Biomedical subjects

J Adams

Publications and source records attributed to J Adams.

At least 91 records · Page 5Linked to original sources

PubMed2000

The kelch repeat superfamily of proteins: propellers of cell function.

The kelch motif was discovered as a sixfold tandem element in the sequence of the Drosophila kelch ORF1 protein. The repeated kelch motifs predict a conserved tertiary structure, a beta-propeller. This module appears in many different polypeptide contexts and contains multiple potential protein-protein contact sites. Members of this growing superfamily are present throughout the cell and extracellularly and have diverse activities. In this review, we discuss current information concerning the structural organization of kelch repeat proteins, their biological roles and the molecular basis of their action.

Amino Acid Sequence↗

PubMed2000

Preliminary evidence for impaired estrogen receptor-alpha protein expression in osteoblasts and osteocytes from men with idiopathic osteoporosis.

Although osteoporosis is usually associated with women, 1 in 12 men in the UK have the disease, and a third of these cases are idiopathic. Estrogen is now known to be associated with bone loss in older men, but we found, previously, that levels of this hormone were normal in younger cases of male idiopathic osteoporosis (MIO) in the age range 33-61 years. We therefore hypothesized that their estrogen responses in bone might be defective, through impaired estrogen receptor-alpha (ER)-alpha expression. Consequently, in the present study, we compared expression of ER-alpha by indirect immunofluorescence, semiquantitative image analysis, and in situ reverse transcription-polymerase chain reaction in bone sections from MIO patients (33-56 years) (N = 7); age-matched control men (N = 7); and, for reference, ovarian steroid (OS)-replete (N = 7) and OS-deficient women (N = 6). In the control men, 23 +/- 6% (mean +/- SEM) of osteoblasts and 14 +/- 2% of osteocytes expressed ER-alpha protein, similar to OS-replete women. Although receptor expression decreased in OS-deficient women, the loss of ER-alpha protein in MIO patients was more severe (1 +/- 0.5% osteocytes, 2 +/- 1% osteoblasts expressed receptor); however, ER-alpha messenger RNA (mRNA) was still expressed in controls and MIO patients. Bone loss in these patients may be due to deficient ER-alpha protein expression.

Adult↗

PubMed2000

Frequency and duration of inattentive behavior after traumatic brain injury: effects of distraction, task, and practice.

Traumatic brain injury (TBI) is associated with impairments of attention, most typically measured through tests of information processing, or by subjective symptom endorsement by patients, families, and clinicians. We have previously shown increased rates of off-task behavior among patients with TBI versus controls as defined by videotaped records of independent work in distracting environments. In this research, we report on a more detailed method of coding such videotaped records which allows measurement of the precise number of off-task behaviors, their durations, and their relationship to distracting events. Using this method, we studied 20 patients with recent moderate-to-severe TBI and 20 demographically comparable controls as they performed independent work tasks while being subjected to controlled distracting events. This research confirms that patients are markedly less attentive than controls both in the presence of distractions and in their absence, that distractions have an influence on off-task behavior in both groups, and that the disruptive impact of distractors wanes relatively quickly for controls but not for patients. The duration of distraction produced by various classes of distracting events appeared similar for patients and controls, although the power to detect differences in behavioral duration between groups was limited. The pattern of inattentiveness among patients showed minimal relationship to measures of injury severity within this sample.

Adolescent↗

PubMed2000

Proteasome inhibition: a new strategy in cancer treatment.

The ubiquitin proteasome pathway is a highly conserved intracellular pathway for the degradation of proteins. Many of the short-lived regulatory proteins which govern cell division, growth, activation, signaling and transcription are substrates that are temporally degraded by the proteasome. In recent years, new and selective inhibitors of the proteasome have been employed in cell culture systems to examine the anti-tumor potential of these agents. This review covers the chemistry of selected proteasome inhibitors, possible mechanisms of action in cell culture and the in vivo examination of proteasome inhibitors in murine and human xenograft tumor models in mice. One inhibitor, PS-341, has recently entered Phase I clinical trials in cancer patients with advanced disease to further test the potential of this approach.

