Baseline levels of circulating galectin-1 associated with radiographic hand but not radiographic knee osteoarthritis at a two-year follow-up.

Objective: We tested the potential of circulating galectin-1, interleukin (IL)-1 beta, IL-6, and tumour necrosis factor alpha (TNF alpha) levels at baseline in individuals with knee pain as biomarkers for development of radiographic knee and/or hand osteoarthritis (OA). Design: This study comprised 212 individuals with knee pain from the Halland osteoarthritis cohort (HALLOA). Clinical characteristics and serum/plasma levels of galectin-1, IL-1 beta, IL-6, and TNF alpha were measured at baseline, and knee and hand radiographs were obtained at a two-year follow-up. The predictive value of circulating inflammatory markers and clinical variables at baseline was assessed using multinominal logistic regression for those who developed radiographic OA in knees only (n â€‹= â€‹25), in hands only (n â€‹= â€‹40), and in both knees and hands (n â€‹= â€‹43); the group who did not develop OA (n â€‹= â€‹104) was used as reference. Correlations were assessed using Spearman's correlation coefficients. Results: As expected, age was identified as a risk factor for having radiographic knee and/or hand OA at the two-year follow-up. Baseline circulating galectin-1 levels did not associate with developing radiographic knee OA but associated with developing radiographic hand OA (odds ratio (OR) for a 20% increased risk: 1.14, 95% confidence interval (CI) 1.01-1.29) and both radiographic knee and hand OA (OR for a 20% increased risk: 1.18, 95% CI 1.05-1.30). However, baseline IL-1 beta, IL-6, and TNF alpha did not associate with developing radiographic knee and/or hand OA. Conclusion: Non-age adjusted circulating galectin-1 is superior to IL-6, IL-1 beta, and TNF alpha in predicting radiographic hand but not knee OA.

Medicines postpartum in Sweden and coverage in Janusmed Breastfeeding.

PURPOSE: The purpose of this article is (1) to investigate which medicines are prescribed and dispensed to women the first 6 months postpartum, (2) to identify medicines dispensed postpartum but not recommended during breastfeeding, and (3) to find medicines commonly dispensed postpartum, but not currently included in Janusmed Breastfeeding. METHODS: In this register-based cohort study covering births between January 2017 and August 2019, the Swedish Medical Birth Register (MBR), the Prescribed Drug Register, and Janusmed Breastfeeding were linked to identify medicines dispensed to women during the first 6 months postpartum, and how they are covered and classified in Janusmed Breastfeeding. RESULTS: During the first 6 months postpartum, 66% of women purchased at least one prescription medicine from the pharmacy. The most common medicines were contraceptive agents, analgesics, antibiotics, and glucocorticoids. A third of the 30 most commonly dispensed medicines have no information available about the safety of use in breastfeeding. The most dispensed medicines, where the database advises against use in breastfeeding, included several antitussive agents, a local anaesthetic, and several gestagens. The most commonly dispensed medicines not covered by the Janusmed Breastfeeding were medicines for dry eyes, for assisted reproduction, and HIV. CONCLUSION: Prescribed medicines compatible with breastfeeding are more common during the first 6 months postpartum than medicines not compatible with breastfeeding, but medicines which lack evidence for safety in breastfeeding are still commonly used.

Comparison of chronic widespread pain prevalence with different criteria in two cohorts of rheumatoid arthritis.

OBJECTIVE: This study aims to investigate chronic widespread pain with the 1990 (CWP1990) and 2019 (CWP2019) definitions 6 years after the onset of rheumatoid arthritis (RA), in one patient cohort with tight controls and one conventional cohort, and factors associated with reporting CWP1990 and CWP2019, respectively. METHODS: A cohort of 80 RA patients with monthly visits to the physician the first 6 months was compared to a cohort of 101 patients from the same clinic with conventional follow-up. Both cohorts had early RA (< 13 months). The prevalence of CWP1990 and the more stringent CWP2019 were in a 6-year follow-up investigated with a questionnaire, including a pain mannequin and a fear-avoidance beliefs questionnaire. RESULTS: In the tight control cohort, 10% reported CWP2019 after 6 years compared to 23% in the conventional cohort (p = 0.026). There was no difference when using the CWP1990 definition (27% vs 31%, p = 0.546). When adjusted for important baseline data, the odds ratio for having CWP2019 was 2.57 (95% CI 1.02-6.50), in the conventional group compared to the tight control group (p = 0.046). A high level of fear-avoidance behaviour towards physical activity was associated with CWP2019, OR 10.66 (95% CI 1.01-112.14), but not with CWP1990 in the tight control cohort. CONCLUSION: A more stringent definition of CWP identifies patients with a more serious pain condition, which potentially could be prevented by an initial tight control management. Besides tight control, caregivers should pay attention to fear-avoidance behaviour and tailor treatment. KEY POINTS: • CWP2019 is a more stringent definition of chronic widespread pain and identifies patients with a more serious pain condition. • Patients with a serious pain condition could be helped by frequent follow-ups. • This study suggests that a special attention of fear-avoidance behaviour towards physical activity in patients with RA is needed.

