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.     

Cardiac arrest during caesarean section

A case is described of a previously healthy obese woman in her fourth pregnancy who presented for caesarean section due to cephalopelvic disproportion (CPD). Forty minutes after a spinal anaesthetic a healthy child was delivered. Shortly after the injection of ergometrine and Syntocinon into the uterus, the patient described a general feeling of discomfort which was followed by convulsions and cardiac arrest. Resuscitation was successful and the circulation was restored. However, it was difficult to maintain oxygenation and the patient was mechanically ventilated for 24 hours and subsequently supplementary oxygen therapy was given for three days. A pulmonary scintigram on the fourth day after delivery showed large uptake defects indicative of pulmonary embolism. The patient recovered completely and was discharged home after two weeks. Differential diagnosis and measures to reduce the risk of deep vein thrombosis (DVT) are discussed.     

Pregnancy: Effects of hyperosmolar glucose, prostaglandin-F2{alpha} and 15-methyl-prostaglandin-F2{alpha} on human placental cells in vitro

The objective of this study was to assess the ability of certaindrugs, used for local injection therapy of ectopic pregnancy,to suppress the activities of cultured human placental cells.Placental cells from legal first trimester abortions were preparedby collagenase treatment and density gradient centrifugation.The cells were exposed to hyperosmolar glucose (500 mg/ml),15-methyl-prostaglandin-F₂ (15-m-PGF₂; 10–7 to 10–3mol/l) and prostaglandin-F₂ (PGF₂; 10–5 to 5X10–3mol/l) for 30 min on days 2–4 after seeding. The effectson the secretion of human chorionic gonadotrophin (HCG) andprogesterone, as well as on the protein content per culturewell, were measured. Hyperosmolar glucose was the most effectivedrug and caused a marked decrease of the protein content inthe culture wells and a reduction of progesterone secretion.Of the two prostaglandins, only 15-m-PGF₂ affected the viabilityof the cells and reduced the protein content of the wells. Theclinical effectiveness of the two groups of drugs seems to besimilar but certain in-vitro effects are different. Thus invivo they may act on different target tissues. Against thisbackground, the combination of hyperosmolar glucose and prostaglandinsmight be an interesting approach for local injection therapyfor tubal pregnancy.     

Leukocyte activation by isolated hyperthermic liver and limb perfusion due to malignancy

Fourteen patients with liver tumor malignancy and sixteen patients with malignant melanoma localized to one limb were studied regarding leukocyte activation with the release of polymorphonuclear neutrophilic (PMN) elastase and of neopterin and formation of cytokines (TNF- and Il-6) during the surgical treatment. Patients undergoing liver resection (n=10), abdominal hysterectomy (n=10), or hip replacement surgery (n=10) served as control groups. Isolated hyperthermic liver perfusion was performed with cytostatic-containing perfusate (melphalan and cisplatinum). Patients with recurrent malignant melanoma confined to one limb underwent isolated hyperthermic limb perfusion with cytostatic-containing perfusate (melphalan). Blood samples for determination of PMN elastase, neopterin, TNF-, and IL-6 were drawn from the patients preoperatively, 1 minute before the start of the perfusion, 60 and 120 minutes after the start of the perfusion, and 24 hours postoperatively. Samples from the perfusate were drawn 60 minutes after the start of the perfusion. High concentrations of plasma PMN clastase were found both in patients undergoing liver and limb perfusion and in patients undergoing liver resection surgery. Elevated concentrations of Il-6 were found in the patients undergoing liver perfusion and in patients undergoing liver resection. In none of the patients were there increased concentrations of neopterin or TNF-. The perfusate contained high concentrations of PMN elastase, neopterin, and IL-6. This study also demonstrated that major surgery leads to elevated concentrations of PMN elastase and IL-6. An increase of PMN elastase and IL-6 was seen in response to perfusion and to surgical trauma.

