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1.
Anaesth Rep ; 12(1): e12287, 2024.
Article in English | MEDLINE | ID: mdl-38533388

ABSTRACT

We collected blank non-specialist anaesthetic records from 71 National Health Service Trusts in England. A data set was established by collating all data items found in an initial tranche of 28 records. All 71 records were subsequently analysed for each data item in this data set. We found significant variation: the most populated record included 216 data items and the least included 38 data items: a greater than five-fold variation. There was significant variation in the inclusion of data items commonly considered important to patient safety; 42% of records omitted documentation of fasting status, 72% omitted documentation of a discussion around the risk of accidental awareness during general anaesthesia, 92% omitted documentation of quantitative neuromuscular blockade monitoring and 63% omitted documentation for 'Stop Before You Block' when performing regional anaesthesia. The study highlights significant variability in the composition of anaesthetic records across England which may impact on its value as a data repository, an action trigger, a medicolegal account, and a tool to facilitate safe handover. Standardisation of the anaesthetic record or the establishment of standards of recording would help to allay potential risks to patient safety and assist in guiding future procurement of electronic solutions for anaesthetic records.

2.
J Public Health (Oxf) ; 42(3): e249-e258, 2020 08 18.
Article in English | MEDLINE | ID: mdl-31565741

ABSTRACT

BACKGROUND: Urban design can influence population levels of physical activity and subsequent health impacts. This qualitative study investigates local level decision-making for 'active living' infrastructure (ALI)-walking and cycling infrastructure and open spaces in new communities. METHODS: Thirty-five semi-structured interviews with stakeholders, and limited ethnographic observations, were conducted with local government and private sector stakeholders including urban and transport planners, public health practitioners, elected councillors and developers. Interview transcripts were coded and analysed thematically. RESULTS: Public health practitioners in local government could act as knowledge brokers and leaders to motivate non-health stakeholders such as urban and transport planners to consider health when designing and building new communities. They needed to engage at the earliest stages and be adequately resourced to build relationships across sectors, supporting non-health outcomes such as tackling congestion, which often had greater political traction. 'Evidence' for decision-making identified problems (going beyond health), informed solutions, and also justified decisions post hoc, although case study examples were not always convincing if not considered contextually relevant. CONCLUSION: We have developed a conceptual model with three factors needed to bridge the gap between evidence and ALI being built: influential public health practitioners; supportive policies in non-health sectors; and adequate resources.


Subject(s)
Local Government , Public Health , England , Private Sector , Qualitative Research
3.
Int J Behav Nutr Phys Act ; 14(1): 102, 2017 07 27.
Article in English | MEDLINE | ID: mdl-28750678

ABSTRACT

BACKGROUND: There is little evidence on how changing the physical environment changes health-related behaviours. We studied the effects of the new M74 motorway (freeway) - opened in 2011 - and the existing M8 motorway in Glasgow, Scotland, on physical activity and sedentary behaviour among local residents. METHODS: This natural experimental study used baseline (T1; 2005) and follow-up data (T2; 2013) from a longitudinal cohort (N = 365) and two cross-sectional samples (T1 N = 980; T2 N = 978). Adult participants were recruited from three study areas: one surrounding the new motorway, one surrounding the existing motorway, and a third, control, area without a motorway. The outcomes were self-reported time spent sitting, walking, and in moderate-to-vigorous physical activity (MVPA). Motorway exposure was defined in terms of (1) study area and (2) distance from home to the nearest motorway junction. Outcomes were regressed on exposures in two-part (walking and MVPA) or linear (sedentary behaviour) cohort and repeat cross-sectional models, adjusted for baseline behaviour and sociodemographic covariates. RESULTS: Cohort participants living in the M8 area were less likely to participate in MVPA at follow-up than those living in the area without a motorway (OR 0.37; 95%CI 0.15, 0.91). Within the M8 area, those living closer to the motorway were also less likely to do so (OR 0.30; 95%CI 0.09, 0.97). No other statistically significant results were found. CONCLUSIONS: We found some evidence of a negative association between exposure to an existing urban motorway and MVPA. However, the behavioural impacts of motorways are likely to be complex and evolve over time.