Animals↗

PubMed2000

Predicting medication adherence in severe mental disorders.

OBJECTIVE: This study explored the utility of the health belief model (HBM) in explaining medication adherence in subjects with severe and disabling mental disorders. METHOD: Six well-established measuring instruments, with confirmed reliability and validity, were used to assess each component of the HBM and medication adherence in 39 hospital-treated subjects with affective disorders (n = 27) or schizophrenia (n = 12). RESULTS: Highly adherent and partially adherent subjects differed significantly in their perception of illness severity, their beliefs about themselves and their control over the disorder, and their concerns about further hospitalization. Two components of the HBM (perceived severity of illness and perceived benefits of treatment) explained 43% of the variance in adherence behaviour. CONCLUSION: Although the study has a number of methodological limitations, the results suggest that clinical assessment of components of the HBM may improve the detection of patients at risk of medication non-adherence.

Adolescent↗

PubMed2000

A systematic review of the role of human papilloma virus (HPV) testing within a cervical screening programme: summary and conclusions.

A systematic review of the available evidence on the role of HPV testing in cervical screening has been published by the Health Technology Assessment Committee of the UK Department of Health. The review summarized relevant data on testing methods, natural history, and prevalence of the virus in different disease groups. Cost-effectiveness modelling was undertaken. Ten major conclusions were reached and are reported here. The key conclusions were that HPV testing was more sensitive than cytology, but that there were concerns about specificity, especially in young women. The increased sensitivity led to a recommendation that HPV testing be introduced on a pilot basis for women with borderline and mild smears. HPV testing has great potential as a primary screening test, but large trials are needed to properly evaluate this application and to determine if its introduction can reduce invasive cancer rates. There is an urgent need to undertake a large trial of HPV testing in conjunction with other new technologies (liquid-based cytology and computer-assisted cytology reading) to determine the best way to integrate them into ongoing screening programmes. A range of issues including the age to start and stop screening, the appropriate screening interval, the role of self-sampling for HPV testing and the choice of primary test (HPV and/or cytology) require further evaluation.

Adult↗

PubMed2000

General practitioners, complementary therapies and evidence-based medicine: the defence of clinical autonomy.

Amidst the substantial change currently gripping primary health care are two developments central to contemporary debate regarding the very nature, territory and identity of general practice - the integration of complementary and alternative medicine (CAM) and the rise of evidence-based medicine (EBM). This paper reports findings from a study based upon 25 in-depth interviews with general practitioners (GPs) personally practising complementary therapies alongside more conventional medicine to treat their NHS patients. The paper outlines the GPs' perceptions of EBM, its relationship to their personal development of CAM, and their notions of good clinical practice more generally. Analysis of the GPs' accounts demonstrates how CAM can be seen as a useful resource with which some GPs defend their clinical autonomy from what they perceive to be the threat of EBM.

Complementary Therapies↗

PubMed2000

Youth mental health promotion in the Hunter region.

OBJECTIVE: To describe the work of the Hunter Institute of Mental Health, with special emphasis on its role in mental health promotion and prevention with adolescents. METHOD AND RESULTS: The Ottawa Charter for Health Promotion is used as a framework to describe the varied functions of this organisation. Four youth mental health promotion programs are given as examples of the Institute's work. Results of preliminary evaluation of the Youth Suicide Prevention - National University Curriculum Project are provided. CONCLUSION: The Hunter Institute of Mental Health, a self-funding unit of the Hunter Area Health Service, provides innovative health promotion programs as part of its role as a provider of mental health education and training. The model may be particularly applicable to mental health services in regional Australia.

Adolescent↗

PubMed2000

Major trauma enhances store-operated calcium influx in human neutrophils.

