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1.
Hernia ; 2024 Jan 22.
Article in English | MEDLINE | ID: mdl-38252397

ABSTRACT

BACKGROUND: Prophylactic mesh augmentation in emergency laparotomy closure is controversial. We aimed to perform a meta-analysis of randomized controlled trials (RCT) evaluating the placement of prophylactic mesh during emergency laparotomy. METHODS: We performed a systematic review of Cochrane, Scopus, and PubMed databases to identify RCT comparing prophylactic mesh augmentation and no mesh augmentation in patients undergoing emergency laparotomy. We excluded observational studies, conference abstracts, elective surgeries, overlapping populations, and trial protocols. Postoperative outcomes were assessed by pooled analysis and meta-analysis. Statistical analysis was performed using RevMan 5.4. Heterogeneity was assessed with I2 statistics. Risk of bias was assessed using the revised Cochrane risk-of-bias tool (RoB 2). The review protocol was registered at PROSPERO (CRD42023412934). RESULTS: We screened 1312 studies and 33 were thoroughly reviewed. Four studies comprising 464 patients were included in the analysis. Mesh reinforcement was significantly associated with a decrease in incisional hernia incidence (OR 0.18; 95% CI 0.07-0.44; p < 0.001; I2 = 0%), and synthetic mesh placement reduced fascial dehiscence (OR 0.07; 95% CI 0.01-0.53; p = 0.01; I2 = 0%). Mesh augmentation was associated with an increase in operative time (MD 32.09 min; 95% CI 6.39-57.78; p = 0.01; I2 = 49%) and seroma (OR 3.89; 95% CI 1.54-9.84; p = 0.004; I2 = 0%), but there was no difference in surgical-site infection or surgical-site occurrences requiring procedural intervention or reoperation. CONCLUSIONS: Mesh augmentation in emergency laparotomy decreases incisional hernia and fascial dehiscence incidence. Despite the risk of seroma, prophylactic mesh augmentation appears to be safe and might be considered for emergency laparotomy closure. Further studies evaluating long-term outcomes are still needed.

2.
Clin Lung Cancer ; 24(8): 689-695.e1, 2023 12.
Article in English | MEDLINE | ID: mdl-37880074

ABSTRACT

BACKGROUND: Lurbinectedin has emerged as a potential treatment option for relapsed small cell lung cancer (SCLC). While clinical trials have demonstrated its efficacy and safety, real-world data are limited. This study aimed to evaluate the safety and efficacy of lurbinectedin in a real-world setting, focusing on its use as a second-line agent and beyond in SCLC patients. METHODS: A retrospective analysis was conducted on 90 patients who received lurbinectedin between June 2020 and June 2022 within the Mayo Clinic Health System. Of these, 50 patients received lurbinectedin as a second-line agent, and 14 patients received it as a third-line or later agent. The primary outcomes assessed were overall survival (OS), progression-free survival (PFS), and treatment-related adverse events. RESULTS: Lurbinectedin was generally well tolerated in this real-world cohort, with a median OS of 5.1 months in the second-line cohort and 5.6 months in the third-line or later cohort. Median PFS was 2.1 months in the second-line cohort and 3.4 months in the third-line or later cohort. Adverse events were manageable, with the most common being neutropenia, anemia, fatigue, and febrile neutropenia. No treatment-related deaths or grade 5 toxicities were reported. CONCLUSION: This real-world study provides valuable insights into the safety and efficacy of lurbinectedin in relapsed SCLC. Lurbinectedin demonstrated modest efficacy and a comparable safety profile to that observed in clinical trials. However, outcomes for relapsed SCLC remain suboptimal, particularly for patients with a shorter chemotherapy-free interval and central nervous system metastases.


Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Small Cell Lung Carcinoma/pathology , Lung Neoplasms/pathology , Retrospective Studies , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology
3.
J Inherit Metab Dis ; 32(5): 640, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19685155

