Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial.

OBJECTIVE: To determine the optimum duration of oral anticoagulant therapy after an episode of deep vein thrombosis or pulmonary embolism, or both. DESIGN: Multicentre, prospective, randomised study with follow-up for one year. SETTING: 46 hospitals in United Kingdom. PARTICIPANTS: Patients aged > or =18 with deep vein thrombosis or pulmonary embolism, or both. INTERVENTIONS: Three (n=369) or six months (n=380) of anticoagulation with heparin for five days accompanied and followed by warfarin, with a target international normalised ratio of 2.0-3.5. MAIN OUTCOME MEASURES: Death from deep vein thrombosis or pulmonary embolism; failure to resolve, extension, recurrence of during treatment; recurrence after treatment; and major haemorrhage during treatment. RESULTS: In the patients allocated to three months' treatment two died from deep vein thrombosis or pulmonary embolism during or after treatment, compared with three in the six month group. During treatment deep vein thrombosis or pulmonary embolism failed to resolve, extended, or recurred in six patients in the three month group without fatal consequences, compared with 10 in the six month group. After treatment there were 23 non-fatal recurrences in the three month group and 16 in the six month group. Fatal and non-fatal deep vein thrombosis or pulmonary embolism during treatment, and after treatment thus occurred in 31(8%) of those who had received three months' anticoagulation compared with 29 (8%) of those who had received six months' (P=0.80, 95% confidence interval for difference -3.1% to 4.7%). There were no fatal haemorrhages during treatment but there were eight major haemorrhages in those treated for six months and none in those treated for three months (P=0.008, -3.5% to -0.7%). Thus 31 (8%) of the patients receiving three months' anticoagulation experienced adverse outcomes as a result of deep vein thrombosis or pulmonary embolism or its treatment compared with 35 (9%) of those receiving six months' (P=0.79, -4.9% to 3.2%). CONCLUSION: For patients in the UK with deep vein thrombosis or pulmonary embolism and no known risk factors for recurrence, there seems to be little, if any, advantage in increasing the duration of anticoagulation from three to six months. Any possible advantage would be small and would need to be judged against the increased risk of haemorrhage associated with the longer duration of treatment with warfarin. TRIAL REGISTRATION: Clinical Trials NCT00365950 [ClinicalTrials.gov].

Converging evidence for the under-reporting of concussions in youth ice hockey.

BACKGROUND: Concussions are potentially serious injuries. The few investigations of prevalence or incidence in youth ice hockey have typically relied on prospective reports from physicians or trainers and did not survey players, despite the knowledge that many athletes do not report probable concussions. OBJECTIVE: This study sought to compare concussion rates in youth ice hockey that were estimated from a variety of reporting strategies. METHODS: Rates were calculated from British Columbia Amateur Hockey Association (BCAHA) official injury reports, from direct game observation by minor hockey volunteers (such as coaches and managers), as well as from retrospective surveys of both elite and non-elite youth players. All research was conducted within the BCAHA. RESULTS: Estimates from official injury reports for male players were between 0.25 and 0.61 concussions per 1000 player game hours (PGH). Concussion estimates from volunteer reports were between 4.44 and 7.94 per 1000 PGH. Player survey estimates were between 6.65 and 8.32 per 1000 PGH, and 9.72 and 24.30 per 1000 PGH for elite and non-elite male youth hockey, respectively. CONCLUSION: It was found that concussions are considerably under-reported to the BCAHA by youth hockey players and team personnel.

The use of absorption enhancers to enhance the dispersibility of spray-dried powders for pulmonary gene therapy.