PURPOSE: Chemotaxins from inflammatory sites prime or activate neutrophils (PMN) by using cytosolic calcium ([Ca2+]i) fluxes as second messengers. [Ca2+]i can be mobilized rapidly by receptor-mediated entry or store-release, or more slowly by store-operated calcium influx (SOCI). We studied [Ca2+]i mobilization by chemotaxins and how trauma impacts the calcium entry mechanisms used by chemotaxins. METHODS: [Ca2+]i flux was studied by spectrofluorometry. The contributions of early and late [Ca2+]i currents to net calcium flux were compared after stimulation by more potent (fMLP, C5a, PAF) or less potent (IL-8, GRO-alpha, and LTB4) agonists. Store operated [Ca2+]i mobilization was reflected by the ratio of area under the [Ca2+]i efflux curve to peak [Ca2+]i (efflux curve). PMN from trauma patients (ISS > 25) and pair-matched volunteer (n = 7 pairs) were then primed and stimulated with thapsigargin to compare cell calcium stores and SOCI. RESULTS: Late [Ca2+]i mobilization made more important contributions to fMLP, PAF, and C5a signals than to IL-8, GRO-alpha, or LTB4 (p < 0.01 all comparisons). Calcium stores and store release were only marginally lower after injury (p = not significant), but trauma PMN showed far higher [Ca2+]i influx after thapsigargin (p = 0.007), and greater net SOCI (p = 0.034). CONCLUSIONS: SOCI may play an important role in PMN activation, and trauma increases PMN SOCI. Prolonged elevations of [Ca2+]i due to enhanced SOCI may alter stimulus-response coupling to chemotaxins and contribute to PMN dysfunction after injury.

Adult↗

PubMed2000

Lateral subcutaneous brow lift and interbrow muscle resection: clinical experience and anatomic studies.

The authors report consistent improvement in 65 patients with lateral brow ptosis by using a lateral subcutaneous brow lift at the temporal hairline. In 48 of these patients, vertical glabellar wrinkles were improved by the direct excision of procerus, corrugator, and orbicularis muscles through 3-mm medial brow incisions. Anatomic dissections in 10 cadavers and examinations of 50 skulls were used to study the location of the supraorbital and supratrochlear nerves. Dissections revealed that the supratrochlear nerve was never closer than 1.6 cm to the midline at the level of the supraorbital ridge. In no dissection was a supratrochlear foramen noted. Lateral subcutaneous brow lift was consistently successful in elevating the lateral brow. In no patient was nerve damage to the supraorbital nerve noted. In most patients, the temporal hairline was improved by excising a triangle of balding scalp. Through 3-mm medial brow incisions, the interbrow musculature can be excised by using a small rongeur in an area 3.2 cm wide without risk of nerve damage, improving vertical glabellar wrinkles.

Facial Muscles↗

PubMed2000

Proteasome inhibitor PS519 reduces infarction and attenuates leukocyte infiltration in a rat model of focal cerebral ischemia.

BACKGROUND AND PURPOSE: Reperfusion brain injury after cerebral ischemia is associated with a developing inflammatory response at the site of infarction. Proteasome inhibitors block nuclear factor-kappaB activation and provide anti-inflammatory effects in several animal models of peripheral inflammation. We tested the novel proteasome inhibitor PS519 in a rat model of transient focal ischemia to establish its pharmacodynamics as a neuroprotection treatment and related effects on leukocyte infiltration. METHODS: Rats were subjected to 2 hours of focal cerebral ischemia by means of the filament method of middle cerebral artery occlusion (MCAo). After either 22 or 70 hours of reperfusion, infarct size was measured and neurological function, electroencephalographic (EEG) activity, and/or neutrophil and macrophage infiltration was quantified. PS519 was administered in a single intravenous bolus at 2 hours after MCAo. In addition, the therapeutic window for PS519 was estimated by delaying treatment for 4 or 6 hours after MCAo. RESULTS: Dose-response analysis of infarct volume at 24 hours revealed that PS519 neuroprotection approached 60%, and clinical evaluations showed significant improvements in neurological function and EEG activity. Neutrophil infiltration at 24 hours was also significantly decreased in cortical and striatal infarcted tissue of PS519-treated rats. Delaying the PS519 treatment up to 4 hours continued to result in significant neuroprotection. In the 72-hour injury model, infarction was reduced 40% by PS519, and significant improvements in neurological function and EEG recovery were again measured. Considerable reductions in both neutrophil and macrophage infiltration were evident. CONCLUSIONS: PS519 mitigates infarction and improves neurological recovery in brain-injured rats, an effect in part caused by a reduction in the leukocyte inflammatory response.