Butyrylcholinesterase deficiency and its clinical importance in anaesthesia: a systematic review.

Butyrylcholinesterase deficiency prolongs the effects of the drugs it degrades; succinylcholine and mivacurium. Existing literature on butyrylcholinesterase deficiency is dominated by genetic and biochemical studies. We searched MEDLINE, Embase, Web of Science and Biosis to systematically review the causes and clinical consequences of butyrylcholinesterase deficiency. We considered outcomes clinically relevant if neuromuscular blockade, induced by succinylcholine or mivacurium, was assessed using clinical criteria or neuromuscular monitoring. We included 66 studies: 25 randomised controlled trials; 13 clinically controlled trials; 26 prospective observational studies; 1 retrospective study; and 1 qualitative study. Data heterogeneity precluded quantitative synthesis. Studies described genetic, physiological, acquired or pharmacologically induced causes of butyrylcholinesterase deficiency. The prolongation of neuromuscular blockade by butyrylcholinesterase deficiency was most pronounced with homozygosity of a genetic variant, but other more common factors included increasing age, pregnancy, severe liver disease, burn injuries and drug interactions.

Cerebral oximetry during preoperative resuscitation in elderly patients with hip fracture: a prospective observational study.

This study explores the association between postadmission and intraoperative cerebral oxygenation (ScO2), reflecting systemic perfusion, and postoperative mortality and delirium. Forty elderly (age > 65 years) patients with hip fractures were included in this prospective observational study. The ScO2 was determined using near-infrared spectroscopy at initial resuscitation after patients were admitted to the hospital and during surgery. Postoperative delirium was assessed up to seven days after surgery using the memorial delirium assessment scale and the confusion assessment method. Ten patients (25%) developed postoperative delirium within the first seven postoperative days. At initial resuscitation ScO2 was lower in patients that later developed delirium, but the difference was not significant (p = 0.331). Intraoperative ScO2 values remained similar in the two groups. Mortality regardless of cause was 10% (4 out of 40 patients) after 30 days. At initial resuscitation ScO2 was significant lower in the mortality group than in the surviving group (p = 0.042), and the ScO2 nadir values were also significant lower (p = 0.047). Low ScO2 during initial resuscitation (defined as ScO2 < 55 for a minimum of two consecutive minutes) was also significantly associated with 30-day mortality (p = 0.015). There were no associations between low blood pressure and postoperative delirium or 30-day mortality. We found that low preoperative ScO2 was better associated with 30-day all-cause mortality in elderly patients undergoing surgery for hip fracture than blood pressure measurements. Future studies in preoperative resuscitation of hip fracture patients should focus on perfusion measures as opposed to conventional haemodynamic.

The effect of amiodarone on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population.

Essentials Data on the effect of introducing amiodarone in patients already using warfarin regime are scarce. Information on 754 patients was extracted from three nationwide registers in Sweden. With amiodaron, 37% of patients had an international normalized ratio (INR) over 3.0 To avoid bleeding, the initiation of amiodarone should be accompanied by closer INR monitoring. SUMMARY: Background Data indicate that the interaction between warfarin and amiodarone results in an increased warfarin effect. There are several large, well-performed studies using genetic and clinical factors such as co-medication to predict an adequate starting dose of warfarin. However, longitudinal data on the effect of introducing amiodarone in patients on an ongoing warfarin regime are more scarce. Objectives An investigation of how initiation of amiodarone affects the anticoagulant effect and dosing of warfarin, using data from three nationwide registries. Patients/Methods In a retrospective cohort study including 754 patients, warfarin doses were compared between two 4-week periods, before and 18-21 weeks after initiating co-treatment with amiodarone. In addition, warfarin doses and international normalized ratio (INR) values were calculated week-by-week after the initiation of amiodarone. Results The initiation of amiodarone increased the mean INR from 2.6 to 3.1. The proportion of patients with a supratherapeutic INR over 3.0 and 4.0 increased from 12% to 37% and 0.9% to 5.5%, respectively. The subsequent mean decrease in warfarin dose was 24.6% (95% confidence interval [CI], 23.5, 25.6). The frequency of INR monitoring within 1 and 2 weeks after initiation of amiodarone was 67% and 90%. Conclusions Although warfarin doses in most patients were within the therapeutic range, more than one in three patients initiating co-treatment with amiodarone were exposed to a supratherapeutic anticoagulative effect within 3 weeks. In order to further avoid severe unnecessary bleeding, the initiation of amiodarone should be accompanied by closer INR monitoring, anticipating an average dose reduction of 25%.

