Induction of circulating activated suppressor-like T cells by methimazole therapy for Graves' disease

Thyrostatic drug treatment of Graves' disease suppresses excessive thyroid hormone synthesis and causes a parallel decrease in serum thyroid autoantibody levels. The mechanism of this immunosuppression is unknown. We studied methimazole-induced immunoregulatory effects prospectively in 14 patients with Graves' disease treated for up to six months. The numbers of circulating activated, HLA-DR-positive T helper/inducer cells decreased gradually, from 8.3+1.7 percent (+SD) to 1.0+1.7 percent (P less than 0.001). HLA-DR-positive T suppressor/cytotoxic cells increased transiently at one month, from 2.0+1.9 percent to 12.6+6.4 percent (P less than 0.001), and returned to 2.9+3.7 percent at six months. Methimazole did not alter the HLA-DR expression of T cells in vitro. In two patients, the helper activity of T cells in inducing autoantibody secretion in vitro was substantially reduced after one month of methimazole treatment. Before treatment, large proportions of thyroid-infiltrating T-cell subsets expressed the activation markers HLA-DR, interferon-gamma, and interleukin-2 receptors, which were partially lost during therapy. Methimazole treatment was accompanied by a gradual reduction in circulating levels of thyrotropin-receptor, microsomal, and thyroglobulin autoantibodies. These results are compatible with the view that methimazole-induced immunoregulation in Graves' disease is mediated by a direct inhibitory effect on thyrocytes. This inhibition is in turn accompanied by marked changes in the proportions of activated T helper-like and T suppressor-like cells. This altered T-cell activation profile reflects, at least in part, the functional suppression of autoantibody production observed in methimazole-treated patients with Graves' disease.     

The cost-effectiveness of routine postoperative radiotherapy after sector resection and axillary dissection for breast cancer stage I. Results from a randomized trial

Background: Cost-effectiveness of routine postoperative radiotherapyafter breast-conserving surgery has not been prospectively evaluatedearlier. In times of rationing of medical resources, valid assessments ofcost-effectiveness are important for rational allocation of resources.Purpose: Cost and cost-effectiveness of routine postoperativeradiotherapy was calculated in a prospective randomized trial comparingsector resection plus axillary dissection with (XRT group) or without(non-XRT group) postoperative radiotherapy in breast cancer stage I. Threehundred eighty-one patients were included. After a median follow-up of fiveyears 43 local recurrences, six of them in the XRT-group occurred (P <0.0001). No difference in regional and distant recurrence (P = 0.23) orsurvival (P = 0.44) was observed.Patients and methods: Direct medical costs as well as indirect costs interms of production lost during the treatment period and travel expenseswere estimated from data in the medical records and the national insuranceregistry of each patient. Average costs of different treatment activitiesand measures were estimated for the XRT-group and the non-XRT grouprespectively. From these estimates differences in costs and effectivenessbetween the groups were calculated and marginal cost-effectiveness ratioswere estimated. For the construction of QALYs each life-year wasquality-adjusted by a utility value depending on which health state thepatient was considered to perceive.Results: Taking into account the cost of primary treatment, the cost offollow-up, the cost of treatment of a local recurrence, travel expenses andindirect costs (production lost) excluding costs for treatment of regionaland distant recurrence the cost per avoided local recurrence at five yearswas SEK 337,727 ($44,438, £27,018).Adjustment for quality of life showed a cost for every gained QALY to beSEK 1.6 million, ($210,526, £128,000), range SEK0.2–3.9 million ($26,315–513,158;£16,000–312,000).Conclusion: The cost of routine postoperative radiotherapy after sectorresection and axillary dissection in breast cancer stage I per avoided localrecurrence and gained QALY is high. The cost per gained QALY show greatvariation depending on utility value, which in this study was derived fromexternal observers and not from the patients themselves. These results stressthe importance of identifying risk factors for local recurrence, betterunderstanding of impact on quality of life of a local recurrence and addingcost evaluations to clinical trials in early breast cancer.     

The effects of different intravenous feeding regimens on the rates of synthesis of alpha1-antitrypsin after surgery

The effects of two nutritional regimens on the synthesis of alpha-1 antitrypsin were investigated postoperatively in gynaecological cancer patients. Total parenteral nutrition (TPN) or a hypocaloric amino acid mixture was administered on the day of surgery and continued for 3 days. The rate of synthesis of alpha-1 antitrypsin was estimated by a computer model from serial plasma concentrations of this protein and a reference protein, albumin. The hypocaloric amino acid mixture resulted in a more negative nitrogen balance than that produced during administration of TPN containing the same amount of nitrogen but more non-protein energy. Urinary excretion of 3-methylhistidine was significantly greater (p = 0.017) in the hypocaloric amino acid group (350 +/- 40 mumol/day; mean +/- SE) on the third postoperative day, as compared to the TPN group (240 +/- 20 mumol/day). In spite of this the synthesis of alpha-1 antitrypsin was apparently greater in the hypocaloric amino acid than in the TPN group. The accumulated plasma appearance rate of alpha-1 antitrypsin was significantly higher (p = 0.0465) in HAA group, at 70 h it was 490 +/- 40 compared to 400 +/- 20 times the pre-operative synthesis in the TPN group.     