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Resumen Catorce pacientes con tumores malignos del hígado y 16 pacientes con melanoma maligno localizado en una extremidad fueron estudiados en relación con la activación de leucocitos con liberación de elastasa de PMN y de neopterina y la formación de citocinas (FNT- e IL-6) en el curso del tratamiento quirúrgico. Pacientes sometidos a resección del hígado (n=10), histerectomía abdominal (n=10) y reemplazo de cadera (n=10) sirvieron como grupos control. Se realizó perfusión hipertérmica aislada del hígado con perfusato citostácico (melfalán y cisplatino). Los pacientes con melanoma maligno recurrente confinado a una extremidad fueron sometidos a perfusión hipertérmica aislada de la extremidad con perfusato citostácico (melfalán). Se tomaron muestras de sangre para determinación preoperatoria de elastasa de PMN, neopterina, FNT- e IL-6, un minuto antes de comenzar la perfusión, 60 y 120 minutos después del comienzo de la perfusión y 24 horas después de la operación. Se tomaron muestras del perfusato a los 60 minutos luego del comienzo de la perfusión. Se encontraron altas concentraciones de elastasa de PMN tanto en los pacientes sometidos a perfusión hepática o de la extremidad, como en los pacientes sometidos a resección hepática. Se encontraron concentraciones elevadas de IL-6 en los pacientes sometidos a perfusión hepática y en los pacientes sometidos a resección del hígado. En ningún paciente se encontraron concentraciones aumentadas de neopterina o de FNT-. El perfusato contenía altas concentraciones de elastasa de PMN, neopterina e IL-6. Se encontró un aumento en la elastasa de PMN y en la IL-6 en respuesta a la perfusión y al trauma quirúrgico.

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Résumé Quatorze patients ayant une tumeur maligne du foie et 16 patients ayant un mélanome malin localisé à une extrémité ont été étudiés en ce qui concerne l'activation des leucocytes associée à un relargage d'élastase PMN et de néoptérine ainsi que la formation de cytokinines (TNF- et IL-6) pendant le traitement chirurgical. Trente patients avant eu soit une résection hépatique (n=10), soit une hystérectomie abdominale (n=10) ou une prothèse de hanche (n=10) ont servi de témoins. On a perfusé le foie avec un perfusât de cytostatiques (mélphalane et cis-platine). Les patients ayant un mélanome malin d'une extrémité ont eu une perfusion isolée hyperthermique avec une perfusion de cytostatique (mélphanane). Des échantillons du sang ont été retirés pour déterminer les taux d'élastase PMN, de la néoptérine, du TNF-, et de l'IL-6 en préopératoire, une minute avant le début de la perfusion, 60 et 120 minutes après le début de la perfusion, et 24 heures postopératoirement. Des échantillons ont été retirés 60 minutes après le début de la perfusion. Des concentration élevées d'élastase PMN ont été retrouvées à la fois chez les patients ayant une perfusion hépatique et de l'extrémité et chez les patients ayant eu une résection du foie. Des concentration élevées en IL-6 ont été retrouvées chez le patient ayant une perfusion du foie et chez le patient ayant une résection hépatique. Les concentrations en néoptérine et en TNF- n'étaient pas élevées. Le liquide de perfusion contenait des concentrations élevées en élastase PMN, néoptérine et en IL-6. Cette étude démontre aussi que la chirurgie majeure est associée avec des concentrations élevées en PMN elastase et IL-6. Une augmentation en PMN-élastase et en IL-6 a été retrouvée en réponse à la perfusion et au traumatisme chirurgical.

     

Persistent Organochlorines in the Effluents from a Chlorine-Bleached Kraft Integrated Pulp and Paper Mill in Southeast Asia

