A simple, reproducible method for monitoring the treatment of tumours using dynamic contrast-enhanced MR imaging.

Dynamic contrast-enhanced MR imaging (DCE-MRI) may act as a biomarker for successful cancer therapy. Simple, reproducible techniques may widen this application. This paper demonstrates a single slice imaging technique. The image acquisition is performed in less than 500 ms making it relatively insensitive to respiratory motion. Data from phantom studies and a reproducibility study in solid human tumours are presented. The reproducibility study showed a coefficient of variation (CoV) of 19.1% for K(trans) and 15.8% for the initial area under the contrast enhancement curve (IAUC). This was improved to 16 and 13.9% if tumours of diameter less than 3 cm were excluded. The individual repeatability (the range within which individual measurements are expected to fall) was 30.6% for K(trans) and 26.5% for IAUC for tumours greater than 3 cm diameter. This approach to DCE-MRI image acquisition can be performed with standard clinical scanners, and data analysis is straightforward. For treatment trials with 10 patients in a cohort, the CoV implies that the method would be sensitive to a treatment effect of greater than 18%. The individual repeatability is well inside the 40% change shown to be important in clinical studies using this DCE-MRI technique.

Hypoxia inhibits the growth, differentiation and bone-forming capacity of rat osteoblasts.

We investigated the effect of hypoxia on rat osteoblast function in long-term primary cultures. Reduction of pO2 from 20% to 5% and 2% decreased formation of mineralized bone nodules 1.7-fold and 11-fold, respectively. When pO2 was reduced further to 0.2%, bone nodule formation was almost abolished. The inhibitory effect of hypoxia on bone formation was partly due to decreased osteoblast proliferation, as measured by 3H-thymidine incorporation. Hypoxia also sharply reduced osteoblast alkaline phosphatase (ALP) activity and expression of mRNAs for ALP and osteocalcin, suggesting inhibition of differentiation to the osteogenic phenotype. Hypoxia did not increase the apoptosis of osteoblasts but induced a reversible state of quiescence. Transmission electron microscopy revealed that collagen fibrils deposited by osteoblasts cultured in 2% O2 were less organized and much less abundant than in 20% O2 cultures. Furthermore, collagen produced by hypoxic osteoblasts contained a lower percentage of hydroxylysine residues and exhibited an increased sensitivity to pepsin degradation. These data demonstrate the absolute oxygen requirement of osteoblasts for successful bone formation and emphasize the importance of the vasculature in maintaining bone health. We recently showed that hypoxia also acts in a reciprocal manner as a powerful stimulator of osteoclast formation. Considered together, our results help to explain the bone loss that occurs at the sites of fracture, tumors, inflammation and infection, and in individuals with vascular disease or anemia.

Acidosis inhibits bone formation by osteoblasts in vitro by preventing mineralization.

The negative effect of acidosis on the skeleton has been known for almost a century. Bone mineral serves an important pathophysiologic role as a reserve of hydroxyl ions to buffer systemic protons if the kidneys and lungs are unable to maintain acid-base balance within narrow physiologic limits. Extracellular hydrogen ions are now thought to be the primary activation signal for osteoclastic bone resorption, and osteoclasts are very sensitive to small changes in pH within the pathophysiologic range. Herein, we investigated the effects of acidosis on osteoblast function by using mineralized bone nodule-forming primary osteoblast cultures. Osteoblasts harvested from neonatal rat calvariae were cultured up to 21 days in serum-containing medium, with ascorbate, beta-glycerophosphate and dexamethasone. pH was manipulated by addition of 5 to 30 mmol/L HCl and monitored by blood gas analyzer. Abundant, matrix-containing mineralized nodules formed in osteoblast cultures at pH 7.4, but acidification progressively reduced mineralization of bone nodules, with complete abolition at pH 6.9. Osteoblast proliferation and collagen synthesis, assessed by 3H-thymidine and 3H-proline incorporation, respectively, were unaffected by pH in the range 7.4 to 6.9; no effect of acidification on collagen ultrastructure and organization was evident. The apoptosis rate of osteoblasts, assessed by the enrichment of nucleosomes in cell lysates, was also unaffected by pH within this range. However, osteoblast alkaline phosphatase activity, which peaked strongly near pH 7.4, was reduced eight-fold at pH 6.9. Reducing pH to 6.9 also downregulated messenger ribonucleic acid (mRNA) for alkaline phosphatase, but upregulated mRNA for matrix Gla protein, an inhibitor of mineralization. The same pH reduction is associated with two-and four-fold increases in Ca2+ and PO4(3-) solubility for hydroxyapatite, respectively. Our results show that acidosis exerts a selective, inhibitory action on matrix mineralization that is reciprocal with the osteoclast activation response. Thus, in uncorrected acidosis, the deposition of alkaline mineral in bone by osteoblasts is reduced, and osteoclast resorptive activity is increased in order to maximize the availability of hydroxyl ions in solution to buffer protons.