Additional value of thallium-201 SPECT to a conventional exercise test for the identification of severe coronary lesions after an episode of unstable coronary artery disease

The additional value of thallium-201 SPECT to a conventional exercise test for the identification of patients with severe coronary lesions was evaluated in 170 men, one month after an episode of unstable coronary artery disease. Severe coronary lesions at coronary angiography — defined as three vessel disease, left main stenosis or proximal left anterior descending artery stenosis as part of two vessel disease — were observed in 45.9%. In the SPECT image, the left ventricular myocardium was divided into nine segments and each segment was classified as either normal (=0), reduced uptake (=1) or uptake defect (=2). The sum of gradings in all segments post-exercise was denoted SPECT score. The patients were divided into nine different groups regarding ST-depression during exercise (no ST-depression, ST-depression in 1–2 leads or 3 leads) and SPECT score (no SPECT score, 1–3 scores or 4 scores). Severe coronary lesions were, in 68% identified by SPECT score 4 and in 65% by ST-depression in 1 lead at exercise test. The specificity for identification of severe coronary lesions was, for both tests, 65%. SPECT score 4 and/or ST-depression in 3 leads identified 82% of the patients with severe coronary lesions with a specificity of 63%. Furthermore, SPECT score 3 identified more patients with isolated proximal left anterior descending artery stenosis than ST-depression alone at exercise test.     

Cerebral uptake and metabolism of (11C) Vinpocetine in monkeys: PET studies]

Vinpocetine, a vinca alkaloid, is a therapeutic agent widely used in the treatment of acute and chronic stroke patients. To explore the uptake and distribution of vinpocetine in the primate brain, vinpocetine was labelled with 11C and positron emission tomography (PET) was used to measure the uptake and distribution of 11C-vinpocetine in the brain and the trunk of a cynomolgous monkey. HPLC was used to determine the concentration of vinpocetine and its labelled metabolites in blood and plasma. Following the radioligand's intravenous administration, after an initial peak, the total concentration of radioactivity in blood was relatively stable with time. The uptake of 11C-vinpocetine into the brain was rapid and about 5% of the total injected radioactivity was present in the brain two minutes after drug administration. These facts indicate that the compound passes the blood-brain barrier readily and enters the brain. The radioactivity uptake was heterogeneously distributed among brain regions. The highest concentrations were found in the thalamus, the basal ganglia and certain neocortical regions. In an earlier PET investigation on chronic stroke patients the highest increases in cerebral blood flow and glucose metabolism after intravenous vinpocetine treatment occurred in these anatomical structures. The heterogenous regional distribution of vinpocetine and the observation that the highest uptake values in brain structures go parallel with the greatest regional blood flow and glucose metabolic rate increases indicate that direct CNS effects of vinpocetine should be considered as an explanation for the therapeutic effects. The confirmation of this suggestion requires further investigations.     

Tau immunoreactivity detected in human plasma, but no obvious increase in dementia

Tau proteins are central to the neuropathology of Alzheimer's disease and tau levels in cerebrospinal fluid are elevated in affected individuals. In this study, we investigated the presence of tau in plasma from subjects with Alzheimer's disease (n = 16), frontotemporal dementia (n = 10), vascular dementia (n = 16) and from healthy controls (n = 15). By using an ELISA with monoclonal tau antibodies, tau immunoreactivity was detected in approximately 20% of the subjects. However, no difference between the disease and control groups was seen. After gel filtration of tau immunopositive plasma, the peak reactivity was found in the 160-kD fraction, indicating the source to be tau-like molecules of high-molecular-weight or polymers of low-molecular-weight tau isoforms. We conclude that measurements of tau in plasma cannot be utilized diagnostically for Alzheimer's disease or for the other dementias investigated. Copyrightz1999S.KargerAG,Basel     

Alpine skiing and acute beta-blockade

The effect of acute unselective (propranolol) and beta 1-selective (atenolol) beta-adrenoceptor blockade was studied on alpine skiing in six leisure and seven elite skiers. Prior to the skiing tests a short time "all out" cycle ergometer test (Wingate muscle power test) was performed to confirm whether a beta-blocking effect (80 mg propranolol and 100 mg atenolol orally) was present or not. Peak and average power of the Wingate test showed an impairment in the order of 4%--6% (P less than 0.05--0.001). Peak blood lactate was only reduced after propranolol (0.05 greater than P greater than 0.01). During leisure skiing under submaximal exercise conditions peak blood lactate was increased (P less than 0.05) as compared to placebo, but rated perceived exertion (RPE) was unchanged as well as the estimated skiing technique. The elite skiers showed prolonged performance times (P less than 0.05) after beta-blockade and in the case of propranolol also reduced peak and mean blood lactates (P less than 0.05). It is suggested that during intense exercise propranolol reduced lactate formation, which is in line with previous reports. This might impair short time, "explosive" type muscular exercise. If there is a risk factor for injury during beta-blockade and alpine skiing, it might be connected to the impaired performance and metabolism in relation to intense exercise and propranolol treatment.     