Subject(s)
Environment Design , Exercise , Sedentary Behavior , Adult , Aged , Cohort Studies , Cross-Sectional Studies , Female , Follow-Up Studies , Humans , Linear Models , Longitudinal Studies , Male , Middle Aged , Scotland , Self Report , Walking
4.
Diabet Med ; 31(11): 1439-45, 2014 Nov.
Article in English | MEDLINE | ID: mdl-24925259

ABSTRACT

AIMS: To determine self-awareness of diabetes-related foot problems and its associates in a community-based cohort of people with Type 2 diabetes. METHODS: A survey concerning diabetic foot problems was administered to 358 consecutive patients with Type 2 diabetes [mean ± SD age 67.4 ± 10.8 years, 56.1% males, median (interquartile range) diabetes duration 9.0 (3.9-16.8) years] attending for detailed clinical, biochemical and questionnaire assessment as part of the longitudinal observational Fremantle Diabetes Study Phase II. RESULTS: Compared with the 213 patients (59.5%) who considered their feet to be normal, the 145 (40.5%) who considered their feet to be abnormal were older, had longer diabetes duration and were more likely to have sensory neuropathic symptoms and self-reported poor circulation (P < 0.001). In those who considered their feet to be normal, 67.9% had peripheral sensory neuropathy (score >2/8 on the Michigan Neuropathy Screening Instrument clinical portion), 9.9% had an ankle-brachial index < 0.9, 6.1% had both peripheral sensory neuropathy and an ankle-brachial index < 0.90, and 86.9% had one or more features on inspection, such as deformity, dry skin, callus and fissures that could facilitate more serious complications, despite the majority having had at least one foot examination by a healthcare professional in the previous year. CONCLUSIONS: Self-assessment of diabetes-related foot problems by patients in the Fremantle Diabetes Study Phase II was unreliable. The present data suggest that self-perceived foot health should be assessed together with foot examination findings. Intensive education and monitoring may be necessary in those who consider their feet to be normal but who have neurovascular, structural and/or other precursors of serious foot pathology.


Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetic Foot/diagnosis , Diagnostic Self Evaluation , Aged , Ankle Brachial Index , Cohort Studies , Combined Modality Therapy , Cross-Sectional Studies , Diabetes Mellitus, Type 2/therapy , Diabetic Foot/epidemiology , Diabetic Foot/physiopathology , Female , Humans , Longitudinal Studies , Male , Middle Aged , Neuritis/complications , Neuritis/epidemiology , Neuritis/physiopathology , Peripheral Nervous System Diseases/complications , Peripheral Nervous System Diseases/epidemiology , Peripheral Nervous System Diseases/physiopathology , Prevalence , Risk , Severity of Illness Index , Surveys and Questionnaires , Western Australia/epidemiology
5.
Obes Rev ; 15(2): 117-33, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24102891

ABSTRACT

Family involvement in interventions to reduce sedentary time may help foster appropriate long-term screen-based habits in children. This review systematically synthesized evidence from randomized controlled trials of interventions with a family component that targeted reduction of sedentary time, including TV viewing, video games and computer use, in children. MEDLINE, PubMed, PsycInfo, CINAHL and Embase were searched from inception through March 2012. Seventeen articles were considered eligible and included in the review. Studies were judged to be at low-to-moderate risk of bias. Despite inconsistent study results, level of parental involvement, rather than the setting itself, appeared an important determinant of intervention success. Studies including a parental component of medium-to-high intensity were consistently associated with statistically significant changes in sedentary behaviours. Participant age was also identified as a determinant of intervention outcomes; all three studies conducted in pre-school children demonstrated significant decreases in sedentary time. Finally, TV exposure appeared to be related to changes in energy intake rather than physical activity. Future studies should assess the effects of greater parental involvement and child age on success of sedentary behaviour interventions. More research is required to better understand the relationship between screen time and health behaviours, particularly energy intake.


