Changes within the thyroid axis after long-term TSH-suppressive levothyroxine therapy

Objective The effects of long‐term TSH‐suppressive levothyroxine (LT4) therapy on thyroid hormone metabolism in patients with differentiated thyroid carcinoma (DTC) are unknown. The aim of the study was to investigate the changes in thyroid hormone metabolism after long‐term TSH‐suppressive LT4 therapy in patients with DTC. Patients and Methods Sixty one patients with DTC were followed. For each patient, frozen remnant sera from two time points were selected: time1 (drawn within 1 year of I‐131 ablation; TSH on file <0·3 mIU/l; recruitment period 1999–2002) and time2 (last available sample with TSH on file <0·3 mIU/l; minimum of 3 years of continuous TSH‐suppressive LT4‐therapy on record). TSH, reverse triiodothyronine (rT3), total triiodothyronine (TT3) and total thyroxine (TT4) levels were measured at both time1 and time2, and relationships between these parameters were analysed. Results Total triiodothyronine, TT4 and TSH levels were significantly reduced at time2 (P < 0·001), whereas LT4 dose, bodyweight and rT3 levels remained constant between time1 and time2. There were no significant changes in the relationship between the dose of LT4/kg bodyweight and TT4 levels (P = 0·14). TT4/TT3 was increased at time2 (P < 0·001), whereas TT4/rT3 and TT3/rT3 were significantly decreased at time2. There appeared to be no relationship of the effects found and advancing age. Conclusion After long‐term TSH‐suppressive LT4 therapy for DTC, there are significant changes in thyroid hormone metabolism, which are best explained by a combined downregulation of deiodinases subtypes 1 and 2 and an upregulation of deiodinase subtype 3.     

Effects of thyroid status and thyrostatic drugs on hepatic glucuronidation of lodothyronines and other substrates in rats : Induction of phenol UDP-glucuronyltransferase by methimazole

Glucuronidation of iodothyronines in rat liver is catalyzed by at least three UDP-glucuronyltransferases (UGTs): bilirubin UGT, phenol UGT, and androsterone UGT. Bilirubin and phenol UGT activities are regulated by thyroid hormone, but the effect of thyroid status on hepatic glucuronidation of iodothyronines is unknown. We examined the effects of hypothyroidism induced by treatment of rats with propylthiouracil (PTU) or methimazole (MMI) or by thyroidectomy as well as the effects of T4-induced hyperthyroidism on the hepatic UGT activities for T4, T3, bilirubin,p-nitrophenol (PNP), and androsterone. Bilirubin UGT activity was increased in MMI- or PTU-induced hypothyroid and thyroidectomized rats, and decreased in hyperthyroid animals. T4 and, to a lesser extent, T3 UGT activities were increased in MMI- or PTU-induced hypothyroid rats, and T4 but not T3 glucuronidation also showed a significant increase in thyroidectomized rats. T4 but not T3 UGT activity was slightly decreased in hyperthyroid rats. While PNP UGT activity was decreased in thyroidectomized rats and increased in hyperthyroid animals, it was also markedly increased by MMI and slightly increased by PTU-induced hypothyroidism. In T4-substituted rats, MMI did not affect T4, T3, bilirubin and androsterone UGT activities but again strongly induced PNP UGT activity, indicating that this represented a direct induction of PNP UGT by the drug independent of its thyrostatic action. Androsterone UGT activity was hardly affected by thyroid status. Our results suggest a modest, negative control of the hepatic glucuronidation of thyroid hormone by thyroid status, which may be mediated by changes in bilirubin UGT activity. To our knowledge, this is the first report of the marked induction of a hepatic enzyme by MMI, which is not mediated by its thyroid hormone-lowering effect.     

