A multicentre, randomized, double-blinded, placebo-controlled Phase III study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND).

BACKGROUND AND HYPOTHESIS: Thrombolytic therapy with tissue plasminogen activator is effective for acute ischaemic stroke within 4·5 h of onset. Patients who wake up with stroke are generally ineligible for stroke thrombolysis. We hypothesized that ischaemic stroke patients with significant penumbral mismatch on either magnetic resonance imaging or computer tomography at three- (or 4·5 depending on local guidelines) to nine-hours from stroke onset, or patients with wake-up stroke within nine-hours from midpoint of sleep duration, would have improved clinical outcomes when given tissue plasminogen activator compared to placebo. STUDY DESIGN: EXtending the time for Thrombolysis in Emergency Neurological Deficits is an investigator-driven, Phase III, randomized, multicentre, double-blind, placebo-controlled study. Ischaemic stroke patients presenting after the three- or 4·5-h treatment window for tissue plasminogen activator and within nine-hours of stroke onset or with wake-up stroke within nine-hours from the midpoint of sleep duration, who fulfil clinical (National Institutes of Health Stroke Score ≥4-26 and prestroke modified Rankin Scale <2) will undergo magnetic resonance imaging or computer tomography. Patients who also meet imaging criteria (infarct core volume <70 ml, perfusion lesion : infarct core mismatch ratio >1·2, and absolute mismatch >10 ml) will be randomized to either tissue plasminogen activator or placebo. STUDY OUTCOME: The primary outcome measure will be modified Rankin Scale 0-1 at day 90. Clinical secondary outcomes include categorical shift in modified Rankin Scale at 90 days, reduction in the National Institutes of Health Stroke Score by 8 or more points or reaching 0-1 at day 90, recurrent stroke, or death. Imaging secondary outcomes will include symptomatic intracranial haemorrhage, reperfusion and or recanalization at 24 h and infarct growth at day 90.

Streptococcus equi subspecies zooepidemicus meningitis--a case report and review of the literature.

A case is described of a 79-year-old man, trampled by his horses, who subsequently developed a wound infection and, later, meningitis. Streptococcus equi subsp. zooepidemicus was isolated as the causative organism. S. equi subsp. zooepidemicus, which carries the Lancefield Group C antigen, is an uncommon human pathogen but is commonly isolated from bacterial infections in animals, particularly horses. It is most commonly acquired by humans following animal contact. A review of the literature identified 20 previously described cases of S. equi subsp. zooepidemicus meningitis. Crude mortality following infection was 24%. All of the patients who died were over 70 years of age and the ingestion of unpasteurised dairy products was associated with all but one of the fatal cases. Hearing loss was a frequent complication, occurring in 19% of cases. Only 38% of patients made a complete recovery. Treatment regimes commonly included benzylpenicillin or a third-generation cephalosporin, with a mean treatment duration in survivors of 23 days.

Clinical characteristics and outcomes of patients with vancomycin-susceptible Enterococcus faecalis and Enterococcus faecium bacteraemia--a five-year retrospective review.

The purpose of this study was to assess the epidemiology and outcomes of enterococcal bacteraemia. A retrospective review of demographic, microbiological and clinical data in patients 16 years of age and over with Enterococcus faecalis or E. faecium bacteraemia at Auckland City Hospital, New Zealand, from June 2002 to May 2007 was carried out. A total of 212 patients fulfilled the inclusion criteria, with 205 being included in the analysis. E. faecalis accounted for 86% (176/205) and E. faecium 14% (29/205) of the patients. Amoxycillin resistance occurred in 69% (20/29) of E. faecium isolates. High-level gentamicin resistance was present in 38% (65/171) of E. faecalis isolates and 25% (7/28) of E. faecium isolates (P = NS). No vancomycin-resistant enterococci were isolated. Healthcare association was present in 73% (149/205) of patients. Co-morbidities were present in 86% (176/205) of patients. The 7-day mortality was 13% (27/205) and the 30-day mortality 25% (52/205). On multivariate analysis, the 7-day mortality was statistically significantly associated with cirrhosis and shorter intravenous amoxycillin therapy. The 30-day mortality was statistically significantly associated with cirrhosis, malignancy, E. faecium bacteraemia and not receiving active antimicrobial therapy. No statistically significant association between high-level gentamicin resistance and mortality was demonstrated on multivariate analysis. Enterococcal bacteraemia occurs in a co-morbid, healthcare-exposed population. Associated mortality is high, and is associated with severe underlying disease, E. faecium bacteraemia and treatment factors.

