Hyperbaric Oxygen for Lower Limb Trauma (HOLLT): an international multi-centre randomised clinical trial.

INTRODUCTION: Hyperbaric oxygen treatment (HBOT) is sometimes used in the management of open fractures and severe soft tissue crush injury, aiming to reduce complications and improve outcomes. METHODS: Patients with open tibial fractures were randomly assigned within 48 hours of injury to receive standard trauma care or standard care plus 12 sessions of HBOT. The primary outcome was the incidence of necrosis or infection or both occurring within 14 days of injury. RESULTS: One-hundred and twenty patients were enrolled. Intention to treat primary outcome occurred in 25/58 HBOT assigned patients and 34/59 controls (43% vs 58%, odds ratio (OR) 0.55, 95% confidence interval (CI) 0.25 to 1.18, P = 0.12). Tissue necrosis occurred in 29% of HBOT patients and 53% of controls (OR 0.35, 95% CI 0.16 to 0.78, P = 0.01). There were fewer late complications in patients receiving HBOT (6/53 vs 18/52, OR 0.22, 95% CI 0.08 to 0.64, P = 0.007) including delayed fracture union (5/53 vs 13/52, OR 0.31, 95% CI 0.10 to 0.95, P = 0.04). Quality of life measures at one and two years were superior in HBOT patients. The mean score difference in short form 36 was 2.90, 95% CI 1.03 to 4.77, P = 0.002, in the short musculoskeletal function assessment (SMFA) was 2.54, 95% CI 0.62 to 4.46, P = 0.01; and in SMFA daily activities was 19.51, 95% CI 0.06 to 21.08, P = 0.05. CONCLUSIONS: In severe lower limb trauma, early HBOT reduces tissue necrosis and the likelihood of long-term complications, and improves functional outcomes. Future research should focus on optimal dosage and whether HBOT has benefits for other injury types.

Validation and assessment of an antibiotic-based, aseptic decontamination manufacturing protocol for therapeutic, vacuum-dried human amniotic membrane.

Amniotic membrane (AM) is used to treat a range of ophthalmic indications but must be presented in a non-contaminated state. AM from elective caesarean sections contains natural microbial contamination, requiring removal during processing protocols. The aim of this study was to assess the ability of antibiotic decontamination of AM, during processing by innovative low-temperature vacuum-drying. Bioburden of caesarean section AM was assessed, and found to be present in low levels. Subsequently, the process for producing vacuum-dried AM (VDAM) was assessed for decontamination ability, by artificially loading with Staphylococcus epidermidis at different stages of processing. The protocol was highly efficient at removing bioburden introduced at any stage of processing, with antibiotic treatment and drying the most efficacious steps. The antibacterial activity of non-antibiotic treated AM compared to VDAM was evaluated using minimum inhibitory/biocidal concentrations (MIC/MBC), and disc diffusion assays against Meticillin-resistant Staphylococcus aureus, Meticillin-resistant S. epidermidis, Escherichia coli, Pseudomonas aeruginosa and Enterococcus faecalis. Antibacterial activity without antibiotic was low, confirmed by high MIC/MBC, and a no inhibition on agar lawns. However, VDAM with antibiotic demonstrated effective antibacterial capacity against all bacteria. Therefore, antibiotic decontamination is a reliable method for sterilisation of AM and the resultant antibiotic reservoir is effective against gram-positive and -negative bacteria.

Protocol for a randomized, double blind, placebo controlled, crossover trial of Melatonin for treatment of Nocturia in adults with Multiple Sclerosis (MeNiMS).

BACKGROUND: Nocturia (the symptom of needing to wake up to pass urine) is common in progressive Multiple Sclerosis (MS) patients. Moderate-to-severe nocturia affects quality of life, can exacerbate fatigue and may affect capacity to carry out daily activities. Melatonin is a natural hormone regulating circadian cycles, released by the pineal gland at night-time, and secretion is impaired in MS. Melatonin levels can be supplemented by administration in tablet form at bedtime. The aim of this study is to evaluate the effect of melatonin on mean number of nocturia episodes per night in MS patients. Secondary outcome measures will assess impact upon quality of life, urinated volumes, lower urinary tract symptoms (LUTS), cognition, sleep quality and sleep disturbance of partners. METHODS: A randomized, double blind, placebo controlled, crossover trial consisting of two, six week treatment phases (active drug melatonin 2 mg or placebo), with a 1 month wash-out period in between. The primary outcome (change in nocturia episodes per night) in this two arm, two treatment, two period crossover design, will be objectively measured using frequency volume charts (FVC) at baseline and following both treatment phases. Questionnaires will be used to assess quality of life, sleep quality, safety and urinary tract symptoms. Qualitative interviews of participants and partners will explore issues including quality of life, mechanisms of sleep disturbance and impact of nocturia on partners. DISCUSSION: This study will evaluate whether melatonin reduces the frequency of nocturia episodes in MS patients, and therefore whether 'Circadin' has the potential to reduce LUTS and fatigue, and improve cognition and overall quality of life. TRIAL REGISTRATION: (EudraCT reference) 2012-00418321 registered: 25/01/13. ISRCTN Registry: ISRCTN38687869.