The effect of carbamazepine on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population.

BACKGROUND: There are data indicating that the interaction between warfarin and carbamazepine results in decreased warfarin efficacy. However, the evidence on the magnitude of and interindividual differences in susceptibility to this interaction has remained scarce. OBJECTIVES: To investigate the effect of carbamazepine on warfarin anticoagulation and warfarin maintenance doses by the use of data from three nationwide registries. PATIENTS/METHODS: In a retrospective cohort study including 166 patients, warfarin doses were compared 2-4 weeks before and 10-13 weeks after initiation of cotreatment with carbamazepine. In addition, warfarin doses and International Normalized Ratio (INR) values were calculated week-by-week during cotreatment. Data on prescribed warfarin doses and INR measurements were obtained from two large Swedish warfarin registers. Data on carbamazepine use were retrieved from the Swedish Prescribed Drug Register. RESULTS: The average warfarin doses were 49% (95% confidence interval 43-56) higher during carbamazepine treatment. The INR decreased upon carbamazepine initiation, and subtherapeutic INR levels were observed in 79% of all patients during the fifth week of cotreatment. Warfarin maintenance dose increases exceeding 50% and 100% were observed in 59% and 17% of patients, respectively. CONCLUSIONS: Four of five warfarin-treated patients in whom cotreatment with carbamazepine was initiated experienced subtherapeutic anticoagulative effect within 3-5 weeks. The warfarin dose was subsequently increased by 49%, a change that differed widely between patients. In order to avoid thrombosis and ischemic stroke, carbamazepine initiation should be accompanied by close INR monitoring to better meet the anticipated increase in dose demand.

Smoking as a risk factor for the radiological severity of rheumatoid arthritis: a study on six cohorts.

BACKGROUND: Smoking is a risk factor for the development of anti -citrullinated protein antibodies (ACPA) positive rheumatoid arthritis (RA). Whether smoking predisposes to severe joint damage progression is not known, since deleterious, protective and neutral observations have been made. OBJECTIVE: To determine the effect of smoking on joint damage progression. METHODS: Smoking status was assessed in 3158 RA patients included in six cohorts (Leiden Early Arthritis Clinic (Leiden-EAC), BARFOT, Lund, Iceland, NDB and Wichita). In total 9412 radiographs were assessed. Multivariate normal regression and linear regression analyses were performed. Data were summarised in a random effects inverse variance meta-analysis. RESULTS: When comparing radiological progression for RA patients that were never, past and current smokers, smoking was significantly associated with more severe joint damage in Leiden-EAC (p=0.042) and BARFOT (p=0.015) RA patients. No significant associations were found in the other cohorts, though a meta-analysis on the six cohorts showed significantly more severe joint damage progression in smokers (p=0.01). Since smoking predisposes to ACPA, analyses were repeated with ACPA as additional adjustment factor. Then the association was lost (meta-analysis p=0.29). CONCLUSIONS: This multi-cohort study indicated that the effect of smoking on joint damage is mediated via ACPA and that smoking is not an independent risk factor for radiological progression in RA.

The impact of interacting drugs on dispensed doses of warfarin in the Swedish population: A novel use of population based drug registers.