A predictive approach to nutrient criteria.

Violation of a water quality standard triggers the need for a total maximum daily load (TMDL); this should result in actions that improve water quality, but sometimes at significant cost. If the standard is well-conceived, a designated-use statement characterizes societal values, and a criterion provides a measurable surrogate for designated use. This latter provision means that scientists measure the criterion and view violations of the criterion as equivalent to noncompliance with the designated use. However, if a criterion is not a good indicator of designated use, it is apt to result in misallocation of the limited resources for water quality improvement through the TMDL process. This concern provides the basis for our assessment of the national nutrient criteria strategy recently proposed by the U.S. EPA. We acquired data sets for four case studies (Lake Washington, Neuse River Estuary, San Francisco Bay, and Lake Mendota) and then used expert elicitation to quantify designated-use attainment for each case. Applying structural equation modeling, we identified good water quality criteria as the best predictors of the designated use elicited response variable. Further, we used the model to relate the level (concentration) of each criterion to the probability of compliance with the designated use; this provides decision-makers with an estimate of risk associated with the criterion level, facilitating the selection of appropriate water quality criteria.

The use of multi-media messaging in the referral of musculoskeletal limb injuries to a tertiary trauma unit using: a 1-month evaluation.

OBJECTIVES: New developments in telecommunications will have a profound effect on the delivery of medical care throughout the world. In Northern Ireland three trauma centres provide fracture care for their own and surrounding Emergency Departments. All trauma referrals are currently taken by telephone. It is our experience that the verbal description of the radiographs of a musculoskeletal limb injury can be inaccurate, necessitating us to view the plain films of the patient. By utilising a recent advance in telecommunications technology, the launch of mobile handsets with multi-media messaging (MMS) service capability, it is now possible to digitally capture and instantly send an image of a plain film. PURPOSE: To evaluate the use of multi-media messaging as a supplement to the telephone referral of musculoskeletal limb injures. METHOD: : Following a referral using, the emergency physician and the trauma surgeon evaluated the multi-media consult through a survey questionnaire. RESULTS: Between the 1st December 2003 and the 1st January 2004, 46 multi-media consultations were performed. Picture quality was acceptable in all but one of the referrals. In 35 of the 46 referrals the multi-media image of the plain films was felt to improve the management of the patient. In 8 of the 46 referrals the multi-media image of the plain films was felt to change the management of the patient. CONCLUSION: A multi-media messaging store- and forward telemedicine system has potential to facilitate the rapid, cost-effective management of musculoskeletal limb injuries thereby enhancing clinical care.

Randomized comparison of enoxaparin with unfractionated heparin following fibrinolytic therapy for acute myocardial infarction.

AIMS: To compare the efficacy and safety of low molecular weight heparin with unfractionated heparin following fibrinolytic therapy for acute myocardial infarction. METHODS AND RESULTS: Three-hundred patients receiving fibrinolytic therapy following acute myocardial infarction were randomly assigned to low molecular weight heparin as enoxaparin (40 mg intravenous bolus, then 40 mg subcutaneously every 8 h, n=149) or unfractionated heparin (5000 U intravenous bolus, then 30 000 U. 24 h(-1), adjusted to an activated partial thromboplastin time 2-2.5x normal, n=151) for 4 days in conjunction with routine therapy. Clinical and therapeutic variables were analysed, in addition to use of enoxaparin or unfractionated heparin, to determine independent predictors of the 90-day composite triple end-point (death, non-fatal reinfarction, or readmission with unstable angina). The triple end-point occurred more frequently in patients receiving unfractionated heparin rather than enoxaparin (36% vs. 26%; P=0.04). Logistic regression modelling of baseline and clinical variables identified the only independent risk factors for recurrent events as left ventricular failure, hypertension, and use of unfractionated heparin rather than enoxaparin. There was no difference in major haemorrhage between those receiving enoxaparin (3%) and unfractionated heparin (4%). CONCLUSION: Use of enoxaparin compared with unfractionated heparin in patients receiving fibrinolytic therapy for acute myocardial infarction was associated with fewer recurrent cardiac events at 90 days. This benefit was independent of other important clinical and therapeutic factors.

