ward study comparing intramuscular (i.m.) placebo (n = 7) with low-dose (65 mg/week; n = 4) and high-dose (200 mg/week; n = 7) nandrolone decanoate, a testosterone analogue. Nitrogen balance, stable isotope-mass spectrometric measurement of de novo lipogenesis (DNL), resting energy expenditure, and gonadal hormone levels were measured. Both low-dose and high-dose nandrolone resulted in significant nitrogen retention (33-52 g nitrogen/14 days, representing gains of 0.5 to 0.9 kg lean tissue/week) compared with placebo (loss of 11 g nitrogen/week). This was reflected biochemically in a borderline significant reduction of high DNL (p < .06). Serum testosterone and gonadotropins were suppressed whereas resting energy expenditure was unchanged by nandrolone treatment. In 10 study subjects completing a 12-week open-label follow-up phase, body weight increased by 4.9 +/- 1.2 kg, including 3.1 +/- 0.5 kg lean body mass, and treadmill exercise performance also improved. In summary, nandrolone decanoate therapy in the absence of an exercise program in borderline hypogonadal men with AWS caused substantial nitrogen retention compared with placebo, similar in extent to the nitrogen retention previously achieved with recombinant growth hormone. It is reasonable to expand the criteria for androgen treatment in AWS to include at least patients in the lowest quartile of serum testosterone.

Adult↗