To investigate the impact of interacting drugs on the dispensed doses of warfarin in the Swedish population. This was a retrospective, cross-sectional population based register study of patients being dispensed warfarin. Warfarin doses were estimated in different age groups, in men and women, and in patients using interacting drugs. The influence of interacting drugs on the dispensed warfarin dose was analyzed using multiple regression. All 143,729 patients dispensed warfarin were analyzed. The dispensed dose of warfarin was highest in patients 30-39 years old and decreased with age. Co-medication with carbamazepine, simvastatin, paracetamol, amiodarone, fluconazole, lactulose, or bezafibrate was associated with significant changes in dispensed warfarin doses, by +40%, -3.4%, -7.3%, -8.2%, -8.8%, -9.0%, and -9.7%, respectively. After adjustment for age and gender, sulfamethoxazole was also found to significantly alter the dispensed warfarin dose (-6.1%). We provide new support for the previous scarce evidence of interactions between warfarin and carbamazepine, bezafibrate, and lactulose. Initiation or discontinuation of bezafibrate or lactulose in a patient on warfarin should warrant close clinical monitoring. The marked increased warfarin requirement associated with carbamazepine use supports moving from a more conservative reactive towards a proactive strategy including preventive warfarin dose adjustments to avoid potential adverse effects.

Impact of the drug-drug interaction database SFINX on prevalence of potentially serious drug-drug interactions in primary health care.

PURPOSE: To investigate the impact of the integration of the drug-drug interaction database SFINX into primary health care records on the prevalence of potentially serious drug-drug interactions. METHODS: The study was a controlled before-and-after study on the prevalence of potential drug-drug interactions before and after the implementation of SFINX at 15 primary healthcare centres compared with 5 centres not receiving the intervention. Data on dispensed prescriptions from health care centres were retrieved from the Swedish prescribed drug register and analysed for September-December 2006 (pre-intervention) and September-December 2007 (post-intervention). All drugs dispensed during each 4 month period were regarded as potentially interacting. RESULTS: Use of SFINX was associated with a 17% decrease, to 1.81 × 10(-3) from 2.15 × 10(-3) interactions per prescribed drug-drug pair, in the prevalence of potentially serious drug-drug interactions (p = 0.042), whereas no significant effect was observed in the control group. The change in prevalence of potentially serious drug-drug interactions did not differ significantly between the two study groups. The majority of drug-drug interactions identified were related to chelate formation. CONCLUSION: Prescriptions resulting in potentially serious drug-drug interactions were significantly reduced after integration of the drug-drug interaction database SFINX into electronic health records in primary care. Further studies are needed to demonstrate the effectiveness of drug-drug interaction warning systems.

CRS-peptides: unique defense peptides of mouse Paneth cells.

The intestine is the most densely colonized site in both mice and man. Recent data suggest that the intestinal flora is, in part, controlled by antimicrobial substances secreted by the intestinal epithelium. The defense system of the small intestine includes a protective mucus layer, a high turnover of epithelial cells, and a regulated secretion of effector molecules, notably antimicrobial peptides. Human and mouse small intestines share many similarities in their intestinal defense micro-organization, including the secretion of the well-known α-defensins. Mice, however, produce an additional unique antimicrobial peptide family, the CRS (cryptdin-related sequences)-peptides, not found in man. This review comprises a detailed presentation of the peptide-based defense of the gut, with specific emphasis on the CRS-peptide family. The first part presents the current knowledge of the CRS-peptide family's biochemical characteristics and nomenclature, and the second part is devoted to the possible role of this family in the homeostasis of the gut.

Natural course of knee osteoarthritis in middle-aged subjects with knee pain: 12-year follow-up using clinical and radiographic criteria.

OBJECTIVE: To explore the natural course of knee osteoarthritis (OA) in a middle-aged population with chronic knee pain. METHODS: A population-based sample of 143 subjects (mean age 45 (range 35-54), 44% women) with knee pain (>3 months) at inclusion was studied. Weight-bearing posteroanterior tibiofemoral (TF) radiographs were obtained at baseline and 12 years later, and classified according to Kellgren/Lawrence (K/L). Patellofemoral (PF) OA was determined at 5- and 12-years' follow-up using a skyline view and a cut-off point of <5 mm joint space width. The ACR clinical criteria were used at baseline. RESULTS: Seventy-six (53%) had no TF OA (K/L 0) at baseline, but 49 had clinical OA. Overall, 65/76 (86%) developed incident TF OA over 12 years (K/L >or=1): 44/49 (90%) of the subjects with clinical OA and 21/27 (78%) without clinical OA. Progression was found in 65/67 (97%) with TF OA at baseline. Of the 84 with no PF OA at the 5-year examination, 26 (31%) developed PF OA over 7 years. CONCLUSION: A majority of the subjects with chronic knee pain developed knee OA over 12 years. It is concluded that knee pain is often the first sign of knee OA.