Plastic bullet injuries in Northern Ireland: experiences during a week of civil disturbance.

BACKGROUND: Plastic bullets were introduced to Northern Ireland for riot-control purposes in 1973. Their use has been controversial, with a number of fatalities. In the week beginning July 7, 1996, some 8,000 plastic bullets were fired during widespread rioting. METHODS: Details of injuries attributed to plastic bullets were obtained retrospectively from patient notes for the period July 8 to 14, 1996, in six hospitals. A total of 172 injuries in 155 patients were recorded. RESULTS: Nineteen percent of injuries were to the face/head/neck, 20% were to the chest or abdomen, and 61% were to the limbs. Abbreviated Injury Scale scores ranged from I to 3. Forty-two patients were admitted for hospitalization, three to intensive care units. No fatalities occurred. CONCLUSION: Plastic bullet impact to the abdomen or above may cause life-threatening injuries. Below this site, major trauma is unlikely.

Investigations of the proximity effect for pollutants in the indoor environment.

More than a dozen indoor air quality studies have reported a large discrepancy between concentrations measured by stationary indoor monitors (SIMs) and personal exposure monitors (PEMs). One possible cause of this discrepancy is a source proximity effect, in which pollutant sources close to the respondent cause elevated and highly variable exposures. This paper describes three sets of experiments in a home using real-time measurements to characterize and quantify the proximity effect relative to a fixed distant location analogous to a SIM. In the first set of experiments, using sulfur hexafluoride (SF6) as a continuously emitting tracer pollutant from a point source, measurements of pollutant concentrations were made at different distances from the source under different air exchange rates and source strengths. A second set of experiments used a continuous point source of carbon monoxide (CO) tracer pollutant and an array of high time resolution monitors to collect simultaneous concentration readings at different locations in the room. A third set of experiments measured particle count density and particle-bound polycyclic aromatic hydrocarbon (PAH) concentrations emitted from a continuous particle point source (an incense stick) using two particle counters and two PAH monitors, and included human activity periods both before and during the source emission period. Results from the SF6 and CO experiments show that while the source is emitting, a source proximity effect can be seen in the increases in the mean and median and in the variability of concentrations closest to the source, even at a distance of 2.0 m from the source under certain settings of air exchange rate and source strength. CO concentrations at locations near the source were found to be higher and more variable than the predictions of the mass balance model. For particles emitted from the incense source, a source proximity effect was evident for the fine particle sizes (0.3 to 2.5 microm) and particle-bound PAH up to at least 1.0 m from the source. Analysis of spatial and temporal patterns in the data for the three tracer pollutants reveal marked transient elevations of concentrations as seen by the monitor, referred to as "microplumes," particularly at locations close to the source. Mixing patterns in the room show complex patterns and directional effects, as evidenced by the variable intensity of the microplume activity at different locations. By characterizing the spatial and temporal variability of pollutant concentrations in the home, the proximity effect can be quantified, leading to improved indoor monitoring designs and models of human exposure to air pollutants.

The balance of pro- and anti-inflammatory cytokines in cardiac surgery.

Homeostatic control of the balance of pro- and anti-inflammatory cytokines is important for the maintenance of health. Cardiac surgery, with its intense pro-inflammatory stimulus, constitutes a major challenge to the patient's ability to maintain this balance. Pre- and intraoperative factors influencing the maintenance of cytokine balance are discussed.