BACKGROUND: Pulmonary gene therapy requires aerosolisation of the gene vectors to the target region of the lower respiratory tract. Pulmonary absorption enhancers have been shown to improve the penetration of pharmaceutically active ingredients in the airway. In this study, we investigate whether certain absorption enhancers may also enhance the aerosolisation properties of spray-dried powders containing non-viral gene vectors. METHODS: Spray-drying was used to prepare potentially respirable trehalose-based dry powders containing lipid-polycation-pDNA (LPD) vectors and absorption enhancers. Powder morphology and particle size were characterised using scanning electron microscopy and laser diffraction, respectively, with gel electrophoresis used to assess the structural integrity of the pDNA. The biological functionality of the powders was quantified using in vitro cell (A549) transfection. Aerosolisation from a Spinhaler dry powder inhaler into a multistage liquid impinger (MSLI) was used to assess the in vitro dispersibility and deposition of the powders. RESULTS: Spray-dried powder containing dimethyl-beta-cyclodextrin (DMC) demonstrated substantially altered particle morphology and an optimal particle size distribution for pulmonary delivery. The inclusion of DMC did not adversely affect the structural integrity of the LPD complex and the powder displayed significantly greater transfection efficiency as compared to unmodified powder. All absorption enhancers proffered enhanced powder deposition characteristics, with the DMC-modified powder facilitating high deposition in the lower stages of the MSLI. CONCLUSIONS: Incorporation of absorption enhancers into non-viral gene therapy formulations prior to spray-drying can significantly enhance the aerosolisation properties of the resultant powder and increase biological functionality at the site of deposition in an in vitro model.

The use of amino acids to enhance the aerosolisation of spray-dried powders for pulmonary gene therapy.

BACKGROUND: Pulmonary delivery of gene therapy offers the potential for the treatment of a range of lung conditions, including cystic fibrosis, asthma and lung cancer. Spray-drying may be used to prepare dry powders for inhalation; however, aerosolisation of such powders is limited, resulting in poor lung deposition and biological functionality. In this study, we examine the use of amino acids (arginine, aspartic acid, threonine, phenylalanine) to enhance the aerosolisation of spray-dried powders containing model non-viral gene vectors. METHODS: Lipid/polycation/pDNA (LPD) vectors, in the presence or absence of amino acids, were dispersed in lactose solutions, and spray-dried to produce appropriately sized dry powders. Scanning electron microscopy and laser diffraction were used to determine particle morphology and diameter, respectively. Gel electrophoresis was used to examine the influence of amino acids on the structural integrity of the LPD complex. In vitro cell (A549) transfection was used to determine the biological functionality of the dry powders, and the in vitro aerosolisation performance was assessed using a multistage liquid impinger (MSLI). RESULTS: Both gel electrophoresis and in vitro cell transfection indicated that certain amino acids (aspartic acid, threonine) can adversely affect the integrity and biological functionality of the LPD complex. All amino acids significantly increased the aerosolisation of the powder, with the arginine and phenylalanine powders showing optimal deposition in the lower stages of the MSLI. CONCLUSIONS: Amino acids can be used to enhance the aerosolisation of spray-dried powders for respiratory gene delivery, allowing the development of stable and viable formulations for pulmonary gene therapy.

A confidential inquiry into asthma deaths in Wales.

BACKGROUND: Death from asthma is regarded as preventable in principle, especially under the age of 65 years. METHODS: In 1994 a confidential inquiry was set up to investigate deaths attributable to asthma in residents of Wales under the age of 65 years. During the period of the inquiry 92 cases were notified as being ascribed to asthma, or (in 1996) having a mention of asthma on the death certificate. Of these, 80 were investigated further with the help of general practitioners, hospital notes, and relatives. The details were then considered by a small panel of doctors who endeavoured to identify factors that may have contributed to the deaths. RESULTS: Asthma was considered to be the underlying cause of 52 deaths. Although disease severity was usually a major factor, some aspect of the patient's behaviour or circumstances seemed to have contributed to 31 deaths, while in 15 cases there was probably a deficiency in medical care. CONCLUSIONS: Some preventable asthma deaths still occur, particularly in relation to inadequate treatment. Factors associated with patients' behaviour and circumstances are more difficult to tackle but, if doctors are aware of high risk patients, increased vigilance may prevent some deaths.

Generic inhaled salbutamol versus branded salbutamol. A randomised double-blind study.