Acetylcysteine↗

PubMed2000

Dynamic changes in the intrafollicular inhibin/activin/follistatin axis during human follicular development: relationship to circulating hormone concentrations.

Previous studies of normal human ovaries suggest that inhibins, activins, and follistatin (FS) are produced in a stage-specific pattern indicative of intraovarian, autocrine/paracrine roles in regulating follicle development. However, these studies relied largely on surgical specimens and thus include little information about the menstrual cycle stage or dominant follicle status at the time follicles or ovaries were obtained. The purpose of this study was to 1) determine the pattern of intrafollicular hormone biosynthesis across antral follicle development in normal women, 2) compare hormone concentrations in dominant and nondominant follicles from the same ovary, and 3) examine the relationship between dominant follicle hormone content and circulating hormone levels. Intrafollicular estradiol, progesterone, and inhibin A concentrations increased significantly with follicle size or maturity, whereas significant inverse relationships were observed for androstenedione and the androstenedione/estradiol (A:E) ratio. In contrast, neither inhibin B, activin A, nor free FS varied consistently with size or maturity. Estradiol, progesterone, and inhibin A levels and A:E ratio were significantly lower in nondominant follicles compared to the dominant follicle aspirated from the same ovary. Although intrafollicular and serum concentrations of each hormone followed the same general pattern as follicles develop, the human follicular fluid/serum gradients changed during the follicular phase and were different for estradiol and inhibin A, suggesting the presence of stage-specific differences in pharmacodynamics. These results are consistent with the hypothesis that the orderly transition from an activin-dominant to an inhibin A/FS-dominant microenvironment is critical for dominant follicle development.

Activins↗

PubMed2000

Workshop to identify critical windows of exposure for children's health: neurobehavioral work group summary.

This paper summarizes the deliberations of a work group charged with addressing specific questions relevant to risk estimation in developmental neurotoxicology. We focused on eight questions. a) Does it make sense to think about discrete windows of vulnerability in the development of the nervous system? If it does, which time periods are of greatest importance? b) Are there cascades of developmental disorders in the nervous system? For example, are there critical points that determine the course of development that can lead to differences in vulnerabilities at later times? c) Can information on critical windows suggest the most susceptible subgroups of children (i.e., age groups, socioeconomic status, geographic areas, race, etc.)? d) What are the gaps in existing data for the nervous system or end points of exposure to it? e) What are the best ways to examine exposure-response relationships and estimate exposures in vulnerable life stages? f) What other exposures that affect development at certain ages may interact with exposures of concern? g) How well do laboratory animal data predict human response? h) How can all of this information be used to improve risk assessment and public health (risk management)? In addressing these questions, we provide a brief overview of brain development from conception through adolescence and emphasize vulnerability to toxic insult throughout this period. Methodological issues focus on major variables that influence exposure or its detection through disruptions of behavior, neuroanatomy, or neurochemical end points. Supportive evidence from studies of major neurotoxicants is provided.

Adolescent↗

PubMed2000

A community-level HIV prevention intervention for inner-city women: results of the women and infants demonstration projects.

OBJECTIVES: This study examined the effects of a multisite community-level HIV prevention intervention on women's condom-use behaviors. METHODS: The theory-based behavioral intervention was implemented with low-income, primarily African American women in 4 urban communities. It was evaluated with data from pre- and postintervention cross-sectional surveys in matched intervention and comparison communities. RESULTS: At baseline, 68% of the women had no intention of using condoms with their main partners and 70% were not using condoms consistently with other partners. After 2 years of intervention activities, increases in rates of talking with main partners about condoms were significantly larger in intervention communities than in comparison communities (P = .03). Intervention communities also had significant increases in the proportion of women who had tried to get their main partners to use condoms (P = .01). The trends for condom use with other partners were similar but nonsignificant. CONCLUSIONS: Many women at risk for HIV infection are still not using condoms. Community-level interventions may be an effective way to reach large numbers of women and change their condom-use behaviors, particularly their behaviors with regard to communication with main sex partners.