A bleached sulfate integrated pulp and paper mill producing printing and writing paper from mixed tropical hardwood and bamboo was studied. The mill uses a “conventional bleaching sequence,” C-E-H1-H2, with an average molecular chlorine consumption of 50 kg per ton of air-dried pulp (ADP). The content of polychlorinated dibenzofurans (PCDFs) and dibenzo-p-dioxins (PCDDs) in the bleaching filtrate in terms of the nordic toxicity equivalent (N-TEQ) was 33.5, 1.15, 0.56, and 0.014 pg/L for the E, C, H1, and H2 bleaching stages, respectively. The corresponding PCDFs and PCDDs loads in ng/t ADP were in the same ranking, i.e., 670, 69, 11.2, and 0.28, respectively. The congener and isomeric pattern of PCDFs and PCDDs of the bleaching filtrate and the bleached pulp was found to be typical for the chlorine bleaching plant effluent. The obtained dioxin load formed in the mill is in agreement with Western studies for the given multiple chlorine of 0.21–0.23. The load is, however, lower than reported discharges from Scandinavian mills using 1980s bleaching technologies, but substantially higher than the discharges from mills with modern bleaching technologies. Modifications in the bleaching plant to reduce molecular chlorine use are necessary to reduce dioxin formation. Received: 15 July 1998/Accepted: 17 March 1999     

Pharmacokinetic and pharmacodynamic responses to chronic administration of the selective serotonin reuptake inhibitor citalopram in rats

The number of drugs used to treat affective disorders such as depression is rapidly increasing. Citalopram (CIT), an antidepressant, is a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI). In the present study, rats were treated with 10 mg/kg/d racemic CIT for two weeks with use of osmotic pumps, and the following were monitored: open-field behavior, racemic and enantioselective concentrations of CIT and metabolites in blood, brain parenchyma, and extracellular space, and the brain extracellular monoamine levels. The racemic CIT concentration in serum was estimated about tenfold lower than in brain parenchyma but much higher than in brain extracellular fluid. The major CIT metabolites, demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT) were 20% and 30%, respectively, of the amounts of CIT in serum and even lower in the brain parenchyma. The S-enantiomer/R-enantiomer ratios for CIT and DCIT were about 1.01 and 0.31, respectively, in blood and brain. There was a clear correlation between the different drug components within and between blood and brain compartments. Citalopram had no measured effect on open-field behavior, but it elevated extracellular 5-HT and decreased 5-HIAA levels. No correlations between any of the drug components and the brain monoamines were found. In summary, the drug components after chronic dosing correlated well between the periphery and the brain, but not with the brain monoamine concentrations. Further studies investigating the combined pharmacokinetic/dynamic effects could take advantage of blood drug monitoring for the commonly used novel antidepressant drugs.     

Altered adaptive behaviour expressed in an open-field paradigm in experimental hepatic encephalopathy

Chronic hepatic encephalopathy (HE) encounters a neuropsychiatric syndrome arising as a complication to liver dysfunction. Patients with chronic HE display a great variety of neuropsychiatric symptoms including such mental derangements as adaptational difficulty, and deteriorated learning and memory capacity. The portacaval shunt (PCS) in the rat is a widely used model for experimental chronic HE. In the present study, the adaptive capacity of unhabituated PCS rats and sham-operated control rats were studied by measuring two exploratory behaviours (locomotion and rearing) during 5 or 60 min, at four consecutive days or nights with 24 h between sessions. The results revealed that PCS and sham-operated control rats showed parallel behavioural outcome over the four sessions in the 5-min trial. However, at the four consecutive test sessions in the 60-min trials, the sham-controls displayed a continuing decrease in overall activity between sessions whereas the PCS rats evidenced a repeated and stable activity level. These results indicate a presence of a long-term habituation deficiency as exhibited by the PCS rats. Additionally, the results indicate that differences in normal open-field motor behaviour between PCS rats and controls may not be found if such tests are conducted repeatedly during night-time but may emerge when tested repeatedly during daytime. The results may also be interpreted as a possible impaired learning/memory capacity in PCS rats. However, further investigations of how the PCS procedure affects entities of adaptation and learning ability are needed before any conclusions may be drawn since this is the first report of such an impairment in experimental chronic HE when represented by the PCS rat.     

Inter-subject variability and normal limits of the SITA Standard, SITA Fast, and the Humphrey Full Threshold computerized perimetry strategies, SITA STATPAC.