ABSTRACT

Canavan disease (CD) is a fatal dysmyelinating genetic disorder associated with aspartoacylase deficiency, resulting in decreased brain acetate levels and reduced myelin lipid synthesis in the developing brain. Here we tested tolerability of a potent acetate precursor, glyceryl triacetate (GTA), at low doses in two infants diagnosed with CD, aged 8 and 13 months. Much higher doses of GTA were evaluated for toxicity in the tremor rat model of CD. GTA was given orally to the infants for up to 4.5 and 6 months, starting at 25 mg/kg twice daily, doubling the dose weekly until a maximum of 250 mg/kg reached. Wild-type and tremor rat pups were given GTA orally twice daily, initially at a dose of 4.2 g/kg from postnatal days 7 through 14, and at 5.8 g/kg from day 15 through 23, and thereafter in food (7.5%) and water (5%). At the end of the trial (approximately 90 to 120 days) sera and tissues from rats were analysed for changes in blood chemistry and histopathology. GTA treatment caused no detectable toxicity and the patients showed no deterioration in clinical status. In the high-dose animal studies, no significant differences in the mean blood chemistry values occurred between treated and untreated groups, and no lesions indicating toxicity were detectable in any of the tissues examined. Lack of GTA toxicity in two CD patients in low-dose trials, as well as in high-dose animal studies, suggests that higher, effective dose studies in human CD patients are warranted.


Subject(s)
Canavan Disease/drug therapy , Rats , Tremor/drug therapy , Triacetin/administration & dosage , Triacetin/adverse effects , Acetates/administration & dosage , Acetates/adverse effects , Acetates/chemistry , Administration, Oral , Animals , Animals, Newborn , Dietary Supplements , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Female , Humans , Infant , Male , Rats, Inbred WKY , Tremor/pathology , Triglycerides/chemistry
4.
Disabil Rehabil ; 31(10): 783-90, 2009.
Article in English | MEDLINE | ID: mdl-19034721

ABSTRACT

PURPOSE: To investigate whether socioeconomic status in patients with back pain participating in a randomised controlled trial was predictive of functional disability (Roland Disability Questionnaire, RDQ). METHOD: Secondary analysis of data (n = 949) from a national primary care trial of physical treatments for back pain (UKBEAM trial) using multilevel modelling. The three indicators were Townsend scores, educational levels and work status. RESULTS: All indicators were significant predictors of outcome after adjusting for baseline variables. As Townsend scores increased (indicating greater deprivation) RDQ scores (functional disability related to back pain) increased. Lower levels of educational attainment were associated with higher RDQ scores. Those 'Not in Work' reported markedly higher levels of RDQ scores which increased over time. There was no evidence that one particular treatment was more suitable for participants of different socioeconomic status. CONCLUSIONS: The findings from this study add to the body of literature which suggests the importance of socioeconomic factors as an influence on health, including resultant disability related to chronic musculoskeletal conditions such as back pain. Work status was particularly dominant in our findings and may suggest that helping patients with back pain back to work where appropriate, is an especially important part of the management process.


Subject(s)
Back Pain/rehabilitation , Disability Evaluation , Social Class , Educational Status , Employment , Humans , Linear Models , Pain Measurement , Predictive Value of Tests , Randomized Controlled Trials as Topic
5.
Minerva Pediatr ; 60(1): 87-101, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18277368

ABSTRACT

There is little information on the treatment of comorbid bipolar disorder and pervasive developmental disorder (PDD) in youth. This paper will provide a review of the literature on appropriate psychopharmacological treatment strategies for bipolar disorder and PDD in children and adolescents and make recommendations for psychopharmacological treatment and monitoring of the comorbid presentation of these two disorders. The purpose of this paper is to provide clinicians with evidence-based research findings of treatment strategies used by the experts in the field of pediatric bipolar disorder and PDD. Sources for the study have been published reviews and research articles. Studies addressing the complex treatment issues of comorbid pediatric bipolar disorder and PDD are limited. Research studies have demonstrated improvement in psychiatric functioning of children and adolescents with bipolar disorder and PDDs who took atypical antipsychotics and mood stabilizers. Children with bipolar disorder have benefited the most from the combination of a mood stabilizer plus an antipsychotic. However, there are no studies looking at combined medication treatments for PDD. Children who manifest both disorders could possibly benefit from this combination. While selective serotonin reuptake and tricyclic antidepressants inhibitors have demonstrated improvement in PDD symptoms, they should be used with caution in children who have comorbid bipolar symptoms as they can cause agitation, mania or, in a limited number of cases, serotonin reuptake inhibitors have increased suicidal behavior. More extensive, long-term research is needed to find better treatments to improve quality of life and outcomes in this difficulty to treat population.