A filter for breast imaging on a radiotherapy X-ray simulator.

Simulator radiographs taken as a record of breast radiotherapy planning often show ill defined breast tissue margins because exposure parameters are set to optimize visualization of the chest wall rather than the bulk of the breast. This creates difficulties when using simulator images as reference images in verification by comparing with either portal film or images from an electronic portal imaging device. Our aim was to improve breast images taken at simulation without changing exposure parameters that have been optimized for visualization of the chest wall. This has been achieved via an external filter to be used when taking radiographs with the treatment simulator. The filter is made of stainless steel coated with tin and is shaped to maintain acceptable imaging of the chest wall by covering only the section of field anterior to the chest wall. Radiographs of breast simulations using the filter have been accepted as satisfactory by both clinicians and radiographers. The filter is now in routine clinical use for breast and chest wall treatment simulation.

Measurement of cardiac output in standing horses by Doppler echocardiography and thermodilution.

Measurement of cardiac output by Doppler echocardiography were compared to simultaneous measurements by thermodilution in 9 conscious horses. In the Doppler technique, mean blood flow velocities for estimation of cardiac output were recorded from the aorta and pulmonary artery. The flow area of each vessel was calculated from the vessel diameter, measured from a 2-dimensional ultrasound image. Differences in the site and method of measuring the vessel diameter altered the estimation of cardiac output by the Doppler method. Cardiac output was modified by the i.v. infusion of 4 micrograms/kg bwt/min dopamine and 4 micrograms/kg bwt/min dobutamine and by the i.v. administration of 10 micrograms/kg bwt detomidine and 20 micrograms/kg bwt butorphanol. Doppler measurements of cardiac output correlated closely with measurement by thermodilution. Measurements from the aortic outflow correlated more closely with thermodilution, than those from the pulmonary artery (r = 0.89 and r = 0.77, respectively). Doppler measurements when the mean flow velocity was recorded from the aorta and the flow area was measured from the ascending aorta using the leading edge method. There was no significant bias between the 2 techniques when Doppler flow velocities were recorded by this method and the limits of agreement were narrow (+/- 12.26 l/min). The differences between the 2 methods increased with increasing cardiac output. Doppler echocardiography is a safe noninvasive method of measuring cardiac output in horses. The agreement between Doppler echocardiography and thermodilution in this study is similar to that reported in man and is similar to that reported between thermodilution and other techniques in man.

Use of neostigmine in the antagonism of residual neuromuscular blockade produced by vecuronium.

Recovery from neuromuscular block produced by vecuronium was studied in 50 patients using electromyography and the train-of-four technique. Twenty patients received neostigmine 2.5 mg, 10 when the initial response of the train-of-four was 50% of control and 10 when it was 10%. Neostigmine 5 mg was investigated in a similar manner and in 10 patients spontaneous recovery was studied. In all patients the time to 70% recovery of the initial response and of the train-of-four ratio was followed. Neostigmine significantly reduced the time to 70% recovery of both ratios with both degrees of block, but neostigmine 5.0 mg did not give a substantially more rapid recovery than 2.5 mg. No evidence of a neostigmine-induced block was encountered. neostigmine 2.5 mg was rapidly effective in antagonizing vecuronium-induced block, even when initial recovery was only slight: there was no advantage in using neostigmine 5.0 mg.

Potentiation of the neuromuscular blockade produced by alcuronium with halothane, enflurane and isoflurane.

The potentiation of alcuronium by halothane, enflurane and isoflurane was investigated using electromyography. In the first study, cumulative dose-response curves were constructed in four groups of 10 patients anaesthetized with one of the inhalation agents and nitrous oxide, or with fentanyl and droperidol (control). All three agents reduced the ED50 of alcuronium; the effect was marked with isoflurane (P less than 0.005) but less so with halothane (P less than 0.05) and enflurane (ns). In the second part of the investigation, designed primarily to test the duration of action of alcuronium with each agent, a single bolus dose of alcuronium 0.2 mg kg-1 was given to four similar groups (n = 5). The duration of action was significantly prolonged by enflurane (P less than 0.01) and isoflurane (P less than 0.05), but not by halothane. The possible reasons for this are discussed.

Neostigmine in the antagonism of the action of atracurium.

