Cost-utility analysis of recombinant factor VIIa (NovoSeven) in six children with long-standing inhibitors to factor VIII or IX.

The high cost of treating patients with inhibitors in an environment of restricted budgets warrants consideration of cost-effectiveness. We determined the clinical response, effect on quality of life and the cost-effectiveness of treatment with rFVIIa in six boys with long-standing inhibitors to factors VIII or IX, compared with other treatment regimes previously used in these patients. The study used a longitudinal before-and-after design and was conducted in three phases. Phase 1 was 6 months preceding the introduction of rFVIIa, during which patients received on-demand 'usual care' with other treatment regimes; phase 2 was 6 months treatment on rFVIIa assessed retrospectively; and phase 3 was 6 months on rfVIIa treatment assessed prospectively. Treatment with rFVIIa was reserved for intrarticular, compartment, psoas, mucosal and suspected intracranial bleeding. Treatment outcomes were obtained by interview using structured questionnaires, the quality-of-life instruments CHQ CF-80 and CHQ PF-50, patient self-reporting diary, interrogation of hospital records, and the EuroQoL EQ-5D for utility valuations. Our results confirm that rFVIIa is clinically effective and resulted in 63-92% reductions in the number of re-treatments, duration of painful episodes, delay to initiation of treatment, days requiring wheelchair or crutches, emergency room visits and lost carer time compared with the patients' other therapies. Quality-of-life improvements were observed in several important areas as perceived by both patients and their families, at an incremental cost per QALY of A$51 533.

Complement and complement regulatory proteins in human tears.

PURPOSE: The complement system is part of the innate defense system of the body, and it contributes to inflammatory conditions. The current study examined tears for the presence of complement components, the activity of the components, and the presence of regulatory components. METHODS: The significance of a functional complement system in tears was examined in four ways. First, the presence and concentration of complement components in tear samples (open-eye, closed-eye, and reflex tears) was examined by sandwich enzyme-linked immunosorbent assay. Second, the presence of an active pathway in each tear type was established by supplementation of complement-deficient sera. Third, Western blotting of tear samples was used to determine whether complement components were activated in tears. Fourth, the presence of regulatory components was examined by enzyme-linked immunosorbent assay and by the inhibition of the ability of tears to supplement deficient sera. RESULTS: Components C1q, C3, factor B, C4, C5, and C9 were detected in closed-eye tears. Only C3, factor B, and C4 were detected in open-eye and reflex tears. Tears were able to supplement complement-deficient sera, indicating that the components were in an active state. Complement components C3, factor B, C4, and C9 were activated in closed-eye tears. The regulatory protein decay-accelerating factor was found only in closed-eye tears. Lactoferrin, another regulatory protein present in all tear types, was shown to inhibit complement-mediated red blood cell lysis, although the inhibition by closed-eye tear lactoferrin was reduced compared to that isolated from other tear types. CONCLUSIONS: This study has demonstrated that the complement system in tears was functionally active and that the concentration of all components was increased greatly in closed-eye tears. In spite of the presence of regulatory proteins, proteins of the complement cascade in tears were shown to be activated.

Challenges in ambulatory surgery: discharge criteria.

The weakest link in ambulatory surgery is often the discharge of patients. Protocols and guidelines are important for the safe discharge of patients. The patient who has recovered sufficiently for discharge is considered "home ready", is in the intermediate stage of recovery and is to continue the recovery at home under the supervision of a responsible adult. There are many tests of recovery but none suitable for routine clinical use. The mean hospital transfer rate for a multidisciplinary ambulatory centre is between 0.12% to 1.2%. Gynaecology and urology have the highest hospital transfer rate. Surgical causes of hospital transfer are three to five times greater than anaesthetic causes. Common anaesthetic reasons for hospital transfer were inadequate recovery, nausea and vomiting, hypotension and syncope. Surgical reasons for hospital transfer included bleeding, extensive surgery, perforated viscus and further treatment. The patient should be discharged by a physician after satisfying a checklist of "discharge criteria".

Fluorescence resonance energy transfer within the regulatory light chain of myosin.