Subject(s)
Anticonvulsants/therapeutic use , Antidepressive Agents/therapeutic use , Antimanic Agents/therapeutic use , Antipsychotic Agents/therapeutic use , Bipolar Disorder/drug therapy , Adolescent , Anticonvulsants/pharmacology , Antidepressive Agents/pharmacology , Antimanic Agents/pharmacology , Antipsychotic Agents/pharmacology , Child , Child Development Disorders, Pervasive/drug therapy , Comorbidity , Drug Interactions , Drug Monitoring , Drug Therapy, Combination , Evidence-Based Medicine , Humans , Treatment Outcome
6.
Minerva Pediatr ; 60(1): 115-27, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18277370

ABSTRACT

Little is known about the overlapping symptoms and comorbidity of pediatric bipolar disorder (BD) and pervasive developmental disorders (PDD) in youth. The aim of this study was to clearly differentiate the symptoms, understand the prevalence and patterns of comorbid presentations, as well as to provide a summary of evidence-based research findings to improve timely diagnosis and treatment for comorbid PDD and BD in children and adolescents, and to provide clinicians with evidence-based research findings of the similarity and differences in symptom presentation, the epidemiology, and diagnostic strategies used by experts in the fields of PDD and pediatric BD. The sources for this study were published review and research articles. According to the results obtained, it can be observed that studies evaluating the epidemiology, symptom presentation and diagnosis of comorbid BD and PDD are limited. However, research studies identified a clear overlap in symptoms between the two disorders and the existence of comorbid PDD and BD. Children with PDD and comorbid BD may be significantly impaired. More extensive research is needed to facilitate timely diagnosis and treatment to improve quality of life and outcomes in this population.


Subject(s)
Bipolar Disorder/diagnosis , Child Development Disorders, Pervasive/diagnosis , Adolescent , Bipolar Disorder/epidemiology , Bipolar Disorder/therapy , Child , Child Development Disorders, Pervasive/epidemiology , Child Development Disorders, Pervasive/therapy , Comorbidity , Diagnosis, Differential , Evidence-Based Medicine , Humans , Italy/epidemiology , Prevalence , Psychiatric Status Rating Scales
7.
Rheumatology (Oxford) ; 46(9): 1495-501, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17711873

ABSTRACT

OBJECTIVES: To assess the cost-effectiveness of a brief physiotherapy pain management approach using cognitive-behavioural principles (Solution-Finding Approach) when compared with a commonly used traditional method of physical therapy (McKenzie Approach). METHODS: Economic evaluation conducted alongside a randomized trial. The study related incremental differences in costs and benefits associated with the Solution Finding and McKenzie approaches over 12 months. Costs were measured in UK pounds sterling. Benefit was measured as health-related quality of life using the EQ-5D, which was used to estimate patient-specific quality adjusted life years (QALYs). RESULTS: The McKenzie treatment required, on average, one extra physiotherapist visit (4.15 vs 3.10). Over a 12-month period, Solution Finding was associated with a lower per patient cost of pound-24.4 (95% CI pound-49.6 to 0.789 pounds). The mean difference in QALYs between the two groups was -0.020 (95% CI -0.057 to 0.017); favouring those receiving McKenzie. Relating incremental mean costs and QALYs gave an incremental cost effectiveness ratio of 1220 pounds (-24.4/-0.020) suggesting the McKenzie treatment is cost effective. CONCLUSIONS: Results suggest that the additional cost associated with the McKenzie treatment when compared with the Solution Finding Approach may be worth paying, given the additional benefit the approach seems more likely to provide. Further research is needed to assess the extent to which the difference in physiotherapy visits between the two strategies is generalizable to other treatment settings.


Subject(s)
Back Pain/therapy , Cognitive Behavioral Therapy/methods , Neck Pain/therapy , Physical Therapy Modalities/economics , Adult , Aged , Back Pain/economics , Back Pain/rehabilitation , Cognitive Behavioral Therapy/economics , Cost-Benefit Analysis , England , Health Care Costs/statistics & numerical data , Health Resources/statistics & numerical data , Humans , Middle Aged , Neck Pain/economics , Neck Pain/rehabilitation , Psychotherapy, Brief/economics , Psychotherapy, Brief/methods , Quality of Life , Quality-Adjusted Life Years , Severity of Illness Index , State Medicine/economics , Treatment Outcome
8.
Rheumatology (Oxford) ; 45(12): 1514-21, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17062645