Psychosocial consequences for children of a parent with cancer: a pilot study

When cancer is diagnosed in a parent, this may also have consequences for the children. The purpose of this pilot study was to gain more insight into the psychosocial consequences for children of a parent with cancer, from the perspective of both the children and their parents. For this study, 14 families participated in semistructured interviews and completed standardized questionnaires. Interviews were tape-recorded, transcribed, and analyzed using content analysis techniques. No significant difference was found in behavioral and emotional problems between the children in these families and the normative sample. However, parents reported problems on a borderline and clinically elevated level in one third of the children, and three of seven children self-reported problems on these levels. The interview results showed that parents reported (temporary) behavioral problems in most children during the acute stage of their parents' illness. Other problems, such as anxiety, sleeping disorders, and compulsive behavior, persisted for longer. Parents reported that their children had more problems than the children themselves reported. This finding was not supported by the quantitative analysis. The results from the Child Behavior Checklist and the Dutch version of the Family Adaptability and Cohesion Evaluation Scales showed that children of families with poor family functioning were more vulnerable. In particular, extremely high adaptation (chaotic) and extremely low family cohesion (disengaged) seemed related to the prevalence of emotional and behavioral problems in these children. Absence of home healthcare was an additional burden for adolescent children.     

Carrier-mediated transport of thyroid hormone into rat hepatocytes is rate-limiting in total cellular uptake and metabolism

We investigated if carrier-mediated transport into rat hepatocytes is rate-limiting in total cellular uptake and metabolism of thyroid hormone. Rat hepatocytes in primary monolayer culture were incubated under equilibrium conditions with tracer T4, T3 or rT3 in the absence or presence of inhibitors of thyroid hormone uptake, i.e., ouabain and ER-22, a monoclonal antibody against the rat hepatocyte plasma membrane. The results for all three iodothyronines show that inhibition of clearance from the medium during incubation is paralleled by a similar decrease in iodide production. This indicates that the decrease in metabolism of thyroid hormone is directly related to the inhibition of cellular uptake. These findings underline the potential importance of the plasma membrane in the regulation of thyroid hormone metabolism and, therefore, determination of expression of thyroid hormone activity.     

Detection of acute myocardial infarction with digital image processing of two-dimensional echocardiograms.

We have previously described the ability of a computer-based image digitizing system to assess early textural changes in acute canine myocardial infarction. To determine whether this technique could be applied to human beings, we studied 12 patients with a first acute transmural myocardial infarction and five normal subjects. Two-dimensional echocardiograms were performed on days 1 and 8 in normal subjects and on days 1 (day of admission), 2, 3, 5, and 14 in the patient population. All recording parameters on the echocardiography machine were kept identical for serial studies. The mean period between hospitalization and first echocardiogram was 11.1 hours (range 4 to 20 hours). End-diastolic frames from the two-dimensional echocardiographic images were digitized and displayed on a monitor. The mean pixel intensity (MPI) (+/- SD) in the region of asynergy (area of myocardial infarction) and a normal area were determined. In normal volunteers, no significant change in MPI was noted between anteroseptal and lateral areas on two separate two-dimensional echocardiographic studies, which were performed 7 days apart (anteroseptal: MPI, 21.6 +/- 1.1 vs 21.8 +/- 0.4, p = not significant) and (lateral: MPI, 21.5 +/- 1.2 vs 21.4 +/- 1.4, p = not significant). In patients with myocardial infarction, a significant increase in MPI was noted on the first day of myocardial infarction between normal and infarcted myocardium (20.4 +/- 2.0 vs 24.3 +/- 2.3, p less than 0.05) and progressively increased thereafter until day 14 (20.5 +/- 1.7 vs 31.9 +/- 3.7, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Contribution of Impedance Measurement of the Respiratory System to Bronchial Challenge Tests

The contribution of impedance measurement of the respiratory system to bronchial challenge tests was studied in 64 asthmatics and 23 control subjects.

After histamine challenge, resistance values increased significantly at all frequencies but most markedly at the lower frequencies in the asthmatic group; reactance values significantly decreased at all frequencies. In the control group, resistance significantly increased at 8 and 12 Hz. However, reactance decreased significantly at all frequencies.