Subject(s)
Energy Intake , Energy Metabolism , Family Health , Obesity/prevention & control , Parents/psychology , Risk Reduction Behavior , Sedentary Behavior , Adolescent , Child , Child, Preschool , Computers , Female , Health Promotion , Humans , Leisure Activities , Male , Randomized Controlled Trials as Topic , Television , Time Factors
6.
J Evol Biol ; 26(6): 1294-306, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23530892

ABSTRACT

Heterochronic changes in the rate or timing of development underpin many evolutionary transformations. In particular, the onset and rate of bone development have been the focus of many studies across large clades. In contrast, the termination of bone growth, as estimated by suture closure, has been studied far less frequently, although a few recent studies have shown this to represent a variable, although poorly understood, aspect of developmental evolution. Here, we examine suture closure patterns across 25 species of carnivoran mammals, ranging from social-insectivores to hypercarnivores, to assess variation in suture closure across taxa, identify heterochronic shifts in a phylogenetic framework and elucidate the relationship between suture closure timing and ecology. Our results show that heterochronic shifts in suture closure are widespread across Carnivora, with several shifts identified for most major clades. Carnivorans differ from patterns identified for other mammalian clades in showing high variability of palatal suture closure, no correlation between size and level of suture closure, and little phylogenetic signal outside of musteloids. Results further suggest a strong influence of feeding ecology on suture closure pattern. Most of the species with high numbers of heterochronic shifts, such as the walrus and the aardwolf, feed on invertebrates, and these taxa also showed high frequency of closure of the mandibular symphysis, a state that is relatively rare among mammals. Overall, caniforms displayed more heterochronic shifts than feliforms, suggesting that evolutionary changes in suture closure may reflect the lower diversity of cranial morphology in feliforms.


Subject(s)
Carnivora/anatomy & histology , Cranial Sutures/anatomy & histology , Animals , Carnivora/classification , Phylogeny
7.
Obes Rev ; 13(8): 711-22, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22429291

ABSTRACT

UNLABELLED: Regular physical activity and limiting extended periods of sitting are two behaviours critical for the prevention of obesity in young people. The purpose of the systematic review was to synthesize the psychometric evidence for self-report use-of-time tools that assess these behaviours. Articles were retrieved that reported reliability and/or validity for use-of-time tools in participants aged 18 years or under. Outcome variables were physical activity, sedentary behaviour and energy expenditure. Study quality was appraised, and the results summarized narratively. Sixteen studies and six different tools were identified. The tools were the Previous Day Physical Activity Recall, the Three-Day Physical Activity Recall, the Physical Activity Interview, the Computerized Activity Recall, the Activitygram, and the Multimedia Activity Recall for Children and Adolescents. Overall, tools indicated moderate validity compared with objective and criterion comparison methods. Generally, validity correlation coefficients were in the range of 0.30-0.40. Correlation coefficients for test-retest reliability ranged widely from 0.24 to 0.98. CONCLUSION: Use-of-time tools have indicated moderate reliability and validity for the assessment of physical activity and energy expenditure. Future research should focus on using criterion methods and on validating specifically for sedentary behaviour outcomes. Implementation of these tools for population surveillance should be considered.


Subject(s)
Energy Metabolism/physiology , Exercise/physiology , Health Behavior , Sedentary Behavior , Adolescent , Child , Child Behavior , Health Status , Humans , Reproducibility of Results , Risk Reduction Behavior , Self Report
8.
Allergy ; 67(4): 574-6, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22309457

ABSTRACT

BACKGROUND: Double-blinded challenges are widely used for diagnosing food allergy but are time-consuming and cause severe reactions. Outcome relies on subjective interpretation of symptoms, which leads to variations in outcome between observers. Facial thermography combined with nasal peanut challenge was evaluated as a novel objective indicator of clinical allergy. METHODS: Sixteen children with positive blinded peanut challenge underwent nasal challenge with 10 µg peanut protein or placebo. Mean skin temperatures were recorded from the mouth and nose using infrared thermography over 18 min. RESULTS: The area under curve of nasal skin temperature was significantly elevated after peanut vs placebo (18.2 vs 4.8°Cmin). The maximum increase in temperature was also significantly greater after peanut: mean difference +0.9°C. CONCLUSION: This feasibility study shows thermography can detect inflammation caused by nasal challenges whilst employing one thousand-fold less peanut than an oral challenge. This novel technique could be developed to provide a rapid, safe and objective clinical allergy test.