Rabbit skeletal muscle myosin regulatory light chain-2 (LC2) contains two reactive cysteine residues, Cys125 and Cys154, and one tryptophan at position 137. Using wild-type rabbit LC2 or its genetically engineered mutant with Cys125-->Arg (C125R), these residues can be selectively modified with fluorescent or chromophoric probes for spectroscopic studies. We have bound suitable donor/acceptor probe pairs to the two cysteine residues and Trp137 in LC2 or C125R, and measured the distance in solution between the probes by fluorescence resonance energy transfer spectroscopy. C125R was made to facilitate specific labelling of the less reactive Cys154, thus allowing the distance between Cys154 and Trp137 to be measured. Our measurements show that these residues are in close proximity to each other, the distance between them ranging from 1.7 nm (between Cys125 and Trp137) to 2.7 nm (Cys125 and Cys154). These results suggest that Cys125, Trp137 and Cys154, spanning up to 29 residues in the sequence of LC2, are spatially close, consistent with these residues residing within a C-terminal globular domain. The distances we obtained are in agreement with previous crosslinking studies [Huber, P. A., Brunner, U.T. & Schaub, M. C. (1989) Biochemistry 28, 9116-9123; Saraswat, L. & Lowey, S. (1991) J. Biol. Chem. 266, 19777-19785] and structure predictions of LC2. LC2 is located at the head-rod junction of the myosin crossbridge, and provides the primary regulatory mechanism in molluscan and smooth muscle. In skeletal muscle, its functional role is unclear, although it has been implicated in modulating actomyosin interaction [Metzger, J. M. & Moss, R. L. (1992) Biophys. J. 63, 460-468]. The incorporation of spectroscopic probes onto the light chains of myosin in solution or in fibres has become a valuable tool for evaluating the dynamic properties of the crossbridge during force generation.

Metabolic profile of patients after elective open heart surgery.

To evaluate the surgical stress of open heart surgery with moderate hypothermic cardiopulmonary bypass (CPB), oxygen consumption (VO2), carbon dioxide production (VCO2), resting energy expenditure (REE), respiratory quotient (RQ), 24 hour-urinary urea nitrogen excretion (UUN), and glucose, fat and protein utilization were determined in 20 patients before and after open heart surgery. Proteins (albumin, prealbumin and transferin) and body weight were measured preoperatively and on 6th postoperative day (POD). Preoperative predicted EE as determined by the Harris-Benedict equation was correlated with measured REE. No significant alteration in VO2, VCO2, REE, 24 hour UUN and protein utilization was observed on the first 6 PODs. RQ decreased significantly on the 1st, 3rd and 4th POD. This was attributed to greater fat utilization due to reduced calorie intake during the early postoperative period. Transport proteins reduced slightly but insignificantly. There was a significant reduction in body weight at the end of the study period due probably to loss of body water. We conclude that patients in the early postoperative period after uneventful open heart surgery are neither hypermetabolic nor hypercatabolic when compared with their stable state before operation.

Uncoupling of actin-activated myosin ATPase activity from actin binding by a monoclonal antibody directed against the N-terminus of myosin light chain 1.

The role of the N-terminal region of myosin light chain 1 (LC1) in actomyosin interaction was investigated using an IgG monoclonal antibody (2H2) directed against the N-terminal region of LC1. We defined the binding site of 2H2 by examining its cross-reactivity with myosin light chains from a variety of species and with synthetic oligopeptides. Our findings suggest that 2H2 is directed against the N-terminal region of LC1 which includes the trimethylated alanine residue at the N-terminus. In the presence of 2H2, the rate of actomyosin superprecipitation was reduced, although the extent was not. 2H2 caused a reduction in the Vmax of both myosin and chymotryptic S1(A1) actin-activated ATPase activity, while the Km appeared to be unaltered. The Mg(2+)-ATPase activity of myosin alone was also unaffected. Binding studies revealed that 2H2 did not prevent the formation of acto-S1 complex, either in the presence or in the absence of ATP, nor did it affect the ability of ATP to dissociate S1 from F-actin. Our findings suggest that the N-terminal region of LC1 is not essential for actin binding but is involved in modulating actin-activated ATPase activity of myosin.

Haemodynamic effects of ketanserin following coronary artery bypass grafting.

The haemodynamic effects of ketanserin were studied consecutively in seventeen patients in the intensive care unit following coronary artery bypass grafting. Hypertensive patients (Group 1, systolic blood pressure (SBP) greater than or equal to 150 mmHg following discontinuation of nitroprusside, n = 10) received intravenous ketanserin 10 mg and infusion of 0.1 mg.kg-1.hr-1 with additional boluses as required to maintain SBP less than or equal to 130 mmHg for one hour. Non-hypertensive patients (Group 2, SBP less than 150 mmHg, n = 7) received a 5 mg bolus and the same infusion. Ketanserin significantly decreased arterial blood pressure (P less than 0.001) in all patients in Group 1. Heart rate was decreased but not significantly. Cardiac index, systemic and pulmonary vascular resistance and pulmonary shunt fraction were not significantly altered from pre-ketanserin values when blood pressure was controlled with nitroprusside. Normotensive patients in Group 2 did not show any undesirable hypotension or significant haemodynamic changes. Mean nitroprusside dose requirements following ketanserin therapy were significantly reduced by 91.6% in Group 1 and 78.4% in Group 2 (P less than 0.05). Ketanserin is effective in treating hypertension following coronary artery bypass grafting with an advantage of lack of reflex tachycardia.