Adult↗

PubMed2000

Determinants of patient satisfaction and willingness to return with emergency care.

STUDY OBJECTIVE: To identify emergency department process of care measures that are significantly associated with satisfaction and willingness to return. METHODS: Patient satisfaction and willingness to return at 5 urban, teaching hospital EDs were assessed. Baseline questionnaire, chart review, and 10-day follow-up telephone interviews were performed, and 38 process of care measures and 30 patient characteristic were collected for each respondent. Overall satisfaction was modeled with ordinal logistic regression. Willingness to return was modeled with logistic regression. RESULTS: During a 1-month study period, 2,899 (84% of eligible) on-site questionnaires were completed. Telephone interviews were completed by 2,333 patients (80% of patients who completed a questionnaire). Patient-reported problems that were highly correlated with satisfaction included help not received when needed (odds ratio [OR] 0.345; 95% confidence interval [CI] 0.261 to 0.456), poor explanation of causes of problem (OR 0.434; 95% CI 0.345 to 0.546), not told about potential wait time (OR 0.479; 95% CI 0.399 to 0.577), not told when to resume normal activities (OR 0.691; 95% CI 0.531 to 0.901), poor explanation of test results (OR 0.647; 95% CI 0.495 to 0.845), and not told when to return to the ED (OR 0.656; 95% CI 0. 494 to 0.871). Other process of care measures correlated with satisfaction include nonacute triage status (OR 0.701, 95% CI 0.578 to 0.851) and number of treatments in the ED (OR 1.164 per treatment; 95% CI 1.073 to 1.263). Patient characteristics that significantly predicted less satisfaction included younger age and black race. Determinants of willingness to return include poor explanation of causes of problem (OR 0.328; 95% CI 0.217 to 0.495), unable to leave a message for family (OR 0.391; 95% CI 0.226 to 0. 677), not told about potential wait time (OR 0.561; 95% CI 0.381 to 0.825), poor explanation of test results (OR 0.541; 95% CI 0.347 to 0.846), and help not received when needed (OR 0.537; 95% CI 0.340 to 0.846). Patients with a chief complaint of hand laceration were less willing to return compared with a reference population of patients with abdominal pain. Willingness to return is strongly predicted by overall satisfaction (OR 2.601; 95% CI 2.292 to 2.951). CONCLUSION: These data identify specific process of care measures that are determinants of patient satisfaction and willingness to return. Efforts to increase patient satisfaction and willingness to return should focus on improving ED performance on these identified process measures.

Adolescent↗

PubMed2000

Proteasome inhibition measurements: clinical application.

BACKGROUND: PS-341, a selective inhibitor of the proteasome, currently is under evaluation as an anticancer agent in multiple phase I clinical trials. In animal-model studies, PS-341 was rapidly removed from the vascular compartment and distributed widely, quickly approaching the limits of detection. An accurate pharmacodynamic assay has been developed as an alternative or complement to pharmacokinetic measurements. METHODS: Fluorogenic kinetic assays for both the chymotryptic and tryptic activities of the proteasome have been optimized for both whole blood and blood cells. Using the ratio of these activities and the catalytic mechanism of the proteasome, we developed a novel method of calculating percentage of inhibition, using two structurally unrelated inhibitors (PS-341 and lactacystin). RESULTS: This ratio method was demonstrated to be sensitive (detection limit of 13% inhibition with 10 microgram of cell lysate), specific to the proteasome (PS-341 provides >98% inhibition), accurate (112% analyte recovery), and precise (0% +/- 5% inhibition at 0 nmol/L PS-341 and 74.5% +/- 1.7% inhibition at 200 nmol/L PS-341). Using these assays, we found that both erythrocytes and leukocytes contain proteasome at 3 micromol/L. Pharmacodynamic results for PS-341 obtained from the whole-blood ratio method were comparable to those using leukocytes determined by another method. CONCLUSIONS: The described assay provides a reliable method for studying the pharmacodynamics of proteasome inhibitors and is now in use in concurrent phase I clinical trials with PS-341.