Generic substitution of salbutamol lags behind that of other drugs in Scotland and a negative perception by both patients and doctors may explain this. The aim of this study was to assess whether, in clinical practice, there was any difference in efficacy between branded salbutamol (Ventolin) and a generic preparation. Asthmatic patients using a Ventolin metered-dose inhaler at least twice a day for symptom relief were entered into a double-blind cross-over study, comparing Ventolin, blinded Ventolin and a generic salbutamol in random order for two weeks each. Daily peak flows, inhaler use and bronchodilator response were recorded. At the end of each treatment period patients rated their inhaler against their usual Ventolin on a 5-point scale. Forty patients were entered into the study; 90% received 1000 micrograms or more of inhaled steroids per day. Eleven patients dropped out during the run-in phase. In the remaining 29 patients, no significant difference between treatments could be found in any of the objective parameters measured. Fifty-five per cent of patients said they could detect a difference between the inhalers, and 45% noted a difference between their usual Ventolin and the open or blinded Ventolin. This study showed clinical equivalence between a generic and branded salbutamol. Patients' own assessment of their relief inhaler seems to be influenced by factors other than efficacy. The study highlights that careful encouragement is required when changing to a generic product and has particular implications for the forthcoming conversion to CFC-free products.

Damp housing and asthma: a case-control study.

BACKGROUND: Several epidemiological studies have reported a higher prevalence of respiratory symptoms in subjects living in damp housing, but links with specific respiratory diseases such as asthma have not been satisfactorily established. METHODS: One hundred and two subjects with physician diagnosed asthma and 196 age and sex matched controls were interviewed; 222 (75%) then agreed to have their dwelling surveyed for dampness. The prevalence of both self-reported and observed dampness in the homes of the asthmatic subjects and controls were compared. Both asthma and the severity of the dampness were quantified so that the possibility of a dose-response relationship could be investigated. RESULTS: Asthmatic subjects reported dampness in their current (odds ratio (OR) 1.92, 95% confidence interval (CI) 1.18 to 3.12) and previous (OR 2.11, 95% CI 1.29 to 3.47) dwellings more frequently than control subjects. The surveyor confirmed dampness in 58 of 90 (64%) dwellings of asthmatic subjects compared with 54 of 132 (41%) dwellings of control subjects (OR 2.62, 95% CI 1.50 to 4.55). This association persisted after controlling for socioeconomic and other confounding variables (adjusted OR 3.03, 95% CI 1.65 to 5.57). The severity of asthma was found to correlate statistically with measures of total dampness (r = 0.30, p = 0.006) and mould growth (r = 0.23, p = 0.035) in the dwelling. Patients living in homes with confirmed areas of dampness had greater evidence of airflow obstruction than those living in dry homes (mean difference in forced expiratory volume in one second (FEV1) 10.6%, 95% CI 1.0 to 20.3). CONCLUSIONS: Asthma is associated with living in damp housing and there appears to be a dose-response relationship. Action to improve damp housing conditions may therefore favourably influence asthma morbidity.

Evaluation of the pharmacological selectivity profile of alpha 1 adrenoceptor antagonists at prostatic alpha 1 adrenoceptors: binding, functional and in vivo studies.