ABSTRACT

OBJECTIVES: Interventions that take psychosocial factors into account are recommended for patients with persistent back or neck pain. We compared the effectiveness of a brief physiotherapy pain management approach using cognitive-behavioural principles (Solution-Finding Approach-SFA) with a commonly used method of physical therapy (McKenzie Approach-McK). METHODS: Eligible patients referred by GPs to physiotherapy departments with neck or back pain lasting at least 2 weeks were randomized to McK (n= 161) or to SFA (n= 154). They were further randomized to receive an educational booklet or not. The primary outcome was the Tampa Scale of Kinesiophobia (TSK) (Activity-Avoidance scale used as a proxy for coping) at 6 weeks, and 6 and 12 months. RESULTS: Of 649 patients assessed for eligibility, 315 were recruited (219 with back pain, 96 with neck pain). There were no statistically significant differences in outcomes between the groups, except that at any time point SFA patients supported by a booklet reported less reliance on health professionals (Multidimensional Health Locus of Control Powerful Others Scale), while at 6 months McK patients showed slightly more improvement on activity-avoidance (TSK). At 6 weeks, patient satisfaction was greater for McK (median 90% compared with 70% for SFA). Both interventions resulted in modest but clinically important improvements over time on the Roland Disability Questionnaire Scores and Northwick Park Neck Pain Scores. CONCLUSIONS: The McK approach resulted in higher patient satisfaction overall but the SFA could be more cost-effective, as fewer (three vs four) sessions were needed.


Subject(s)
Back Pain/rehabilitation , Neck Pain/rehabilitation , Physical Therapy Modalities , Primary Health Care/methods , Adaptation, Psychological , Adolescent , Adult , Aged , Aged, 80 and over , Back Pain/psychology , Cognitive Behavioral Therapy/methods , Female , Humans , Male , Middle Aged , Neck Pain/psychology , Pamphlets , Patient Education as Topic/methods , Patient Satisfaction
10.
Nature ; 439(7072): 68-71, 2006 Jan 05.
Article in English | MEDLINE | ID: mdl-16397497

ABSTRACT

The factors that control the growth and nitrogen fixation rates of marine diazotrophs such as Trichodesmium have been intensively studied because of the role that these processes have in the global cycling of carbon and nitrogen, and in the sequestration of carbon to the deep sea. Because the phosphate concentrations of many ocean gyres are low, the bioavailability of the larger, chemically heterogeneous pool of dissolved organic phosphorus could markedly influence Trichodesmium physiology. Here we describe the induction, by phosphorus stress, of genes from the Trichodesmium erythraeum IMS101 genome that are predicted to encode proteins associated with the high-affinity transport and hydrolysis of phosphonate compounds by a carbon-phosphorus lyase pathway. We show the importance of these genes through expression analyses with T. erythraeum from the Sargasso Sea. Phosphonates are known to be present in oligotrophic marine systems, but have not previously been considered to be bioavailable to marine diazotrophs. The apparent absence of genes encoding a carbon-phosphorus lyase pathway in the other marine cyanobacterial genomes suggests that, relative to other phytoplankton, Trichodesmium is uniquely adapted for scavenging phosphorus from organic sources. This adaptation may help to explain the prevalence of Trichodesmium in low phosphate, oligotrophic systems.


Subject(s)
Cyanobacteria/metabolism , Organophosphonates/metabolism , Seawater/microbiology , Biological Availability , Cyanobacteria/enzymology , Cyanobacteria/genetics , Gene Expression Regulation, Bacterial , Genes, Bacterial/genetics , Hydrolysis , Lyases/genetics , Lyases/metabolism , Marine Biology , Molecular Sequence Data , Multigene Family/genetics , Oceans and Seas , Phosphorus/metabolism , Phylogeny , Seawater/chemistry
11.
Rheumatology (Oxford) ; 45(6): 751-6, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16418201

ABSTRACT

OBJECTIVES: To explore the views of participants in a randomized controlled trial of physical treatments for low back pain about the treatment packages they received in the trial. METHODS: Within a randomized controlled trial that found small to moderate benefits from adding a manipulation package or an exercise programme to general practice care, we elicited participants' views on the treatment using an open question in participant questionnaires. These data were analysed using an adapted framework approach. RESULTS: We received a total of 1259 comments from 1334 participants. Participants randomized to usual general practice care reported dissatisfaction with receiving only 'usual care', which consisted of providing analgesic medication without providing an explanation for their pain. Those randomized to a manipulation package felt the intervention was appropriate to their needs and commonly reported striking benefits. Participants assigned to the exercise programme developed a sense of self-reliance in managing back pain, although some failed to be sufficiently motivated to continue their exercise regimen outside the classes. CONCLUSIONS: This qualitative analysis has found much clearer differences between the groups than the main quantitative analysis. This suggests that some of the added value from being allocated to additional physical treatment for low back pain is not being captured by existing methods of measurement. Improved methods of assessment that consider a wider range of domains may be needed when interpreting the added value of such treatments to individual patients.