Subject(s)
Nose , Peanut Hypersensitivity/diagnosis , Skin Temperature , Thermography/methods , Area Under Curve , Humans , ROC Curve
9.
Scand J Med Sci Sports ; 22(6): 816-21, 2012 Dec.
Article in English | MEDLINE | ID: mdl-21564307

ABSTRACT

Imagery can improve functional outcomes post-anterior cruciate ligament repair (ACLR). Research is needed to investigate potential mechanisms for this effect. The aim of this study was to (a) evaluate the effectiveness of an imagery intervention to improve functional outcomes post-ACLR, and (b) explore potential mechanisms. A randomized-controlled pilot trial was conducted. Participants were randomized to guided imagery and standard rehabilitation or standard rehabilitation alone (control). The primary outcome was knee strength 6-month post-operatively. Secondary outcomes were knee laxity at 6-months, and change in psychological (self-efficacy) and neurohormonal (adrenaline, noradrenaline, dopamine) variables. Participants (n=21; 62% male) were 34.86 (SD 8.84) years. Following the intervention, no statistical differences between groups for knee strength extension at 180°/s (t=-0.43, P=0.67), or at 60°/s (t=-0.72, P=0.48) were found. A statistically significant effect was found for knee laxity, F=4.67, P<0.05, mean difference of -3.02 (95% CI -4.44 to -1.60), favoring the intervention. No differences were found for self-efficacy; however, an overall effect was found for noradrenaline, F(1, 19) 19.65, P<0.001, η(2) =0.52, and dopamine, F(1, 19) 6.23, P=0.02, η(2) =0.29, favoring the intervention. This imagery intervention improved knee laxity and healing-related neurobiological factors.


Subject(s)
Anterior Cruciate Ligament Reconstruction/psychology , Anterior Cruciate Ligament Reconstruction/rehabilitation , Imagery, Psychotherapy , Joint Instability/physiopathology , Knee Joint/physiology , Adult , Analysis of Variance , Dopamine/blood , Epinephrine/blood , Female , Humans , Male , Middle Aged , Muscle Strength , Norepinephrine/blood , Pilot Projects , Recovery of Function , Self Efficacy , Single-Blind Method
10.
Scand J Med Sci Sports ; 22(5): 695-703, 2012 Oct.
Article in English | MEDLINE | ID: mdl-21496107

ABSTRACT

Previous observational studies examining imagery, self-efficacy, and adherence during injury rehabilitation have been cross-sectional and thus have not provided a clear representation of what occurs over the course of the rehabilitation period. The objectives of this research were (1) to examine the temporal patterns of imagery, self-efficacy, and rehabilitation adherence during an 8-week rehabilitation program and (2) to identify the time-order relationships between imagery, self-efficacy, and adherence. The design of the study was prospective and observational. 90 injured people (n=57 males; n=33 females) aged 18-78 years attending an injury rehabilitation clinic participated. The main outcome measures were imagery (cognitive, motivational, and healing), self-efficacy (task and coping), and rehabilitation adherence (duration, quality, and frequency). Results indicated that task efficacy, imagery use, and adherence levels remained stable, while coping efficacy declined over time. During the course of rehabilitation, moderate to strong reciprocal relationships existed between self-efficacy and adherence to rehabilitation. Weak to moderate relationships were found between imagery use and rehabilitation adherence. The results of this study can be used to inform the development of interventions steeped in self-efficacy and imagery aimed at improving rehabilitation adherence and treatment outcome.


Subject(s)
Athletic Injuries/psychology , Imagery, Psychotherapy/methods , Patient Compliance/psychology , Self Efficacy , Adolescent , Adult , Aged , Analysis of Variance , Athletic Injuries/rehabilitation , Female , Health Knowledge, Attitudes, Practice , Humans , Male , Middle Aged , Prospective Studies , Psychometrics , Surveys and Questionnaires , Time Factors , Young Adult
11.
Ir Med J ; 103(4): 113-6, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20486315

ABSTRACT

Newborn cystic fibrosis (CF) screening facilitates early diagnosis and nutritional intervention, which prevents malnourishment and improves growth in childhood. To provide baseline information on the natural history of CF in the Republic of Ireland, where newborn screening has not yet been introduced and CF incidence is high (1:1353 live births), we examined the effect of presentation mode, symptom type and gender on age at diagnosis. Median age at diagnosis was calculated by gender and for presentation mode/symptom type for 601 CF registry children diagnosed 1986-2007. Modes of presentation were each significantly associated with delayed presentation. An adjusted odds ratio of 4.5 (95% CI: 1.8, 11.1) was determined for presentation with family history, 43.1 for gastrointestinal symptoms presentation (95% CI: 18.3, 101.4), 96.9 for both respiratory and gastrointestinal symptoms (95% CI: 38.6, 243,4), and 115.4 for respiratory symptoms (95% CI: 45.2, 294.7). Children with respiratory symptoms had the greatest likelihood of delayed diagnosis (median age: 20.4 months), followed by those with respiratory and gastrointestinal symptoms (9.2 months). Gender was not significantly associated with a delayed presentation when presentation mode was taken into account.


