Induction of type 3 deiodinase activity in inflammatory cells of mice with chronic local inflammation

During illness, changes in thyroid hormone metabolism occur, so-called nonthyroidal illness (NTI). NTI has been characterized by a fall of serum T(3) due to decreased extrathyroidal conversion of T(4) into T(3) by liver type 1 deiodinase (D1), without an increase in serum TSH. Type 3 deiodinase (D3) was thought not to play an important role during NTI, but recently it has been shown that D3 activity is up-regulated in liver and skeletal muscle of critically ill patients related to hypoxia. We studied D3 gene expression and activity in liver and muscle/subcutis of mice during illness, which was induced by two different stimuli: bacterial endotoxin (lipopolysaccharide) administration, resulting in an acute systemic response, and a turpentine injection in each hindlimb, resulting in a local sc abscess. Lipopolysaccharide induced a rapid decrease in liver D1 and D3 activity but not skeletal muscle of hindlimb. In contrast, local inflammation induced by turpentine did not decrease liver D1 and D3 activity but increased markedly D3 activity in the muscle/subcutis sample containing the abscess, associated with strongly increased IL-1beta and IL-6 mRNA expression. Inflammatory cells, surrounding the abscess showed D3 and T(3)-transporter monocarboxylate transporter-8 immunoreactivity, whereas muscle cells did not show any immunoreactivity. In conclusion, local inflammation strongly induces D3 activity in inflammatory cells, especially in invading polymorphonuclear granulocytes, suggesting enhanced local degradation of T(3).     

Serum triiodothyronine sulfate in man measured by radioimmunoassay

In humans deiodination and perhaps glucuronidation are important pathways of thyroid hormone metabolism. In animals, sulfation plays an important role in T4 and especially in T3 metabolism, but little is known about sulfate conjugation of thyroid hormone in humans. In this study we used a specific T3 sulfate (T3S) RIA to address this question. Eight normal subjects were given oral T3 (1 microgram/day.kg BW) for 7 weeks. During the fifth week they also received propylthiouracil (PTU; four doses of 250 mg/day) for 2 days and during the seventh week iopanoic acid (IOP; 1 g/day) for 3 days. The mean pre-T3 serum iodothyronine values were: T4, 92 +/- 6 (+/- SE) nmol/L; rT3, 0.24 +/- 0.02 nmol/L; T3, 2.30 +/- 0.10 nmol/L; and T3S, less than 0.1 nmol/L (at or below the detection limit of the RIA). After 4 weeks of T3 administration the mean serum values were: T4, 39 +/- 6; rT3, 0.11 +/- 0.01; T3, 5.31 +/- 0.39; and T3S, 0.10 +/- 0.01 nmol/L. After 2 days of PTU administration, mean serum T4 increased to 48 +/- 7 (P less than 0.005), rT3 to 0.20 +/- 0.03 (P less than 0.025), and T3S to 0.13 +/- 0.01 nmol/L (P = NS), but serum T3 did not change (4.91 +/- 0.35 nmol/L). The effect of IOP was more pronounced; after its administration for 3 days the mean serum T4 was 49 +/- 8 (P less than 0.001), rT3 was 0.48 +/- 0.09 (P less than 0.005), and T3S was 0.29 +/- 0.04 nmol/L (P less than 0.005), and serum T3 decreased to 3.95 +/- 0.25 nmol/L (P less than 0.005). The T3S/T3 ratio was increased by PTU from 0.018 +/- 0.003 to 0.024 +/- 0.004 (P less than = NS) and by IOP to 0.055 +/- 0.007 (P less than 0.005). In conclusion, 1) serum T3S is virtually undetectable (less than 0.1 nmol/L) in normal subjects; 2) low serum T3S concentrations are detected in humans given T3; 3) serum T3S in T3-treated subjects is increased by inhibition of type I deiodinase activity with PTU and especially IOP; and 4) in comparison with previous estimates of the serum T3S/T3 ratio in rats, the low ratio in humans may indicate that sulfation is not an important mechanism of T3 metabolism in humans and/or the kinetics of plasma T3 and T3S differ in humans and rats.     

Distinct variants of erythrocyte protein 4.1 inherited in linkage with elliptocytosis and Rh type in three white families

Hereditary elliptocytosis is a heterogeneous disorder resulting from defects in the erythrocyte membrane skeleton. Although some cases of elliptocytosis result from defects in spectrin, the specific structural abnormality has yet to be identified in the majority of cases. Protein 4.1 plays an essential role in erythrocyte membrane physiology, and deficiencies have been implicated in only a few rare cases of elliptocytosis. By using 4.1 immunoblots and a 4.1 radioimmunoassay we identified distinct variants of protein 4.1 in 15 elliptocytic members of three US white families with the Rh-linked form of elliptocytosis. Elliptocytic members of family G were heterozygotes for a low-molecular weight (mol wt) 4.1 variant (65,000 to 68,000 daltons; normal, 80,000) inherited in linkage with the Rz phenotype. Elliptocytic members of family C expressed a simple partial deficiency of protein 4.1 (63% of the normal level) that was inherited in linkage with the r phenotype. Elliptocytic members of family N were heterozygotes for a high-mol wt 4.1 variant (100,000 daltons) also inherited in linkage with the r phenotype. These studies indicate that mutant forms of protein 4.1 are not uncommon in elliptocytosis among whites and that different kindreds probably express different mutations. The observed linkage of elliptocytosis and Rh blood type most likely results from the close proximities of the 4.1 gene (site of the mutation) and the Rh gene, which is located nearby on the short arm of chromosome 1.     