Diurnal variation in serum levels of cartilage oligomeric matrix protein in patients with knee osteoarthritis or rheumatoid arthritis.

OBJECTIVE: To monitor changes in serum concentrations of cartilage oligomeric matrix protein (COMP) during a 24-h period to determine any diurnal variation, and to estimate the half life of COMP in the circulation in patients with symptomatic knee osteoarthritis and in those with rheumatoid arthritis. METHODS: Serum samples were drawn every 4 h (7 samples/patient over 24 h) in 10 patients with knee osteoarthritis and 14 patients with rheumatoid arthritis. Osteoarthritis was defined radiographically and clinically (American College of Rheumatology (ACR) criteria) and rheumatoid arthritis according to the 1987 ACR criteria. Serum COMP was measured by sandwich ELISA. A statistical model for the diurnal variation in the COMP levels was developed using the computer program NONMEM. RESULTS: No considerable changes in COMP levels were observed during the day between 08:00 and 21:00 in either group. A significant decrease in serum COMP was apparent during bed rest at night, reaching the lowest levels between 04:00 and 05:00 (p<0.03 or better v all other time points) in patients with osteoarthritis and in those with rheumatoid arthritis. From the rate of decreasing serum COMP levels, a putative half life of COMP in the circulation was estimated to be 7.4 h. CONCLUSION: During normal daytime activities, serum COMP levels are constant. The decrease during the night indicates a rapid elimination of COMP once it has reached the circulation. The stable COMP levels during the day suggest that it is not necessary to further standardise the time of serum sampling in clinical practice.

A choice between transcriptional enhancement and repression by the v-erbA oncoprotein governed by one nucleotide in a thyroid hormone responsive half site.

The v-erbA oncoprotein (P75gag-v-erbA) can repress thyroid hormone receptor induced transcriptional activation of target genes. A central question is how hormone responsive elements in a target gene determine the transcriptional regulation mediated by P75gag-v-erbA. We addressed this with receptors chimeric between P75gag-v-erbA and thyroid hormone receptor (TR) by testing their regulatory activities on thyroid hormone response elements (TREs) differing in the sequence of the consensus core recognition motif AGGTCA. We report here that enhances, TR dependent transcriptional activation is conferred by P75gag-v-erbA when the thymidine in the half site recognition motif is exchanged for an adenosine. The enhancement was independent of the DNA binding region of P75gag-v-erbA, whereas increased expression of corepressor abolished the enhancing effect. The data indicate that the enhancement results from an impaired DNA binding by the oncoprotein combined with an effective scavenging of corepressors. Our data thus suggest the P75gag-v-erbA indirectly can contribute to enhancement of thyroid hormone induced gene expression.

Diversity of human endogenous retrovirus class II-like sequences.

Class II human endogenous retroviruses (HERVs), often referred to as mouse mammary tumour virus (MMTV)-like or HERV-K elements, have similarities to several animal infectious retroviruses. Single clones from each of nine class II HERV groups (NMWV 1 to NMWV 9), isolated from a human breast cancer cell genomic library, were sequenced over a 244 bp stretch of the conserved reverse transcriptase region. These sequences were aligned to related exogenous and endogenous retroviruses and a phylogenetic tree was constructed. Sequences with more than 80% identity were considered as members of one group and we report here that the class II HERV family consists of at least ten groups. Three of the sequenced clones, from groups NMWV 3, 7 and 9, could not be related to any other previously identified elements and constituted their own groups. NMWV 8 had no similarity to any retroviral sequences in the sequenced region and is so far considered to be non-retroviral.

Chicken thyroid hormone receptor alpha requires the N-terminal amino acids for exclusive nuclear localization.

The subcellular localization of natural and engineered forms of the chicken thyroid hormone receptor (cTR alpha) is dependent on amino acids encoded in the N-terminal region. The full length receptor protein, cTR alpha-p46, was found to localize exclusively to the nucleus, whereas the N-terminally shorter variant, cTR alpha-p40, localizes to both the nucleus and the cytoplasm. The exclusive nuclear localization of cTR alpha-p46 is dependent on the presence of the first 11 N-terminal amino acids, but independent of the phosphorylation of the serine at position 12. Our data identify a novel role for an N-terminal domain of the full length thyroid hormone receptor.