Subject(s)
Cystic Fibrosis/diagnosis , Neonatal Screening/statistics & numerical data , Adolescent , Adult , Female , Humans , Infant, Newborn , Logistic Models , Male , Middle Aged , Odds Ratio , Time Factors , Young Adult
12.
Ir Med J ; 100(8): 557-60, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17955689

ABSTRACT

There were four objectives in this study: (1) determine the incidence of cystic fibrosis (CF) in Ireland; (2) estimate the cost of diagnosing CF; (3) clarify the characteristics and outcomes of the nationwide diagnostic efforts and (4) identify disparities. Surveys were conducted to determine the number, methods, costs and outcomes for sweat tests in Ireland from 2001 through 2003. The results allowed us to determine that Ireland's CF incidence is the world's highest at 1:1353. The average cost for diagnosis was Euro 2663 per patient. Analyses of data in The Cystic Fibrosis Registry of Ireland revealed longer delays when diagnosis followed respiratory symptoms, rather than gastrointestinal signs, and also in girls compared to boys, particularly those presenting with respiratory symptoms. Although expenditures for diagnosing of CF in Ireland are relatively modest, the high incidence and age of diagnosis, as well as gender-related disparities, are sufficient to warrant investment in national newborn screening.


Subject(s)
Cystic Fibrosis/diagnosis , Diagnostic Services/economics , Adult , Child, Preschool , Cystic Fibrosis/economics , Cystic Fibrosis/epidemiology , Female , Health Care Costs , Health Surveys , Humans , Incidence , Infant , Ireland/epidemiology , Male , Risk Assessment/economics , Sex Factors , Surveys and Questionnaires
13.
Pediatr Radiol ; 32(7): 465-75, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12107579

ABSTRACT

BACKGROUND: Scoliosis surgery has undergone a dramatic evolution over the past 20 years with the advent of new surgical techniques and sophisticated instrumentation. Surgeons have realized scoliosis is a complex multiplanar deformity that requires thorough knowledge of spinal anatomy and pathophysiology in order to manage patients afflicted by it. Nonoperative modalities such as bracing and casting still play roles in the treatment of scoliosis; however, it is the operative treatment that has revolutionized the treatment of this deformity that affects millions worldwide. As part of the evolution of scoliosis surgery, newer implants have resulted in improved outcomes with respect to deformity correction, reliability of fixation, and paucity of complications. Each technique and implant has its own set of unique complications, and the surgeon must appreciate these when planning surgery. MATERIALS AND METHODS: Various surgical techniques and types of instrumentation typically used in scoliosis surgery are briefly discussed. Though scoliosis surgery is associated with a wide variety of complications, only those that directly involve the hardware are discussed. The current literature is reviewed and several illustrative cases of patients treated for scoliosis at the Connecticut Children's Medical Center and the Newington Children's Hospital in Connecticut are briefly presented. CONCLUSION: Spine surgeons and radiologists should be familiar with the different types of instrumentation in the treatment of scoliosis. Furthermore, they should recognize the clinical and roentgenographic signs of hardware failure as part of prompt and effective treatment of such complications.


Subject(s)
General Surgery/instrumentation , Scoliosis/surgery , Adolescent , Adult , Bone Nails/adverse effects , Bone Screws/adverse effects , Bone Wires/adverse effects , Child , Equipment Failure/statistics & numerical data , Female , Humans , Male , Musculoskeletal System/diagnostic imaging , Musculoskeletal System/surgery , Orthopedics/methods , Orthopedics/standards , Radiography , Scoliosis/diagnostic imaging
14.
J Cataract Refract Surg ; 27(7): 1124-5, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11489587

ABSTRACT

Although there have been many proposed etiologies for interface inflammation after laser in situ keratomileusis, the causative factor(s) remains an enigma. This case of late-onset interface inflammation suggests that the many previously suspected interface contaminants from the surgical environment were not involved. Transformation of a previously inert material to an inflammatory stimulus is proposed as a potential cause; however, a sample of inflammatory focus was not obtained because of the immediate and complete response to frequent topical steroid drops.