PURPOSE: To establish and evaluate inter-subject variability and normal threshold limits for the new SITA strategies and to compare them with those obtained with the traditional Humphrey Full Threshold algorithm. METHODS: Data from 330 eyes of 330 normal subjects were collected at 10 centres in order to establish limits of normality for the new SITA strategies and thus, to make it possible to subject SITA fields to computer-assisted visual field analysis. Two visual field tests were obtained with each of the SITA Standard, SITA Fast, and the Full Threshold algorithms. RESULTS: Inter-subject variance was 31% smaller with SITA Standard and 41% smaller with SITA Fast than with Full Threshold (p<0.0001). Age-dependent decrease of differential light sensitivity was also significantly smaller with both SITA algorithms than with Full Threshold (p<0.0001), 23% and 25% respectively. Mean sensitivity was somewhat higher with both SITA Standard (29.5 dB) and SITA Fast (29.9 dB) as compared to Full Threshold (28.3 dB) (p<0.0001). Normal limits were tightened between 9 to 29% at different significance levels with SITA. CONCLUSION: SITA test results from eyes with normal visual fields will on average be more even from centre to mid-periphery as compared with Full Threshold fields. They will also appear slightly lighter in grey-scale representations. Because of smaller inter-subject variance, shallower depressions are needed in SITA fields for statistical and clinical significance.     

Comparing significance and magnitude of glaucomatous visual field defects using the SITA and Full Threshold strategies.

PURPOSE: To evaluate and compare visual field test results as presented by the Statpac interpretation tools in tests obtained with the new short SITA Standard and the even shorter SITA Fast strategies to the traditional Humphrey Full Threshold strategy. SUBJECTS AND METHODS: One eye of each of 44 glaucoma patients was examined four times with each of the Humphrey SITA Standard, SITA Fast, and Full Threshold strategies. Another 21 eyes of 21 normal subjects had one eye examined once with each of the three strategies. RESULTS: Average light sensitivity was highest with the shortest SITA Fast strategy and lowest with the longest Full Threshold strategy. Magnitude of field loss as defined by the Statpac Mean Deviation (MD) did not differ between the three strategies. In the glaucoma patients, both SITA strategies showed larger number of significantly depressed points in Statpac probability maps than the Full Threshold strategy. In the normal subjects SITA Standard showed more significantly depressed points, close to the statistically expected number, at the lowest probability level (p<5%) than both Full Threshold and SITA Fast. At higher probability levels (p<1%) SITA Standard and Full Threshold showed similar numbers of significantly depressed points. CONCLUSION: Both SITA Standard and SITA Fast identified at least as much significant glaucomatous field loss as the Full Threshold using the Statpac interpretation tools.     

Optic nerve head sector analysis recognizes glaucoma most effectively around disc poles

PURPOSE: To analyze the topography of normal and glaucomatous discs with the goal of developing improved strategies to discriminate between normal and glaucomatous eyes. SUBJECTS AND METHODS: Raster tomography was performed in both eyes of 225 healthy subjects and in 296 eyes of 214 glaucoma patients. Cup area, average cup radius, rim area and minimal rim width were measured in 24 sectors around the optic nerve head at nine different depths from the reference plane. Receiver Operating Curves (ROC) for numerous combinations of parameter, sector and depth were calculated and compared. RESULTS: Discrimination between glaucomatous and normal eyes varied widely between single sectors of the optic disc, and was best at the vertical poles of the disc, intermediate in nasal sectors and worst in temporal sectors. When single sectors or combinations of sectors at the superior pole were combined with their counterparts at the inferior pole of the optic nerve, the gain in sensitivity exceeded the loss in specificity, and discrimination improved. Separation declined dramatically if any of the 8 temporal sectors were involved in such analysis. Depth influenced discrimination only slightly. CONCLUSION: Single sectors located close to the vertical meridian yielded better discrimination than global measurements. When two or more sectors at the superior pole were combined with each other, as well as with their counterparts at the inferior pole, discrimination improved even further. Localized changes concurred frequently, but asymmetrically at both poles of the disc. The depth from reference plane used to define the cup was not critical for separation between normal and glaucomatous eyes.