Effect of visual art on patient anxiety and agitation in a mental health facility and implications for the business case.

There is a growing body of evidence on the impact of the environment on health and well-being. This study focuses on the impact of visual artworks on the well-being of psychiatric patients in a multi-purpose lounge of an acute care psychiatric unit. Well-being was measured by the rate of pro re nata (PRN) medication issued by nurses in response to visible signs of patient anxiety and agitation. Nurses were interviewed to get qualitative feedback on the patient response. Findings revealed that the ratio of PRN/patient census was significantly lower on the days when a realistic nature photograph was displayed, compared to the control condition (no art) and abstract art. Nurses reported that some patients displayed agitated behaviour in response to the abstract image. This study makes a case for the impact of visual art on mental well-being. The research findings were also translated into the time and money invested on PRN incidents, and annual cost savings of almost $US30,000 a year was projected. This research makes a case that simple environmental interventions like visual art can save the hospital costs of medication, and staff and pharmacy time, by providing a visual distraction that can alleviate anxiety and agitation in patients.

Delineating inflammatory and mechanical sub-types of low back pain: a pilot survey of fifty low back pain patients in a chiropractic setting.

BACKGROUND: An instrument known as the Mechanical and Inflammatory Low Back Pain (MAIL) Scale was drafted using the results of a previous expert opinion study. A pilot survey was conducted to test the feasibility of a larger study designed to determine the MAIL Scale's ability to distinguish two potential subgroups of low back pain: inflammatory and mechanical. METHODS: Patients with a primary complaint of low back pain (LBP) presenting to chiropractic clinics in Perth, Western Australia were asked to fill out the MAIL Scale questionnaire. The instrument's ability to separate patients into inflammatory and mechanical subgroups of LBP was examined using the mean score of each notional subgroup as an arbitrary cut-off point. RESULTS: Data were collected from 50 patients. The MAIL Scale did not appear to separate cases of LBP into the two notionally distinct groups of inflammatory (n = 6) or mechanical (n = 5). A larger "mixed symptom" group (n = 39) was revealed. CONCLUSIONS: In this pilot study the MAIL Scale was unable to clearly discriminate between what is thought to be mechanical and inflammatory LBP in 50 cases seen in a chiropractic setting. However, the small sample size means any conclusions must be viewed with caution. Further research within a larger study population may be warranted and feasible.

Nutritional decline in cystic fibrosis related diabetes: the effect of intensive nutritional intervention.

BACKGROUND: Reports indicate that nutritional and respiratory decline occur up to four years prior to diagnosis of cystic fibrosis related diabetes (CFRD). Our aim was to establish whether intensive nutritional intervention prevents pre-diabetic nutritional decline in an adult population with CFRD. METHODS: 48 adult patients with CFRD were matched to 48 controls with CF, for age, gender and lung pathogen status. Nutritional and other clinical indices were recorded at annual intervals from six years before until two years after diagnosis. Data were also analysed to examine the impact of early and late acquisition of CFRD. RESULTS: No important differences in weight, height, body mass index (BMI), lung function or intravenous treatment were found between groups in the six years prior to diagnosis, nor any significant deviation over time. In those who developed diabetes, use of overnight enteral tube feeding (ETF) was four times as likely at the time of diagnosis, compared to controls [ETF 43.8% (CFRD) v 18.8% (CF Controls), OR 4.0, CI 1.3 to 16.4, p=0.01]. Age at onset of CFRD played a significant role in determining the pre-diabetic clinical course. Younger diabetics with continued growth at study onset (n=17) had a lower BMI from 2 years prior to diagnosis compared to controls [BMI 18.9 kg/m(2) (CFRD) v 20.8 kg/m(2) (CF Controls), diff=1.9, CI -0.1 to 3.7 p=0.04]. The BMI of older diabetics (completed growth at study onset) was equal to that of controls throughout. CONCLUSION: Pre-diabetic nutritional decline is not inevitable in adults with CFRD, but is influenced by age of onset. In the group overall, those with CFRD are more likely to require ETF from 2 years prior to diagnosis. Despite intensive nutritional intervention, patients who continue to grow throughout the pre-diabetic years, show a level of nutritional decline absent in older adults.