Sexuality in patients with asthma and COPD

Sexual quality of life was examined in 55 outpatients with chronic obstructive pulmonary disease (COPD) and asthma, using disease-specific questionnaires. Compared to an age- and sex-matched norm group, male patients with COPD reported a significantly lower sexual quality of life on all dimensions of the questionnaire. Female patients with COPD reported a lower frequency of sexual intimacy and lower sexual quality of life overall. Patients with asthma reported sexual quality-of-life scores that were somewhat better than COPD patients but worse than the healthy control group. Patients reported that they did not discuss sexual quality-of-life issues with their physician. Sexuality needs to be discussed by the health care provider in the consultation in order to improve quality of life of patients with chronic respiratory disorders.     

Erythroid failure in Diamond-Blackfan anemia is characterized by apoptosis

Programmed cell death, also known as apoptosis, is frequently initiated when cells are deprived of specific trophic factors. To investigate if accelerated apoptosis contributes to the pathogenesis of Diamond- Blackfan anemia (DBA), a rare pure red blood cell aplasia of childhood, we studied the effect of erythropoietin (epo) deprivation on erythroid progenitors and precursors from the bone marrow of DBA patients as compared with hematologically normal controls. Apoptosis in response to epo deprivation was evaluated by enumeration of colony-forming unit- erythroid (CFU-E)- and burst-forming unit-erythroid (BFU-E)-derived colonies in plasma clot semisolid culture and by the identification of typical DNA oligosomes by gel electrophoresis from marrow mononuclear cells in liquid culture. In all DBA patients there was a marked decrease in CFU-E- and BFU-E-derived colony formation compared with normal controls at comparable time points of epo deprivation, with a complete loss of CFU-E-derived colonies in semisolid culture by 9 hours of epo deprivation versus 48 hours in controls. The BFU-E-derived colony response to epo deprivation displayed a similar pattern of decrement. Apoptotic changes assessed by the presence of characteristic DNA fragmentation began in the absence of epo deprivation and were readily detected within 3 hours of epo deprivation in DBA cultures versus 9 hours in controls. We conclude that DBA is characterized by accelerated apoptosis as measured by the loss of erythroid progenitor clonogenicity and increased progenitor and precursor DNA fragmentation leading to the formation of characteristic oligosomes, consistent with an intrinsic erythroid-progenitor defect in which increased sensitivity to epo deprivation results in erythroid failure.     

The development and validation of the Leiden Bother and Needs Questionnaire for patients with pituitary disease: the LBNQ-Pituitary

Background

Patients report persisting impairment in quality of life (QoL) after treatment for pituitary disease. At present, there is no questionnaire to assess (a) whether patients with pituitary disease are bothered by these consequences, and (b) their needs for support.

Objective

To develop and validate a disease-specific questionnaire for patients with pituitary disease which incorporates patient perceived bother related to the consequences of the disease, and their needs for support.

Methods

Items for the Leiden Bother and Needs Questionnaire for patients with pituitary disease (LBNQ-Pituitary) were formulated based on results of a recent focus group study (n = 49 items). 337 patients completed the LBNQ-Pituitary and six validated QoL questionnaires (EuroQoL-5D, SF-36, MFI-20, HADS, AcroQol, CushingQoL). Construct validity was examined by exploratory factor analysis. Reliabilities of the subscales were calculated with Cronbach’s alphas, and concurrent validity was assessed by calculating Spearman’s correlations between the LBNQ-Pituitary and the other measures.

Results

Factor analyses produced five subscales (i.e., mood problems, negative illness perceptions, issues in sexual functioning, physical and cognitive complaints, issues in social functioning) containing a total of 26 items. All factors were found to be reliable (Cronbach’s alphas all ≥.765), and the correlations between the dimensions of the LBNQ-Pituitary and other questionnaires (all P ≤ .0001) demonstrated convergent validity.

Conclusions

The LBNQ-Pituitary can be used to assess the degree to which patients are bothered by the consequences of the pituitary disease, as well as their needs for support. It could also facilitate an efficient assessment of patients’ needs for support in clinical practice. We postulate that paying attention to needs for support will lead to optimal patient care (e.g., improvement in psychosocial care), and positively affect QoL.