Antagonism of atracurium-induced neuromuscular blockade with neostigmine (one or two doses of 2.5 mg) was compared, using electromyography, with spontaneous recovery. Two levels of blockade were studied, one in which the initial response of the train-of-four has reached 10% of control and the other 50% of control. Adequate recovery was considered to be present when the ratio of the fourth response to the first (train-of-four ratio) had reached 70%. Neostigmine always accelerated recovery and "neostigmine block" was not detected. This acceleration of recovery after neostigmine was most marked with the greater degree of blockade, but two doses of neostigmine were no more effective than one. Spontaneous recovery to the train-of-four ratio of 70% was slow, in the order of 1 h after an initial dose of 0.5 mg kg-1 and 45 min after incremental doses of 0.2 mg kg-1. It is concluded that antagonism of atracurium with one dose of neostigmine is usually desirable, that two doses are unnecessary, and that spontaneous recovery is slower than is generally realized.

Carcinoid syndrome with myasthenia gravis. An unusual and interesting case.

The anaesthetic management of a patient suffering from carcinoid syndrome and myasthenia gravis is described including the successful treatment of a carcinoid attack with intravenous aprotonin. The differences between myasthenia gravis and the myasthenic (Eaton-Lambert) syndrome are considered and the rationale for the choice of vecuronium as the muscle relaxant is discussed.

A comparison of the induction characteristics of thiopentone and propofol (2,6-di-isopropyl phenol).

A study has been undertaken to compare the induction characteristics of the new intravenous anaesthetic agent 2,6 di-isopropyl phenol, newly prepared in a lipid emulsion (propofol) with those of thiopentone. Despite a significantly higher incidence of pain on injection and spontaneous movement, the new agent was felt to perform comparably to thiopentone as an induction agent. Unfortunately, propofol caused decreases in blood pressure which were significantly greater than those seen after thiopentone. This feature may prove to be a considerable hurdle to the general acceptance of propofol.

Vecuronium in the myasthenic patient.

The use of vecuronium in six patients with myasthenia gravis undergoing thymectomy is described the train-of-four twitch technique was used to monitor neuromuscular function. The first two patients received an initial dose of 0.02 mg/kg and incremental doses of 4 micrograms/kg, which is in the order of one fifth of that normally used. Satisfactory depression of the first twitch of the train-of-four, however was not obtained and, therefore, in the remaining four patients the doses were doubled. At this dose satisfactory depression of the first twitch was achieved. Neostigmine 5.0 mg produced adequate reversal of residual neuromuscular blockade and the train-of-four twitch response recovered to normal levels. With reduced dosage and with careful neuromuscular monitoring, vecuronium can be used safely in the myasthenic patient.

The use of different doses of vecuronium in patients with liver dysfunction.

The clinical neuromuscular effects of two doses of vecuronium (0.15 mg kg-1 and 0.2 mg kg-1) were investigated in 20 healthy patients and 20 patients with cirrhosis, and compared with previous work in which vecuronium 0.1 mg kg-1 was given under identical conditions of anaesthesia and monitoring. Ten healthy patients received vecuronium 0.15 mg kg-1 and 10 received 0.2 mg kg-1. Similarly, 10 patients with cirrhosis received vecuronium 0.15 mg kg-1 and 10 received 0.2 mg kg-1. Vecuronium 0.1 mg kg-1 has previously been shown to have a somewhat shorter duration of action in cirrhotic as opposed to healthy patients. In this study, vecuronium 0.15 mg kg-1 was found to have a similar duration of action in both groups, and vecuronium 0.2 mg kg-1 had a significantly longer action in the cirrhotic group. It is suggested that vecuronium should be used with caution in patients with hepatic dysfunction and that, in such patients, monitoring of neuromuscular function is desirable.

Use of atracurium and vecuronium in patients with oesophageal varices.

The effects of atracurium (initial dose 0.5 mg kg-1; incremental doses 0.2 mg kg-1) and vecuronium (initial dose 0.1 mg kg-1; incremental doses 0.04 mg kg-1) are described in patients with portal hypertension and some degree of liver dysfunction, and the findings compared with those from normal patients. With these doses there was no evidence of gross resistance to the two neuromuscular blockers in the patients with liver problems, although the duration of action of the initial dose was somewhat shorter, and the same may have been true of incremental doses. The method of elimination would suggest that atracurium may be the better drug in patients with severe liver dysfunction, but the use of small doses of vecuronium is not contraindicated in this type of patient.

Atracurium in the myasthenic patient.

The use of the new competitive muscle relaxant, atracurium, is described in five myasthenic patients presenting for thymectomy. With an initial dose of 0.1 mg/kg, that is approximately one-fifth of that normally used, and incremental doses of 0.02-0.04 mg/kg, satisfactory clinical conditions were achieved. Neuromuscular function was monitored throughout using the train-of-four mechanical twitch response, and residual neuromuscular blockade was reversed satisfactorily at the end of the procedure with neostigmine 5.0 mg. A marked increase in the magnitude of the first twitch of the train-of-four to greater than control levels, accompanied by pronounced fade, was found on reversal. In reduced dosage and with careful neuromuscular monitoring, atracurium is safe to use in the myasthenic patient.