Subject(s)
Keratitis/etiology , Keratomileusis, Laser In Situ/adverse effects , Adult , Female , Humans , Visual Acuity
15.
Biochim Biophys Acta ; 1526(3): 230-6, 2001 Jun 15.
Article in English | MEDLINE | ID: mdl-11410331

ABSTRACT

Histology on a core or open biopsy is considered the gold standard for the diagnosis of tumours. While the non-invasive technique of magnetic resonance imaging can direct some of the decision diagnostic making, it has limitations and disadvantages, that can be partly overcome with the use of in vivo magnetic resonance spectroscopy (MRS). In vivo MRS is able to provide a specific biochemical profile on tumour tissue, compared with normal tissue. The capability of this technique is demonstrated here by the long-term development of hepatocellular carcinoma in an animal model. It allows the observation of the biochemical changes that occur in tumour tissue during its progression from preneoplastic nodules to hepatocellular carcinoma. Specifically the changes in the lipid profiles of tumour tissue at various stages of development are observed with proton ((1)H) MRS. Significant increases occurred in the lipid acyl chain methylene and methyl hydrogens during the early developmental stages of hepatocarcinogenesis, whereas during later stages associated with tumour development there was a significant increase in the levels of olefinic acyl chain hydrogens from unsaturated lipids. It is anticipated that this model will precede the application of the same technology to the non-invasive diagnosis and grading of human hepatocellular carcinoma.


Subject(s)
Liver Neoplasms/diagnosis , Precancerous Conditions/diagnosis , Animals , Disease Models, Animal , Hydrogen , Lipids/analysis , Liver/chemistry , Liver/pathology , Liver Neoplasms/chemically induced , Liver Neoplasms/pathology , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Male , Precancerous Conditions/chemically induced , Precancerous Conditions/pathology , Rats , Rats, Inbred F344 , Time Factors
16.
Bioorg Med Chem Lett ; 11(8): 969-72, 2001 Apr 23.
Article in English | MEDLINE | ID: mdl-11327602

ABSTRACT

The 5,5-disubstitutedpyrimidine-2,4,6-triones represent a new class of MMP inhibitors showing selectivity for the gelatinases A and B, collagenase-3, and human neutrophil collagenase. The SAR presented here is in good agreement with an X-ray structure of compound 5 bound to the catalytic domain of stromelysin-1. While of the barbiturate structural class, compound 5 did not show any toxic or sedative effects.


Subject(s)
Matrix Metalloproteinase Inhibitors , Pyrimidinones/pharmacology , Animals , Collagenases/metabolism , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Matrix Metalloproteinase 13 , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 3/metabolism , Matrix Metalloproteinase 8/metabolism , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinases/metabolism , Mice , Pyrimidinones/chemical synthesis , Structure-Activity Relationship
17.
Protein Sci ; 10(5): 923-6, 2001 May.
Article in English | MEDLINE | ID: mdl-11316871

ABSTRACT

A new class of matrix metalloproteinase (MMP) inhibitors has been identified by screening a collection of compounds against stromelysin. The inhibitors, 2,4,6-pyrimidine triones, have proven to be potent inhibitors of gelatinases A and B. An X-ray crystal structure of one representative compound bound to the catalytic domain of stromelysin shows that the compounds bind at the active site and ligand the active-site zinc. The pyrimidine triones mimic substrates in forming hydrogen bonds to key residues in the active site, and provide opportunities for placing appropriately chosen groups into the S1' specificity pocket of MMPS: A number of compounds have been synthesized and assayed against stromelysin, and the variations in potency are explained in terms of the binding mode revealed in the X-ray crystal structure.


Subject(s)
Matrix Metalloproteinase 3/chemistry , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Binding Sites , Crystallography, X-Ray , Hydrogen Bonding , Inhibitory Concentration 50 , Matrix Metalloproteinase 3/metabolism , Models, Molecular , Protease Inhibitors/chemical synthesis , Protease Inhibitors/metabolism , Protein Conformation , Structure-Activity Relationship , Zinc/metabolism
18.
Anticancer Drug Des ; 16(1): 7-17, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11762646