Transcription of human endogenous retroviral sequences related to mouse mammary tumor virus in human breast and placenta: similar pattern in most malignant and nonmalignant breast tissues.

The human genome contains a large variety of sequences related to the mouse mammary tumor virus (MMTV). We have investigated the range of expression of human endogenous retroviral sequences (HERVs) related to MMTV (human MMTV-like; HML) as RNA in 60 breast cancers, 8 nonmalignant breast tissues, and 9 placentas. This was monitored using HML group-specific oligonucleotide probes in hybridizations toward PCR amplificates of HML pol sequences and internal control. The degree of expression of five HML groups varied between individuals and between tissues. On average, all HML groups were less expressed in breast tissues than in placenta. The hybridization signals of some HML RNAs were strongly correlated, indicating a nonstochastic mechanism and a concerted regulation of their expression. The PCR product from one breast cancer (BC 6), which gave an exceptionally high expression with probe hml-6, with a 20 times stronger signal than the rest of the cancers, was cloned and sequenced. The HML-6 transcript sequences were homogeneous in BC 6. The most predominant clone derived from the cancer was used as a probe in Southern hybridizations. The same restriction fragments were detected in human breast tissues, PBMCs (peripheral blood mononuclear cells), and breast cancer cell lines, except for one of the breast cancers and one of the nonmalignant breast tissues, which gave different banding patterns. A comparison of HML expression in normal and malignant breast tissue from the same individual would have been more precise than our comparison of samples from different persons. Bearing this limitation in mind, with a single exception, human MMTV-like sequences were not more actively expressed in malignant than in nonmalignant breast tissues. Nevertheless, an interesting diversity in their expression, especially between individuals, was found.

Differential expression of human endogenous retroviral sequences similar to mouse mammary tumor virus in normal peripheral blood mononuclear cells.

Mouse mammary tumor virus (MMTV) is a retrovirus that causes breast cancer in certain strains of mice. In a previous study we identified, by sequencing clones from human lymphocytes, six groups with similarities to MMTV. Using a primer pair derived from pol sequences conserved within types A, B, and D retroviruses and probes from the six human MMTV-like (HML-1 to HML-6) groups in an internally controlled hybridization assay we investigated the normal variation of expression in PBMCs. Variations occurred within all groups but was most significant within group HML-1, where hybridization signals differed by more than 500-fold between individuals. Groups HML-2 and HML-3 showed consistently stronger hybridization signals than groups HML-1 and HML-5, while group HML-6 resulted in weak signals for all individuals. Stringent hybridization of the amplified cDNA to 20 individual HML clones also demonstrated a marked heterogeneity of expression. Hybridization signals from some groups and sequences were found to be correlated, either in a positive or negative fashion. RNA isolated from PBMCs collected from two donors at four different time points (in the morning and in the afternoon on the same day, repeated 1 week later) was also analyzed using the six hml probes. A small variation in hybridization signals was seen in samples collected on the same day, but a larger difference was observed in samples taken 1 week later. The correlations and the differences in the expression of HMLs between individuals implicate a complex transcriptional regulation system of these sequences.

Thyroid hormone alters the DNA binding properties of chicken thyroid hormone receptors alpha and beta.

The effects of thyroid hormone agonists on thyroid hormone receptor (TR)/DNA complex formation was investigated to elucidate the mechanism by which TRs transactivate genes in response to ligand. The data, obtained from gel shift experiments, indicate that thyroid hormones alter the conformation of TRs bound to DNA, irrespective of if the element is occupied by monomeric TR, homodimeric TR/TR, or heterodimeric complexes with the retinoid receptors RAR or RXR. Furthermore, triiodo-thyronine (T3) prevents 2 TR molecules from binding to oligonucleotides containing direct repeats or inverted palindromes of the consensus AGGTCA motif, an effect that was not detected with palindromic elements. Heterodimers bound to direct repeats were less affected: RXR/TR were fully and RAR/TR complexes partially resistant to thyroid hormone. The data suggest that a ligand-induced conformational change in TR prevents double TR occupancy of a response element containing 2 direct repeats of the consensus binding motif, possibly by steric hindrance, whereas such an event does not prevent TR/RXR heterodimers from binding to DNA. Finally, our data show that a monomeric, liganded TR bound preferentially to the second half site in a AGGTCActcaAGGTCA element, and therefore indicate that nucleotides adjacent to the consensus half site contribute to binding specificity.