Acetylcysteine↗

PubMed2000

Isometric progressive resistive exercise for osteoporosis.

OBJECTIVE: To assess the effect of site-specific resistive isometric exercises on muscle strengthening of 10 muscle groups over 2 months. A second study measured bone alkaline phosphatase (ALP) as a marker of bone formation and bone resorption [urine deoxypyridinoline (D-Pyr) crosslinks] in a similar cohort. METHODS: Twenty postmenopausal Caucasian women aged 56 to 69 yrs (mean 61) on a stable or no medication regimen for the previous 6 months participated in the initial exercise cohort. Twenty-one women ages 52-69 (mean 62) participated in the second cohort. All women had osteopenia (DXA T less than -1.0) or osteoporosis (DXA T less than -2.5). An inflatable ball with attached nonelastic straps provided progressive resistance. Exercises consisted of a 5 s maximum contraction against progressively increasing resistance of the ball or nonelastic straps. Muscle strengthening was measured by a hand held dynamometer at 0, 4, and 8 weeks. Twenty women completed 8 weeks of the initial study and 21 women completed the second study. RESULTS: Muscles showing increased strength in the first cohort were neck extensors (p < 0.04), hand grips (p < 0.02), elbow flexors (p < 0.05), quadriceps (p < 0.04), trunk extensors (p > 0.05, not significant = NS). Elbow extensors were purposely not exercised (as a control) and showed no significant strength increase. In the second cohort, increased muscle strength was measured in the neck extensors (p < 0.001), trunk extensors (p < 0.001), and left quadriceps (p < 0.024); and bone ALP increased (p < 0.05), with no change detected in bone resorption (urine D-Pyr). CONCLUSION: Brief progressively resisted isometric exercises for 10 min daily are an adequate stimulus for muscle strengthening of the neck, back, upper and lower extremities, and are capable of enhancing bone formation measured by bone ALP.

Alkaline Phosphatase↗

PubMed2000

Lack of multicellular drug resistance observed in human ovarian and prostate carcinoma treated with the proteasome inhibitor PS-341.

Almost all known conventional cytotoxic anticancer drugs are less effective in killing tumor cells grown as multicellular spheroids than in killing tumor cells grown as monolayer cell cultures. This "multicellular resistance" reflects the relative intrinsic drug-resistant phenotype of most solid tumors growing in vivo and is due to factors such as limited drug penetration or reduced fractions of proliferating cells. Proteasome inhibitors such as PS-341, a dipeptide boronic acid analogue, represent an interesting new class of potential anticancer drugs, which are entering early-phase clinical trials. PS-341 has been found to have good broad-spectrum cytotoxic activity in the 60-monolayer cell line National Cancer Institute screen. However, because its relative potency has not been tested in spheroid systems, we analyzed the activity of PS-341 in a spheroid/solid tumor context using four different human ovarian carcinoma cell lines and three prostate carcinoma cell lines, respectively. We found, with one exception, that PS-341 showed equal or greater activity in spheroids than in the respective monolayer cell cultures, even in a prostate cancer spheroid model with a very low growth fraction. PS-341 induced apoptotic cell death in carcinoma cells in both culture systems. We also noted a decrease in XIAP protein, a member of the inhibitor of apoptosis (IAP) family of apoptosis inhibitors, and phosphorylation of Bcl-XL in PS-341-treated ovarian carcinoma cells. Furthermore, DNA fragmentation, a hallmark of apoptosis (in this case, induced by PS-341), was completely inhibited by the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD). Taken together, the results indicate that unlike most other known anticancer cytotoxic drugs, PS-341 appears to be as effective in killing tumor cells grown in the form of multicell spheroids as in killing tumor cells grown in monolayer cell culture. Hence, this compound has the potential to circumvent multicellular drug resistance and, as such, may show promising activity against solid tumors with low growth fractions in vivo, which are frequently intrinsically resistant to conventional cytotoxic anticancer drugs.

Antineoplastic Agents↗