ABSTRACT

A cell-based in vitro screening approach for identification of antitumor drug leads that exploits the differential sensitivity between normal and cancer cells was developed. It is a three-step, high-throughput screen for antiproliferative and/or cytotoxic activity measured by a 7 day MTT [3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromidel assay using small panels of proliferating primary human cells and established cancer cell lines. Proof-of-concept experiments successfully identified 11 known cancer drugs randomly mixed with 5000 test compounds. Application of this screening approach to a library of 110000 compounds allowed for the identification of several novel chemical classes of compounds active against an expanded panel of cancer cell lines in vitro. Two of the compounds representing novel mitotic inhibitors with in vivo potency against established breast cancer xenografts (MDA-MB-435) are reported here.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , Drug Screening Assays, Antitumor/methods , Neoplasms/pathology , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Female , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Metaphase/drug effects , Phosphorylation , Proto-Oncogene Proteins c-bcl-2/metabolism , Tubulin/biosynthesis , Tumor Cells, Cultured
19.
Crit Care Clin ; 16(3): 429-44, vi, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10941582

ABSTRACT

In this article, a number of alternatives to direct laryngoscopy are examined. These alternatives include the laryngeal mask airway (LMA; LMA North America, San Diego, CA), cuffed oropharyngeal airway (COPA; Mallinckrodt, St. Louis, MO), and Combitube (Kendall-Sheridan, Mansfield, MA), that have been designed to act as bridges to establish an airway. Other devices, such as rigid stylets, the lightwand (a blind technique) and indirect fiberoptic rigid stylets, such as the Bullard scope, Upsher scope, and Wu scope are also briefly discussed.


Subject(s)
Airway Obstruction/therapy , Intubation, Intratracheal/instrumentation , Intubation, Intratracheal/methods , Laryngoscopes/supply & distribution , Resuscitation/instrumentation , Resuscitation/methods , Equipment Design , Humans , Laryngeal Masks
20.
J Biol Chem ; 275(33): 25751-9, 2000 Aug 18.
Article in English | MEDLINE | ID: mdl-10835422

ABSTRACT

Rho family GTPases play roles in cytoskeletal organization and cellular transformation. Tiam1 is a member of the Dbl family of guanine nucleotide exchange factors that activate Rho family GTPases. These exchange factors have in common a catalytic Dbl homology and adjacent pleckstrin homology domain. Previous structural studies suggest that the pleckstrin domain, a putative phosphoinositide-binding site, may serve a regulatory function. We identified ascorbyl stearate as a compound that binds to the pleckstrin domain of p120 Ras GTPase-activating protein. Furthermore, ascorbyl stearate appears to be a general pleckstrin domain ligand, perhaps by mimicking an endogenous amphiphilic ligand. Tiam1 nucleotide exchange activity was greatly stimulated by ascorbyl stearate. Certain phosphoinositides also stimulated Tiam1 activity but were less potent than ascorbyl stearate. Tiam1 contains an additional N-terminal pleckstrin domain, but only the C-terminal pleckstrin domain was required for activation. Our results suggest that the pleckstrin domains of Dbl-type proteins may not only be involved in subcellular localization but may also directly regulate the nucleotide exchange activity of an associated Dbl homology domain. In addition, this paper introduces ascorbyl stearate as a pleckstrin domain ligand that can modulate the activity of certain pleckstrin domain-containing proteins.


Subject(s)
Blood Proteins/metabolism , Guanine Nucleotide Exchange Factors/metabolism , Phosphoproteins/metabolism , Proteins/metabolism , Animals , Aorta/metabolism , Ascorbic Acid/analogs & derivatives , Ascorbic Acid/pharmacology , Baculoviridae/metabolism , Blood Proteins/chemistry , Cells, Cultured , Cloning, Molecular , DNA, Complementary/metabolism , Dose-Response Relationship, Drug , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Glutathione Transferase/metabolism , Guanine Nucleotide Exchange Factors/chemistry , Guanosine Triphosphate/metabolism , Humans , Inositol Phosphates/metabolism , Ligands , Models, Chemical , Mutagenesis , Nucleotides/metabolism , Peptides/metabolism , Phosphatidylinositol 4,5-Diphosphate/metabolism , Phosphoproteins/chemistry , Protein Binding , Protein Structure, Tertiary , Proteins/chemistry , Recombinant Fusion Proteins/metabolism , Swine , T-Lymphoma Invasion and Metastasis-inducing Protein 1 , Time Factors , ras Proteins/metabolism
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