Comparison of propofol and thiopentone as induction agents for laparoscopy.

Fifty two patients for laparoscopy were randomly divided into two groups and induced with propofol 2 mgkg-1 or thiopentone 4 mgkg-1. The two groups were similar for race, age, weight, premedication and duration of operation. General anaesthesia with endotracheal intubation, nitrous oxide/oxygen with 0.5% halothane and muscle relaxation with suxamethonium was used throughout. Induction times were similar for both groups. The systolic, diastolic blood pressures and heart rates of both groups fell significantly from baseline values two minutes after induction. The fall in systolic blood pressure was greater with propofol (p less than 0.01). Following intubation the rise in systolic, diastolic blood pressures and heart rate above baseline values were greater with thiopentone (p less than 0.001 for all three variables). Discomfort on injection and involuntary movements were significantly more common with propofol. Laryngospasm was significantly more common with thiopentone. Patients given propofol could sit up unaided earlier after the anaesthesia (p less than 0.01). There was no difference in eye opening and orientation time.

Pain control.

There are two components to the perception of pain; the 'sensory' and the 'reactive'. Psychological factors control the latter. Pain research is rapidly advancing: the discovery of endorphins and opioid receptors, the appreciation of the psychological component of pain and the multidisciplinary approach to chronic pain are major advances. Pain can be classified as acute or chronic. Acute pain is easy to diagnose, the cause of pain obvious and the treatment logical, chronic pain has a greater psychological component, is difficult to diagnose and treatment is often empirical. Methods of pain control include drugs, injection techniques, electro stimulation, non invasive therapies, denervation procedures and palliative procedures. A multidisciplinary approach and a combination of methods is necessary to treat chronic pain. Spinal opioids, radiofrequency thermocoagulation, intrapleural bupivacaine, cryoanalgesia and patient controlled analgesia are recent advances in pain control. However, most pain can be controlled adequately with simple methods; what is essential is the interest and commitment of the physician towards achieving optimum therapeutics.

Comparison of propofol and thiopentone as anaesthetic agents for electroconvulsive therapy.

Propofol and thiopentone were compared as anaesthetic agents for electroconvulsive therapy in 31 patients on four occasions in a repeated measure crossover study. Discomfort on injection was significantly more common with propofol (51.6% of anaesthetics) compared to thiopentone (1.6% of anaesthetics). The duration of seizure was shorter with propofol in both treatments but there was significant drug-time interaction. Propofol gave a milder tonus and clonus during seizure when both treatments were considered together. The increase in systolic and diastolic arterial pressures and heart rate after treatment were significantly higher with thiopentone. Apnoea was significantly longer with propofol. The times to sitting up unaided and opening the eyes on command were the same for both drugs. The ability to walk 10 m 20 minutes after anaesthesia was significantly better with propofol (p less than 0.0001).

The role of protamine dose assay in reversal of heparin following extracorporeal circulation for open heart surgery.

The amount of protamine required for the neutralisation of heparin following cardiopulmonary bypass was determined by a Protamine Titration Assay using the principle of the dose--response curve and the patient's estimated blood volume. In 300 open heart surgery patients, infusion of the determined dose of protamine normalised the Activated Clotting Time (ACT) to baseline levels in 97% of these patients and produced adequate hemostasis. Our present study showed that the dose of protamine dropped to 75% of the dose calculated by conventional method of heparin to protamine ratio of 1:1. This had minimised the adverse effects of excessive protamine administration and optimised coagulation control after extracorporeal circulation.

Analgesia and respiratory function following intrapleural bupivacaine after cholecystectomy.

Analgesia and pulmonary function following intrapleural bupivacaine were compared with those following intramuscular pethidine in thirty-four patients after cholecystectomy. The patients were randomly allocated to two groups of seventeen patients each to receive either intrapleural bupivacaine or intramuscular pethidine. The positions of seventeen intrapleural catheters inserted were confirmed by chest radiography. Two out of seventeen catheters were found to be located in the extrapleural space. It was also recognized by fluoroscopy that phrenic nerve palsy did not develop on patients given intrapleural bupivacaine. The subjective quality of analgesia following intrapleural bupivacaine was significantly better than that following intramuscular pethidine. The mean duration of analgesia obtained after each injection of bupivacaine was 4.68 hr (range 3.5-6.1 hr). Forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV 1), which decreased markedly in the postoperative period improved significantly after being given bupivacaine or pethidine. But there was no significant difference in the improvement of FVC and FEV 1, between both groups in spite of the higher percentage of pain relief in the intrapleural bupivacaine group. All respiratory function tests studied thirty days after surgery were not significantly different when compared with those before surgery.