Immunomodulation: an important concept in modern anaesthesia.

This review summarises evidence for immunomodulatory effect of drugs administered peri-operatively. The clinical significance of the balance of pro- and anti-inflammatory cytokines may be seen in certain disease states, for example, meningococcal meningitis and Lyme arthritis. This balance may be altered peri-operatively. Traditionally, these changes are considered to be due to the stress response of surgery, the response to cardiopulmonary bypass, or endotoxaemia. This review presents in vitro evidence suggesting that drugs modulating this cytokine balance include non-steroidal anti-inflammatory agents, phosphodiesterase inhibitors and opioids, acting through effects on intracellular cyclic nucleotide messenger systems. An important consequence of the pro-inflammatory cytokine activity is increased adhesion of neutrophils. Aspects of this process may be inhibited by avoiding low blood flow states, by reducing adhesion molecule expression (for example by use of pentoxifylline), or by use of negatively charged anions such as heparin. Neutrophil activity is generally depressed by intravenous anaesthetic induction agents, but is enhanced by opioids. Natural killer cell activity, which is involved in immunity against tumour cells and virally infected cells is transiently depressed by volatile anaesthetic agents and opioids. In contrast catecholamines enhance natural killer cell activity. Whereas decrease in immunoglobulin levels occur peri-operatively, this is not thought to be as a result of drugs at clinically used concentrations but rather due to haemodilution.

Markers of inflammatory activation: upregulation of complement receptors CR1 and CR3 on synovial fluid neutrophils from patients with inflammatory joint disease.

Expression of the C3 receptors CR1 and CR3 was investigated on neutrophils from paired peripheral blood and synovial fluid samples from 34 patients with inflammatory joint disease (21 patients with rheumatoid arthritis (RA) and 13 patients with other articular diseases (OAD)). Using monoclonal antibodies (anti-CD35, anti-CD11b) and immunofluorescence flow cytometric analyses the percentages of positively labeled cells and the relative fluorescence intensities (as a measure of receptor number) were determined. CR1 and CR3 were found to be present on the majority (> 85%) of circulating neutrophils from normal subjects, RA and OAD patients, and on synovial fluid neutrophils from both patient groups. A strong correlation between neutrophil CR1 and CR3 expression was observed in peripheral blood samples from normal subjects (r = 0.81; P = 0.001), RA (r = 0.79; P = 0.001), and OAD patients (r = 0.83; P = 0.001); in each case the levels of CR3 expression were approximately twice those recorded for CR1. Both CR1 and CR3 expression was upregulated on synovial fluid neutrophils compared with that observed on the corresponding peripheral blood cells. Mean percentage increases observed were: RA patients: CR1, 16.5% (P < 0.001) and CR3, 28.7% (P < 0.001); and OAD patients: CR1, 4.1% and CR3, 26.9% (P = 0.001). Correlation of serum and synovial fluid IL-6, IL-8, and immune complex levels with neutrophil CR1 and CR3 expression failed to demonstrate any significant relationship between the concentrations of these soluble factors and receptor expression. Upregulation of CR1 and CR3 receptors, reflecting neutrophil activation within the inflamed joint, is a consistent finding in patients with inflammatory arthropathies.

Treatment of chronic fatigue syndrome.

Chronic Fatigue Syndrome is a disorder which is characterised by profound fatigue together with a variety of other subjective clinical features which persist over a prolonged period of time. The aetiology remains at present uncertain and therefore rational therapeutic strategies are difficult to plan. This paper reviews currently used forms of treatment aimed at correcting the possible pathophysiological mechanisms and discusses the problems associated with the management of this condition.

Selective C7 complement deficiency causing recurrent meningococcal infection.

We report on two sisters both with complete absence of the 7th component of complement. This congenital immunodeficiency disorder is associated with recurrent bacterial infection, especially that due to Neisseria species. These cases illustrate many of the well-recognised features of this disorder, but in one patient the illness was complicated by infective endocarditis due to N. meningitidis, a feature not previously reported.