Subject(s)
Low Back Pain/rehabilitation , Patient Satisfaction , Physical Therapy Modalities/psychology , Adolescent , Adult , Analgesics/therapeutic use , Combined Modality Therapy , Exercise Therapy , Family Practice/standards , Follow-Up Studies , Humans , Low Back Pain/drug therapy , Low Back Pain/psychology , Middle Aged , Musculoskeletal Manipulations/psychology , Treatment Outcome
12.
Rheumatology (Oxford) ; 45(4): 371-8, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16332949

ABSTRACT

This paper provides an overview of best practice for the role of physiotherapy in managing back pain and neck pain, based mainly on evidence-based guidelines and systematic reviews. More up-to-date relevant primary research is also highlighted. A stepped approach is recommended in which the physiotherapist initially takes a history and carries out a physical examination to exclude any potentially serious pathology and identify any particular functional deficits. Initially, advice providing simple messages of explanation and reassurance will form the basis of a patient education package. Self-management is emphasized throughout. A return to normal activities is encouraged. For the patient who is not recovering after a few weeks, a short course of physiotherapy may be offered. This should be based on an active management approach, such as exercise therapy. Manual therapy should also be considered. Any passive treatment should only be used if required to relieve pain and assist in helping patients get moving. Barriers to recovery need to be explored. Those few patients who have persistent pain and disability that interferes with their daily lives and work need more intensive treatment or a different approach. A multidisciplinary approach may then be optimal, although it is not widely available. Liaison with the workplace and/or social services may be important. Getting all players on side is crucial, especially at this stage.


Subject(s)
Back Pain/therapy , Neck Pain/therapy , Physical Therapy Modalities , Back Pain/psychology , Chronic Disease , Cognitive Behavioral Therapy/methods , Exercise Therapy/methods , Humans , Manipulation, Spinal/methods , Neck Pain/psychology , Patient Compliance , Patient Education as Topic/methods , Triage/methods
13.
Cell Mol Life Sci ; 60(10): 2266-71, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14618272

ABSTRACT

The objective of the present study was to determine levels of DNA fragmentation in blood leukocytes from guinea pigs by single-cell gel electrophoresis (comet assay) after exposure to the chemical warfare nerve agent (CWNA), soman, at doses ranging from 0.1 LD50 to 0.4 LD50, once per day for either 5 or 10 days. Post-exposure recovery periods ranged from 0 to 17 days. Leukocytes were imaged from each animal, and the images analyzed by computer. Data obtained for exposure to soman demonstrated significant increases in DNA fragmentation in circulating leukocytes in CWNA-treated guinea pigs compared with saline-injected control animals at all doses and time points examined. Notably, significantly increased DNA fragmentation was observed in leukocytes 17 days after cessation of soman exposure. Our findings demonstrate that leukocyte DNA fragmentation assays may provide a sensitive biomarker for low-dose CWNA exposure.


Subject(s)
Chemical Warfare Agents/pharmacology , DNA Fragmentation/drug effects , Leukocytes/drug effects , Soman/pharmacology , Animals , Apoptosis/drug effects , Biomarkers , Comet Assay , Guinea Pigs , Male
14.
Exp Brain Res ; 153(1): 16-26, 2003 Nov.
Article in English | MEDLINE | ID: mdl-12955387