Prenatal glucocorticoid exposure alters hypothalamic-pituitary-adrenal function in juvenile guinea pigs.

The neurodevelopmental consequences of prenatal glucocorticoid exposure are not well-understood, particularly in species that give birth to neuroanatomically mature offspring. In the present study, we hypothesised that repeated prenatal glucocorticoid administration would alter hypothalamo-pituitary-adrenal (HPA) function in juvenile guinea pig offspring. Pregnant guinea pigs were injected with betamethasone (1 mg/kg) or vehicle on gestational days 40, 41, 50, 51, 60 and 61 (six doses). Prenatal glucocorticoid exposure abolished the pituitary-adrenal response to maternal separation in juvenile males, but had no effect in female offspring. Indeed, female offspring (vehicle and betamethasone) did not mount a significant HPA response to separation at 10 days of age. Although there were no effects of prenatal glucocorticoid exposure on hippocampal or hypothalamic corticosteroid receptor expression or corticotrophin-releasing factor (CRF) mRNA, there were significant effects in the pituitary and adrenal; again males were more affected than females. Prenatal glucocorticoid exposure increased pituitary pro-opiomelanocortin and CRF receptor mRNA, and markedly decreased adrenocortical CYP17 mRNA. In conclusion, repeated prenatal glucocorticoid exposure has profound influences on HPA function and regulation in the juvenile guinea pig, and this involves altered regulation at the level of the pituitary and adrenal cortex. Furthermore, juvenile males appear to be more vulnerable to the effects of prenatal glucocorticoid exposure than females.

Is pain ever "normal"?

This article analyzes the Pain Terminology adopted by the International Association for the Study of Pain (IASP), noting that most of their pain categories are defined in terms of a reference standard of "normal" pain. Given the lack of any officially adopted operational definition of the word "normal," we argue that the use of this word expresses and maintains a paradigm that drives many clinicians' reasoning about their patients' pain. We offer evidence that this uninterrogated paradigm is being tacitly used to differentiate legitimate pain reports from malingering and drug seeking. We consider this unsubstantiated "folk" sense of "normal" in light of evidence-based, rationalized prototypes based on statistical analysis of empirical evidence. We conclude that evidence for consistency in the experience and expression of pain and for clinician accuracy in evaluating the veracity of that pain is lacking; therefore, the logical preconditions needed for a rationalized, evidence-based prototype of "normal" pain have yet to be met. We conclude that the use of "normal" as a reference standard leads to ineffective and inhumane management of patient pain and to the danger that third parties, such as insurance companies and drug enforcement agencies, will use this unsubstantiated reference standard to arbitrarily limit pain therapy options. The authors recommend that the word "normal" be expunged from the International Association for the Study of Pain, Pain Terminology.

The influence of voluntary tonic EMG level on the vestibular-evoked myogenic potential.

Vestibular-evoked myogenic potentials (VEMPs) are proposed as a reliable test to supplement the current vestibular test battery by providing diagnostic information about saccular and/or inferior vestibular nerve function. VEMPs are short-latency electromyograms (EMGs) evoked by high-level acoustic stimuli and recorded from surface electrodes over the tonically contracted sternocleidomastoid muscle. VEMP amplitude is influenced by the EMG level, which must be controlled. This study examined the ability of subjects to achieve the EMG target levels over a range of target levels typically used during VEMP recordings. In addition, the influence of target EMG level on the latency and amplitude of the click- and tone-evoked VEMP was examined. The VEMP amplitude increased as a function of EMG target level, and the latency remained constant. EMG target levels ranging from 30 microV to 50 microV are suggested for clinical application of the VEMP.

How do homeopaths make decisions? An exploratory study of inter-rater reliability and intuition in the decision making process.

The validity of clinical decision making in homeopathy is largely unexplored and little is understood about the process or its reliability. This exploratory study investigated, in the context of a questionnaire based re-proving of Belladonna 30c, the extent to which decisions are based on clinical facts or intuition and how reliable decisions are. Three experienced, independent homeopathic clinicians/proving researchers rated the symptom diaries of the 206 subjects taking part. They reported their proving decision (ie positive proving response, no proving response or undecided) based on the total symptom profiles and rated (on a scale of 0-10) their use of clinical facts or intuition. Keynote symptoms and overall confidence scores were also reported. The level of agreement between raters was generally poor (weighted kappa 0.349-0.064). All raters used both facts and intuition. The rater's reliance on the facts was significantly associated with classifying those subjects who had no proving response [rater 1, P<0.001; rater 2, P<0.001]. Raters used significantly higher intuition scores when classifying a prover [rater 2, P= 0.001; rater 3, P= 0.012]. Issues regarding the education and practice of homeopathy are discussed.