By multiple logistic model analysis, a simple discriminant score was found with great discriminating power to differentiate asthmatics and nonasthmatics. The discriminating score equals 9 x FEV_{1 aft} - 7 x FEV_1bef

Adding the forced oscillation technique to the equipment for measuring the bronchial response after challenging procedures can give information about the localization of the response to the challenge in the respiratory system.     

Partial purification of the microsomal rat liver iodothyronine deiodinase. I. Solubilization and ion-exchange chromatography

Rat liver microsomal fraction was treated with several non-ionic, anionic or zwitterionic detergents in order to investigate which is most suitable for subsequent purification of the iodothyronine deiodinase. Criteria for effective solubilization were (a) no or little inhibitory effect of the detergent on deiodinase activity, (b) non-sedimentable activity by centrifugation at 105,000 X g, and (c) a low molecular weight of the soluble complex as determined by Sephacryl S-300 gel filtration in the presence of detergent. Optimal solubilization was obtained by treatment of the microsomes with cholate and subsequent precipitation of dispersed protein with 30% ammonium sulfate, resulting in the removal of adhering phospholipids. Enzyme was resolubilized best with the non-ionic detergents Brij 56 or Emulgen 911 in the presence of 0.5 M NaCl. This deiodinase preparation had an isoelectric point at pH 9.3 and was further purified by subsequent chromatography on DEAE-Sephacel and CM-Sepharose. Only the Emulgen 911-dispersed enzyme was retained by the CM-Sepharose column. Further purification was investigated by chromatofocusing. This resulted in a rapid inactivation of the Emulgen 911 preparation whereas the Brij 56-soluble enzyme was ultimately purified 400 times after DEAE-Sephacel and chromatofocusing.     

Comparison of intravenous anisoylated plasminogen streptokinase activator complex and intracoronary streptokinase in acute myocardial infarction

Coronary angiography was used to compare the efficacy of anisoylated plasminogen streptokinase activator complex (APSAC) administered intravenously and streptokinase given by intracoronary infusion in inducing reperfusion in patients with a proven acute myocardial infarction. Forty-two patients received 30 U of APSAC intravenously over 5 minutes and 43 patients received 250,000 IU of streptokinase given via intracoronary infusion over 90 minutes, after occlusion of the infarct-related vessel was demonstrated by angiography. Reperfusion was achieved in 23 (64%) of 36 patients (mean time to reperfusion 46 minutes) treated with APSAC and 25 (67%) of 37 patients (mean time to reperfusion 45 minutes) treated with intracoronary streptokinase, who were angiographically evaluated 90 minutes after the start of treatment. Twenty-four hours after treatment, reocclusion had occurred in 1 (5%) of 22 patients in the APSAC group and in 3 (13%) of 23 patients in the streptokinase group. No major bleeding was observed in either treatment group despite a similar systemic lytic state that lasted for up to 48 hours. Two patients treated with APSAC died after severe left ventricular failure unrelated to therapy. The results indicate that APSAC given intravenously is as effective as streptokinase given intracoronary in producing thrombolysis in acute myocardial infarction. The major advantages of APSAC are its rapid and convenient administration by a single intravenous injection, the low rate of arterial reocclusion and good patient tolerance.     

Budd-Chiari syndrome in a young patient with anticardiolipin antibodies: need for prolonged anticoagulant treatment.

The case of a 20 year old woman is reported with Budd-Chiari syndrome in whom lupus anticoagulant and anticardiolipin antibodies were shown; treatment with oral anticoagulants induced a considerable improvement. This treatment was interrupted after one year; interruption was followed by redevelopment of ascites. Further treatment with anticoagulants was continued for five years with noticeable improvement. When treatment with oral anticoagulants was stopped because of pregnancy, the patient redeveloped ascites and had a spontaneous miscarriage. Subsequently, treatment with oral anticoagulants was reintroduced and again resulted in noticeable improvement. In conclusion patients with Budd-Chiari syndrome should be tested for lupus anticoagulants and anticardiolipin antibodies, Budd-Chiari syndrome resulting from this cause may have a good response to treatment with oral anticoagulants; this treatment should be maintained permanently, and pregnancy in such patients may initiate serious difficulties.