ABSTRACT

Delayed cell death following ischemic brain injury has been linked to alterations in gene expression. In this study we have evaluated the upregulation of several genes associated with delayed cell death (c-fos, bax, and bcl-2) during the initial 24 h of transient middle cerebral artery occlusion (MCAo) in the rat and the effects of postinjury treatment with the NR2B subunit specific NMDA receptor antagonist CGX-1007 (Conantokin-G, Con-G). C-fos mRNA levels peaked at 1 h postinjury in both cortical and subcortical ischemic brain regions (30-fold increase), remained elevated at 4 h and returned to within normal, preinjury levels 24 h postinjury. The increase in mRNA levels correlated to increased protein expression in the entire ipsilateral hemisphere at 1 h. Regions of necrosis at 4 h were void of C-Fos immunoreactivity with continued upregulation in surrounding regions. At 24 h, loss of C-Fos staining was observed in the injured hemisphere except for sustained increases along the border of the infarct and in the cingulate cortex of vehicle treated rats. CGX-1007 treatment reduced c-fos expression throughout the infarct region by up to 50%. No significant differences were measured in either bcl-2 or bax mRNA expression between treatment groups. However, at 24 h postinjury CGX-1007 treatment was associated with an increase in Bcl-2 immunoreactivity that correlated to a reduction in DNA fragmentation. In conclusion, CGX-1007 effectively attenuated gene expression associated with delayed cell death as related to a neuroprotective relief of cerebral ischemia.


Subject(s)
Brain Ischemia/drug therapy , Brain Ischemia/physiopathology , Conotoxins/pharmacology , DNA Damage/drug effects , Excitatory Amino Acid Antagonists/pharmacology , Animals , Antibodies , Brain Ischemia/pathology , Cell Death/drug effects , Gene Expression/drug effects , Histocytochemistry , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/pathology , Infarction, Middle Cerebral Artery/physiopathology , Male , Proto-Oncogene Proteins/analysis , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/immunology , Proto-Oncogene Proteins c-bcl-2/analysis , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/immunology , Proto-Oncogene Proteins c-fos/analysis , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/immunology , RNA, Messenger/analysis , Rats , Rats, Sprague-Dawley , bcl-2-Associated X Protein
15.
BMC Health Serv Res ; 3(1): 16, 2003 Aug 01.
Article in English | MEDLINE | ID: mdl-12892566

ABSTRACT

BACKGROUND: Low back pain has major health and social implications. Although there have been many randomised controlled trials of manipulation and exercise for the management of low back pain, the role of these two treatments in its routine management remains unclear. A previous trial comparing private chiropractic treatment with National Health Service (NHS) outpatient treatment, which found a benefit from chiropractic treatment, has been criticised because it did not take treatment location into account. There are data to suggest that general exercise programmes may have beneficial effects on low back pain. The UK Medical Research Council (MRC) has funded this major trial of physical treatments for back pain, based in primary care. It aims to establish if, when added to best care in general practice, a defined package of spinal manipulation and a defined programme of exercise classes (Back to Fitness) improve participant-assessed outcomes. Additionally the trial compares outcomes between participants receiving the spinal manipulation in NHS premises and in private premises. DESIGN: Randomised controlled trial using a 3 x 2 factorial design. METHODS: We sought to randomise 1350 participants with simple low back pain of at least one month's duration. These came from 14 locations across the UK, each with a cluster of 10-15 general practices that were members of the MRC General Practice Research Framework (GPRF). All practices were trained in the active management of low back pain. Participants were randomised to this form of general practice care only, or this general practice care plus manipulation, or this general practice care plus exercise, or this general practice care plus manipulation followed by exercise. Those randomised to manipulation were further randomised to receive treatment in either NHS or private premises. Follow up was by postal questionnaire one, three and 12 months after randomisation. The primary analysis will consider the main treatment effects before interactions between the two treatment packages. Economic analysis will estimate the cost per unit of health utility gained by adding either or both of the treatment packages to general practice care.


Subject(s)
Exercise Therapy , Family Practice/methods , Low Back Pain/rehabilitation , Manipulation, Spinal , Primary Health Care/methods , Adult , Exercise Therapy/economics , Family Practice/education , Family Practice/standards , Follow-Up Studies , Health Knowledge, Attitudes, Practice , Humans , Low Back Pain/psychology , Manipulation, Spinal/economics , Middle Aged , Primary Health Care/standards , Private Practice , Quality-Adjusted Life Years , State Medicine , Surveys and Questionnaires , Treatment Outcome , United Kingdom
16.
Man Ther ; 8(1): 46-51, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12635637