1. The profile of a range of alpha 1 adrenoceptor antagonists was determined in vitro against cloned human alpha 1A, alpha 1B and alpha 1D adrenoceptors and against noradrenaline-mediated contractions of rat aorta and human prostate. The in vivo profile of compounds was determined in an anaesthetized dog model which allowed the simultaneous assessment of antagonist potency against phenylephrine-mediated increases in blood pressure and prostatic pressure. 2. The quinazoline antagonists, prazosin, doxazosin and alfuzosin displayed high affinity but were non selective for the three cloned human alpha 1 adrenoceptors. Indoramin and SNAP 1069 showed selectivity for alpha 1A and alpha 1B adrenoceptors relative to the alpha 1D subtype. Rec 15/2739, WB 4101, SL 89,0591, (+)- and (-)- tamsulosin showed selectivity for alpha 1A and alpha 1D adrenoceptors relative to the alpha 1B subtype. RS 17053 showed high affinity and selectivity for alpha 1A adrenoceptors (pKi 8.6) relative to alpha 1B (pKi = 7.3) and alpha 1D (pKi = 7.1) subtypes. 3. (+)-Tamsulosin, (-)-tamsulosin, SL 89,0591, Rec 15/2739, SNAP 1069 and RS 17053 appeared to act as competitive antagonists of noradrenaline-mediated contractions of rat aorta yielding pA2 affinity estimates which were similar to binding affinities at cloned human alpha 1D adrenoceptors. The following rank order was obtained: prazosin = (-)-tamsulosin > doxazosin > SL 89,0591 = (+)-tamsulosin > Rec 15/2739 > RS 17053 = SNAP 1069. 4. (-)-Tamsulosin was a very potent, insurmountable antagonist of noradrenaline-mediated contractions of human prostate, yielding an approximate pA2 estimate of 9.8 at 1 nM. The corresponding (+)-enantiomer was 30 fold weaker. SL 89,0591, SNAP 1069 and Rec 15/2739 yielded pA2 estimates which compared well with their alpha 1A binding affinities. The affinity estimate for prazosin on human prostate was lower than the corresponding binding affinity determined at alpha 1A adrenoceptors and RS 17053 was a very weak antagonist on human prostate (pA2 = 6.0) relative to the high affinity (pKi = 8.6) determined at cloned human alpha 1A adrenoceptors. 5. In the anaesthetized dog, in vivo pseudo "pA2' values showed that doxazosin, (+)- and (-)-tamsulosin inhibited phenylephrine-induced increases in prostatic and blood pressure with similar affinity, implying that these agents show little or no selectivity for prostatic responses in this model. SL 89,0591 and SNAP 1069 were moderately selective (3 and 6 fold respectively) for prostatic pressure relative to blood pressure. Rec 15/2739 was a more potent antagonist of phenylephrine-mediated increases in prostatic pressure ("pA2' = 8.74) compared to blood pressure ("pA2' = 7.51). 6. Data in this study suggest that the alpha 1 adrenoceptor mediating noradrenaline-induced contractions of human prostate, whilst having some of the characteristics of an alpha 1A adrenoceptor, cannot be satisfactorily aligned with cloned alpha 1A, alpha 1B or alpha 1D adrenoceptors. In addition, studies in the anaesthetized dog have shown that agents having high affinity and selectivity for prostatic alpha 1 adrenoceptors, particularly over the alpha 1D subtype, appear to inhibit phenylephrine-induced increases in prostatic pressure selectively compared to blood pressure.

Frequency of voice problems and cough in patients using pressurized aerosol inhaled steroid preparations.

The aim of the study was to assess the prevalence of throat and voice symptoms in asthma patients using pressurized aerosol, metered-dose, inhaled corticosteroid preparations. A questionnaire was administered to hospital out-patients in an asthma clinic and to a control group attending a diabetic clinic. Two hundred and fifty five consecutive out-patients using pressurized aerosol inhaled corticosteroids and 100 controls were surveyed. One hundred and forty seven (58%) patients taking inhaled steroids reported voice dysphonia or throat symptoms compared with 13% of control patients. Women admitted to symptoms more frequently than men. Throat symptoms were more prevalent in patients using higher doses of inhaled steroid. Aerosol inhaler-induced cough was reported by 87 (34%) patients. Local side-effects were equally prevalent both with beclomethasone dipropionate and budesonide aerosol inhalers. The use of a large volume spacing device with either steroid aerosol did not appear to protect against these symptoms. Local side-effects are common in asthmatics taking pressurized aerosol, metered-dose, inhaled steroids.

Anxiolytic-like effect of paroxetine in a rat social interaction test.