Selfotel in acute ischemic stroke : possible neurotoxic effects of an NMDA antagonist

BACKGROUND AND PURPOSE: Based on neuroprotective efficacy in animal models, we evaluated the N-methyl D-aspartate antagonist Selfotel in patients with ischemic stroke, after doses up to 1.5 mg/kg were shown to be safe in phase 1 and phase 2a studies. METHODS: Two pivotal phase 3 ischemic stroke trials tested the hypothesis, by double-blind, randomized, placebo-controlled parallel design, that a single intravenous 1.5 mg/kg dose of Selfotel, administered within 6 hours of stroke onset, would improve functional outcome at 90 days, defined as the proportion of patients achieving a Barthel Index score of >/=60. The trials were performed in patients aged 40 to 85 years with acute ischemic hemispheric stroke and a motor deficit. RESULTS: The 2 trials were suspended on advice of the independent Data Safety Monitoring Board because of an imbalance in mortality after a total enrollment of 567 patients. The groups were well matched for initial stroke severity and time from stroke onset to therapy. There was no difference in the 90-day mortality rate, with 62 deaths (22%) in the Selfotel group and 49 (17%) in the placebo-treated group (RR=1.3; 95% CI 0.92 to 1.83; P=0.15). However, early mortality was higher in the Selfotel-treated patients (day 30: 54 of 280 versus 37 of 286; P=0.05). In patients with severe stroke, mortality imbalance was significant throughout the trial (P=0.05). CONCLUSIONS: Selfotel was not an effective treatment for acute ischemic stroke. Furthermore, a trend toward increased mortality, particularly within the first 30 days and in patients with severe stroke, suggests that the drug might have a neurotoxic effect in brain ischemia.     

The CINOD, AZD3582, exhibits an improved gastrointestinal safety profile compared with naproxen in healthy volunteers

COX-inhibiting nitric oxide donators (CINODs) are a new class of drugs in development for the treatment of acute and chronic pain. They comprise a COX-inhibiting moiety linked to a nitric-oxide-donating component and are designed to provide an innovative mechanism of action of balanced COX inhibition and controlled nitric oxide donation. Through these pathways, CINODs should provide analgesic and anti-inflammatory efficacy, while offering gastrointestinal safety through the tissue-protective effects of nitric oxide donation. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is the first agent in the CINOD class to enter extensive clinical development. Pre-clinical studies demonstrate that AZD3582 has a superior gastrointestinal safety profile to naproxen, while demonstrating analgesic and anti-inflammatory efficacy. In healthy human volunteers, AZD3582 caused little gastrointestinal damage compared with equimolar doses of naproxen. Studies to evaluate the longer-term gastrointestinal safety of AZD3582, alongside its efficacy in alleviating chronic and acute pain, are ongoing.     

Intensity modulated radiation therapy with electrons using algorithm based energy/range selection methods.

BACKGROUND AND PURPOSE: In recent years photon intensity modulated radiation therapy (IMRT) has gained attention due to its ability to improve conformity of dose distributions. A potential advantage of electron-IMRT is that the dose fall off in the depth dose curve makes it possible to modulate the dose distribution in the direction of the beam by selecting different electron energies. This paper examines the use of a computer based energy selection in combination with the IMRT technique to optimise the electron dose distribution. MATERIALS AND METHODS: One centimetre square electron beamlets ranging from 2.5 to 50 MeV were pre-calculated in water using Monte Carlo methods. A modified IMRT optimisation tool was then used to find an optimum mix of electron energies and intensities. The main principles used are illustrated in some simple geometries and tested on two clinical cases of post-operated ca. mam. RESULTS: It is clearly illustrated that the energy optimisation procedure lowers the dose to lung and heart and makes the dose in the target more homogeneous. Increasing the energy at steep gradients compensates for lack of target coverage at beam edges and steep gradients. Comparison with a clinically acceptable four segment plan indicates the advantage of the used electron IMRT technique. CONCLUSIONS: Using an intensity optimised mix of computer selected electron energies has the potential to improve electron treatments for mastectomy patients with good target coverage and reduced dose to normal tissue such as lung and heart.