ABSTRACT

Trials of manipulative treatment have been compromised by, amongst other things, different definitions of the therapeutic procedures involved. This paper describes a spinal manipulation package agreed by the UK professional bodies that represent chiropractors, osteopaths and physiotherapists. It was devised for use in the UK Back pain Exercise And Manipulation (UK BEAM) trial--a national study of physical treatments in primary care funded by the Medical Research Council and the National Health Service Research and Development Programme. Although systematic reviews have reported some beneficial effects of spinal manipulation for low-back pain, due to the limited methodological quality of primary studies and difficulties in defining manipulation, important questions have remained unanswered. The UK BEAM trial was designed to answer some of those questions. Early in the design of the trial, it was acknowledged that the spinal manipulation treatment regimes provided by practitioners from the three professions shared more similarities than differences. Because the trial design specifically precluded comparison of the effect between the professions, it was necessary to devise a homogenous package representative of, and acceptable to, all three. The resulting package is 'pragmatic', in that it represents what happens to most people undergoing manipulation, and 'explanatory' in that it excludes discipline-specific variations and other ancillary treatments.


Subject(s)
Chiropractic/standards , Low Back Pain/therapy , Manipulation, Spinal , Osteopathic Medicine/standards , Physical Therapy Specialty/standards , Exercise Therapy/methods , Exercise Therapy/standards , Humans , Interprofessional Relations , Manipulation, Spinal/methods , Manipulation, Spinal/standards , Muscle, Skeletal/physiopathology , Societies, Medical , United Kingdom
17.
Neurotox Res ; 5(7): 505-14, 2003.
Article in English | MEDLINE | ID: mdl-14715434

ABSTRACT

Anti-inflammatory treatment with the proteasome inhibitor MLN519 has been previously reported to be neuroprotective against ischemic brain injury in rats. These effects have been related to inhibition of the transcription factor NF-kappaB, which is activated through ubiquitin-proteasomal degradation. The aim of this study was to evaluate the effects of MLN519 to alter the expression of several inflammatory genes under the control of NF-kappaB. Male Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAo) followed by vehicle or MLN519 (1.0 g/kg, i.v.) treatment immediately after reperfusion of blood to the brain at 2h. Gene expression was evaluated 3-72 h post-MCAo. The most striking effects of intravenous treatment with MLN519 were associated with reductions in ICAM-1 expression at 3 h followed by reductions in E-selectin (12-72 h). Less dramatic reductions were observed in IL-1Beta (3-24 h) and TNF-Alpha (24 h) with no apparent effects on IL-6 and VCAM-1 mRNA levels. Immunohistochemical analysis revealed that the genes most dramatically affected by MLN519 had highest expression in endothelial cells and leukocytes (E-selectin, ICAM-1),indicating that these cell types may be the primary targets of intravenously delivered MLN519 treatment.


Subject(s)
Acetylcysteine/analogs & derivatives , Acetylcysteine/pharmacology , Cysteine Endopeptidases/drug effects , Infarction, Middle Cerebral Artery/pathology , Inflammation/metabolism , Middle Cerebral Artery/physiology , Multienzyme Complexes/drug effects , Neuroprotective Agents/pharmacology , Reperfusion Injury/drug therapy , Reperfusion Injury/metabolism , Animals , Cell Adhesion Molecules/metabolism , Cytokines/biosynthesis , DNA/chemistry , DNA/genetics , DNA/isolation & purification , Gene Expression Regulation/drug effects , Immunohistochemistry , Infarction, Middle Cerebral Artery/drug therapy , Inflammation/genetics , Kinetics , Male , NF-kappa B/metabolism , Proteasome Endopeptidase Complex , RNA, Messenger/biosynthesis , RNA, Messenger/isolation & purification , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction
18.
Gastroenterology ; 121(6): 1437-50, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11729123