The effects of short- and long-term administration of the selective serotonin reuptake inhibitor paroxetine were investigated in a rat social interaction test. A single administration of paroxetine at oral doses of 0.3, 1, 3 and 10 mg/kg had no effect on social interaction between pairs of male rats under bright light (high anxiety) conditions. After 21 days of daily administration, paroxetine given orally at 3 mg/kg significantly (p < 0.01) increased the time spent in social interaction by pairs of rats tested under the same conditions, with no effect on locomotor activity, indicating an anxiolytic-like effect. The magnitude of increase (+97%) was comparable to that seen after a single dose of chlordiazepoxide (4 mg/kg orally). Although there was also an increase in time spent in social interaction after 21 days of repeated oral administration of paroxetine at 0.3, 1, and 10 mg/kg (+44, +56, and +54% increases, respectively), statistical significance was not achieved. These results indicate that in the long term paroxetine has an anxiolytic action, and thus support the clinical evidence for its therapeutic use in the treatment of anxiety disorders in addition to its established role as an antidepressant.

Plasma lactate dehydrogenase: a marker of disease activity in cryptogenic fibrosing alveolitis and extrinsic allergic alveolitis?

Total plasma lactate dehydrogenase (LDH) activity may be elevated in cryptogenic fibrosing alveolitis (CFA) and extrinsic allergic alveolitis (EAA), and may be a useful monitor of disease progress. In a retrospective, primary referral centre study, we compared LDH at presentation, prior to bronchoalveolar lavage BAL, and after treatment and follow-up with changes in pulmonary function, in patients with CFA, EAA and pulmonary sarcoidosis. Plasma levels of LDH at presentation in CFA (n = 47) and EAA (n = 10) were significantly higher than in patients with sarcoidosis (n = 36). LDH activity decreased in patients with improving lung function (EAA, p = 0.008; CFA, p = 0.02), whereas it increased in CFA patients with deteriorating lung function (p = 0.015). Total plasma LDH is a simple, though nonspecific test, which appears to reflect changes of disease activity in patients with CFA and EAA.

Fulminant hyperkalaemia and multiple complications following ibuprofen overdose.

A previously healthy 17-year-old man was admitted in coma following major overdosage with ibuprofen and minor overdosage of doxepin (plasma concentrations 809 and 0.49 mg/L, respectively). Initially, potassium chloride (20 mmol 3-hourly) was infused because of mild hypokalaemia (K+ 2.8 mmol/L). 14 hours after admission the patient developed a hypermetabolic state with pyrexia, metabolic acidosis and progressive respiratory failure despite ventilation at 16 L/min, and a malignant broad complex tachycardia was associated with acute hyperkalaemia (K+ 8.3 mmol/L). The arrhythmia resolved with correction of the hyperkalaemia. Chest x-rays showed diffuse opacification throughout both lung fields and subsequently there was transient impairment of renal function, with evidence of mild rhabdomyolysis. Ventilatory support was required for 60 hours and a chest x-ray at 6 days showed extensive bilateral nodular shadowing, which was still present at follow-up 4 weeks later.

Choline acetyltransferase activity in the pars distalis, preoptic area and striatum during the rat estrous cycle.

Choline acetyltransferase (CAT) activity of the striatum, preoptic area (POA), and pars distalis (PD) of the anterior pituitary gland was measured on each day of the 4-day estrous cycle of adult Wistar rats. Only in the PD did CAT activity vary significantly during the cycle, with the activity being lower during estrus than at other stages of the cycle. The CAT activity of the PD was extremely low, approximately 500 nmol/h/g protein, and, therefore, the specificity of the CAT activity of the PD was verified in studies on substrate requirement, the effect of a CAT inhibitor, and by paper chromatography of the reaction products. Measurement of CAT activity in saline-perfused glands, in sections of tissue taken from the lateral extremes of the PD and in hypophysial portal blood showed that the CAT activity of the PD was intrinsic, and not due to CAT activity in entrapped blood or adjacent tissues. The precise cellular origins of CAT in PD and the significance of the cyclical variation require further investigation.