The effects of click and tone-burst stimulus parameters on the vestibular evoked myogenic potential (VEMP).

Vestibular evoked myogenic potentials (VEMP) are short latency electromyograms (EMG) evoked by high-level acoustic stimuli and recorded from surface electrodes over the tonically contracted sternocleidomastoid (SCM) muscle and are presumed to originate in the saccule. The present experiments examined the effects of click and tone-burst level and stimulus frequency on the latency, amplitude, and threshold of the VEMP in subjects with normal hearing sensitivity and no history of vestibular disease. VEMPs were recorded in all subjects using 100 dB nHL click stimuli. Most subjects had VEMPs present at 500, 750, and 1000 Hz, and few subjects had VEMPs present at 2000 Hz. The response amplitude of the VEMP increased with click and tone-burst level, whereas VEMP latency was not influenced by the stimulus level. The largest tone-burst-evoked VEMPs and lowest thresholds were obtained at 500 and 750 Hz. VEMP latency was independent of stimulus frequency when tone-burst duration was held constant.

Learning experiences--what works for postgraduates.

Supervision and postgraduate education for health professionals studying homeopathy was investigated using feedback and comparative questioning of participants who have taken part in group supervision. Objectives set by supervisors, influenced by previous feedback, are scored and ranked. The key areas of postgraduate learning of homeopathy and how well the supervision model met these are analysed and discussed. Learning experiences are ranked in order of preference. Aspects of case presentation are compared for interest and relevance.

Tamulustoxin: a novel potassium channel blocker from the venom of the Indian red scorpion Mesobuthus tamulus.

We have characterized tamulustoxin, a novel 35-amino-acid peptide found in the venom of the Indian red scorpion (Mesobuthus tamulus). Tamulustoxin was identified through a [125I]toxin I screen, designed to identify toxins that block voltage-activated potassium channels. Tamulustoxin has also been cloned by RT-PCR, using RNA extracted from scorpion venom glands. Tamulustoxin shares no homology with other scorpion venom toxins, although the positions of its six cysteine residues would suggest that it shares the same structural scaffold. Tamulustoxin rapidly inhibited both peak and steady-state currents (18.9 +/- 1.0 and 37 +/- 1.1%, respectively) produced by injecting CHO cells with mRNA encoding the hKv1.6 channel.

Complementary and alternative medicine (CAM) in the undergraduate medical curriculum: the Southampton experience.

OBJECTIVE: We describe the planning, development and evaluation of a special study module (SSM) on Complementary and Alternative Medicine (CAM) as part of the Southampton Medical School undergraduate curriculum. AIM: To address how the module was received by students, the themes that emerged, the effect on student attitudes to CAM and how the teaching aims developed into learning objectives. METHOD: Student feedback questionnaires and regular teaching staff meetings over a period of 3 years. RESULTS: The course resulted in a significant change in student attitudes to CAM and was well received by the students. It offered a reflective insight into conventional medicine. We have developed and validated core teaching objectives. CONCLUSIONS: We hope that our well validated and well received core teaching objectives will provide a broadly applicable base for those who wish to run similar courses.

Complementary medicine: the Southampton undergraduate experience.

We describe our experiences in the development of a complementary and alternative medicine familiarization special study module for a multidisciplinary group of students, involving medical students, nurses and chiropractors. Our observations suggest that the model we have developed is an effective, interesting and exciting experience for both students and teachers. We have defined, by consensus between students and teachers, a series of clear educational objectives. The course is now established, having run for 4 academic years, but we are concerned about its sustainability, particularly in relation to ongoing funding.

The structure and function of the beta 2-adaptin appendage domain.

The heterotetrameric AP2 adaptor (alpha, beta 2, mu 2 and sigma 2 subunits) plays a central role in clathrin-mediated endocytosis. We present the protein recruitment function and 1.7 A resolution structure of its beta 2-appendage domain to complement those previously determined for the mu 2 subunit and alpha appendage. Using structure-directed mutagenesis, we demonstrate the ability of the beta 2 appendage alone to bind directly to clathrin and the accessory proteins AP180, epsin and eps15 at the same site. Clathrin polymerization is promoted by binding of clathrin simultaneously to the beta 2-appendage site and to a second site on the adjacent beta 2 hinge. This results in the displacement of the other ligands from the beta 2 appendage. Thus clathrin binding to an AP2-accessory protein complex would cause the controlled release of accessory proteins at sites of vesicle formation.