ABSTRACT

BACKGROUND & AIMS: Cdx2 is critical in intestinal proliferation and differentiation. Modulation of Cdx2 function in response to cellular signaling is to be elucidated. We hypothesize that phosphorylation of the Cdx2 activation domain can modulate its function. METHODS: The Cdx2 activation domain was delineated in transient transfections using different portions of Cdx2 fused to the Gal4-DNA binding domain. In vivo phosphorylation was studied by metabolic labeling with (32)P-orthophosphate. To study a potential phosphorylation site, polyclonal antibodies were generated: CNL was raised against amino acids 54-66 of Cdx2 and P-Cdx2-S60 against the same epitope in which serine 60 was phosphorylated. RESULTS: A critical region for transactivation resides within amino acids 60-70. Substitution of serine 60 with alanine reduces incorporation of (32)P-orthophosphate substantially. S60-phosphorylation decreases Cdx2 transactivation. Phosphorylation of serine 60 can be inhibited with the mitogen-activated protein kinase inhibitors PD98059 or UO126. P-Cdx2-S60 recognizes phosphorylated serine 60 mainly in proliferative compartment of the intestinal epithelial layer. In contrast, CNL recognizes Cdx2 predominantly in the differentiated compartment. CONCLUSIONS: The Cdx2 activation domain is phosphorylated at serine 60 via the mitogen-activated protein kinase pathway. S60-phosphorylated and S60-nonphosphorylated Cdx2 have different transcriptional activity, as well as different spatial expression patterns in the intestinal epithelium.


Subject(s)
Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Transcriptional Activation/physiology , Amino Acid Sequence/genetics , Animals , CDX2 Transcription Factor , Cell Division/physiology , Cell Line , Cell Nucleus/metabolism , Colon/cytology , Colon/metabolism , DNA-Binding Proteins/metabolism , Homeodomain Proteins/chemistry , Humans , Immunohistochemistry , Intestine, Small/cytology , Intestine, Small/metabolism , Mice , Mitogen-Activated Protein Kinases/metabolism , Molecular Sequence Data , Phosphorylation , Protein Structure, Tertiary , Serine/metabolism , Trans-Activators
19.
J Comp Neurol ; 440(4): 311-20, 2001 Nov 26.
Article in English | MEDLINE | ID: mdl-11745626

ABSTRACT

We used transsexual limb transplants in fiddler crabs to examine how peripheral sensory structures interact with the central nervous system (CNS) to produce a sexually dimorphic behavior. Female and male chemosensory feeding claws were transplanted onto male hosts in place of nonfeeding, nonchemosensory claws. Successfully transplanted claws retain donor morphologies and contain chemosensory neurons. Neurons in successfully transplanted female feeding claws express the enhanced sensitivity to chemical cues seen in female, but not male, neurons in claws of normal animals. When chemically stimulated, the transplanted claws evoke feeding behavior not observed in normal males, even though the sensory neurons in the transplanted limb project to the host's sexually dimorphic neuropil not known to receive chemosensory input. Behavioral sensitivity is directly related to the sensitivity of peripheral neurons in the transplanted feeding claw. Thus, the interactions between peripheral neurons and their targets may restructure the CNS so that novel sensory capabilities are expressed, and this can produce sexually dimorphic behaviors.


Subject(s)
Brachyura/physiology , Chemoreceptor Cells/physiology , Extremities/transplantation , Sex Characteristics , Action Potentials/physiology , Animals , Behavior, Animal/physiology , Extremities/anatomy & histology , Extremities/innervation , Female , Male , Nervous System Physiological Phenomena , Neuronal Plasticity/physiology , Neurons, Afferent/physiology
20.
Appl Environ Microbiol ; 67(12): 5444-52, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11722891

ABSTRACT

Cyanobacteria are prominent constituents of the marine biosphere that account for a significant percentage of oceanic primary productivity. In an effort to resolve how open-ocean cyanobacteria persist in regions where the Fe concentration is thought to be limiting their productivity, we performed a number of Fe stress experiments on axenic cultures of marine Synechococcus spp., Crocosphaera sp., and Trichodesmium sp. Through this work, we determined that all of these marine cyanobacteria mount adaptive responses to Fe stress, which resulted in the induction and/or repression of several proteins. We have identified one of the Fe stress-induced proteins as an IdiA homologue. Genomic observations and laboratory data presented herein from open-ocean Synechococcus spp. are consistent with IdiA having a role in cellular Fe scavenging. Our data indicate that IdiA may make an excellent marker for Fe stress in open-ocean cyanobacterial field populations. By determining how these microorganisms respond to Fe stress, we will gain insight into how and when this important trace element can limit their growth in situ. This knowledge will greatly increase our understanding of how marine Fe cycling impacts oceanic processes, such as carbon and nitrogen fixation.


Subject(s)
Bacterial Proteins , Cyanobacteria/growth & development , Cyanobacteria/metabolism , Heat-Shock Response/physiology , Iron-Binding Proteins , Iron/metabolism , Seawater/microbiology , Carrier Proteins/metabolism , Culture Media , Gene Expression Regulation, Bacterial
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